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ISSN 2348-7410

PRAJNAN O SADHONA – A SCIENCE ANNUAL

VOL 1, 2014

DEPARTMENT OF CHEMISTRY

FAKIR CHAND COLLEGE

1 | Prajnan O Sadhona ……

Prajnan O Sadhona – a Science Annual

Volume 1, 2014

Published by:

The Principal

Fakir Chand College

Diamond Harbour, West Bengal

Ph.: 03174-255230

Email: [email protected]

Web: www.fakirchandcollege.org

January, 2014

Cover Design:

Prajnamoy Pal, Rana Karmakar

Moumita Sen Sarma, Tapas Kumar Mandal

Printed by:

Adhunik Press, Diamond Harbour

24 Parganas (S)

Mob: 9800415767

ISSN 2348–7410

http://www.barcodesinc.com/generator/image.php?code=ISSN 2348-7410&style=165&type=C128B&width=200&height=75&xres=1&font=3

vol 1, 2014 2

EDITORIAL ADVISORY COMMITTEE

1. Dr. Subires Bhattacharyya

Principal

Fakir Chand College, Diamond Harbour, South 24 Parganas, W.B.

2. Dr. Kalyan K. Mukherjea

Professor in Chemistry

Jadavpur University, Jadavpur, Kolkata-700032

3. Dr. Debprasad Chattopadhyay

Deputy Director, ICMR Virus Unit

ID & BG Hospital, Beliaghata, Kolkata-700010

4. Dr. Debashis Bandyopadhyay

Principal Scientist

Programme Management Division (CSIR)

Central Glass & Ceramic Research Institute

Jadavpur, Kolkata-700032

5. Dr. Pralay Das

Assistant Professor & Scientist

Institute of Himalayan Bioresource Technology.

Palampur, Himachal Pradesh

6. Dr. Prajnamoy Pal

Associate Professor, Department of Chemistry


7. Dr. Rana Karmakar

Assistant Professor, Department of Chemistry


8. Dr. Moumita Sen Sarma



9. Dr. Tapas Kumar Mandal




Preface

For an all-round development of one‟s thoughts and intellect the

customary bookish learning is not only insufficient but also harmful as it

prevents the development of a complete mind. A good journal/periodical

is such a device through which one can express and nurture one‟s thoughts

and intellect that significantly assist to comprehend the self-potentiality.

College/departmental journal is an important torch in this direction. Here

the views and knowledge are communicated in a common platform and

thus offers a successful surge and transaction of knowledge benefiting the

whole community. With this in mind the Department of Chemistry has

developed its brain child „Spandan‟ which was first formally published in

January 2013, as a departmental journal. „Prajnan O Sadhona – a Science

Annual‟ is an upgraded version of „Spandan‟, which is a peer-reviewed

journal with ISSN no. where a large arena of science has been covered

with an aim to significantly widen our knowledge spectrum in the area of

current trends in science.

sd/-

EDITORS

vol 1, 2014 4

Contents

Pages

1. Basic Ideas of Supramolecular Chemistry

Debabrata Pal

2. Organotin Compounds – A Short Review on the

Nature of Bonding and Other Related Properties

Moumita Sen Sarma

3. Formula for the Wiener Index of n-polyphenacene

systems

Piyali Ghosh

4. Nanotechnology in medicine

Prajnamoy Pal

5. Solvation Dynamics

Rana Karmakar

6. Chemistry of the Brain in Depression and its relation

to the Immune system

Sanjukta Chaudhuri

7. Controlled Drug Delivery in Chemotherapy using

Polymeric Drug Carriers

Suchandra Biswas

8. Recent applications of iodine in organic synthesis

Tapas Kumar Mandal

9. Stabilization of Lipophilic Drug, Curcumin within

Micelles

Ummul Liha Khatun

05-10

11-19

20-24

25-33

34-41

42-59

60-70

71-86

87-89


Basic Ideas of Supramolecular Chemistry

Debabrata Pal *

Science encompasses everything around us. We want justification of our

every instant. The moment we fail to logically follow a situation from our

existing knowledge, there comes a stage of generation of newer ideas,

with an aim to explain the facts, thus newer theories are developed and

science proceeds in its own way towards better and better apprehension.

The different branches of science have been ascribed own territories

regarding the field of application. In the early days, the boundary was

quite rigid among the different branches, but with the development of

science which is essentially the growth and spreading out of various

interdisciplinary subjects such that the initial delineation is largely

scrambled. In this context the range of a subject is interpreted solely in

view of its relevance to the area of basic sciences. In the field of

Chemistry, “Supramolecular Chemistry”, not necessarily a newer branch,

is expanding immensely in view of the development of theories and

methodologies, characterization of newer systems and owing to the

increasing area of applicability in diversified fields.

* Assistant Professor, Department of Chemistry, Sreegopal Banerjee

College, Bagati, Magra, Hooghly, West Bengal, Pin - 712148


vol 1, 2014 6

Supramolecular chemistry refers to the area of chemistry beyond the

molecules and focuses on the chemical systems made up of a discrete

number of assembled molecular subunits or components. This is the

branch of chemistry that describes self-organization or self-assembly of

systems to well defined molecular architectures. It refers to the area that

focuses on the noncovalent bonding interactions of molecules. While

traditional chemistry focuses on the covalent bond, supramolecular

chemistry examines the weaker and reversible noncovalent interactions

between molecules. These forces include hydrogen bonding, metal

coordination, hydrophobic forces, van der Waals forces, pi-pi interactions

and electrostatic effects. Important concepts that have been demonstrated

by supramolecular chemistry include molecular self-assembly, folding,

molecular recognition, host-guest chemistry, mechanically-interlocked

molecular architectures and dynamic covalent chemistry. The study of

non-covalent interactions is crucial to understanding many biological

processes from cell structure to vision that rely on these forces for

structure and function. Biological systems are often the inspiration for

supramolecular research.

The supramolecular chemistry has its origin long before. Johannes Diderik

van der Waals first postulated the existence of intermolecular forces in

1873. However, it is with nobel lauriate Hermann Emil Fischer that

supramolecular chemistry has its philosophical roots. In 1890, Fischer

suggested that enzyme-substrate interactions take the form of a "lock and

key", pre-empting the concepts of molecular recognition and host-guest

chemistry. In 1891 Villers isolated „cellulosine‟, followed by preparation

of cyclodextrin-iodine complexes by Schradinger in 1903. In the early

twentieth century non covalent bonds were understood in gradually more


detail, with the hydrogen bond being described by Latimer and Rodebush

in 1920. And thus led to the understanding of the principles towards

elucidation of structures of DNA and functioning of various biological

processes. In 1954 Cramer published Einschiussverbindungen (Inclusion

Compounds). The breakthrough came in the 1960s with the synthesis of

the crown ethers by Charles J. Pedersen. The field exploded when three of

the pioneers, namely, Jean-Marie Lehn, Donald Cram and Charles

Pedersen won the 1987 Nobel Prize in chemistry for synthesizing

molecules and compounds with cavities and cages within which metal ions

and other molecules could be bound. The words of J. M. Lehn in defining

the term are still noteworthy. “Just as there is a field of molecular

chemistry based on the covalent bond, there is a field of supramolecular

chemistry, the chemistry of molecular assemblies and of the

intermolecular bond.”

In the 1990s, supramolecular chemistry became even more sophisticated,

with researchers such as James Fraser Stoddart developing molecular

machinery and highly complex self-assembled structures, and Itamar

Willner developing sensors and methods of electronic and biological

interfacing. During this period, electrochemical and photochemical motifs

became integrated into supramolecular systems in order to increase

functionality, research into synthetic self-replicating system began, and

work on molecular information processing devices began. The emerging

science of nanotechnology also had a strong influence on the subject, with

building blocks such as fullerenes, nanoparticles, and dendrimers

becoming involved in synthetic systems.

The two major principles involved in supramolecular chemistry are

namely molecular recognition and self-assembly. Supramolecular

vol 1, 2014 8

chemistry is essentially termed as “Host-Guest Chemistry”, where a

molecule "host" combines with a molecule "guest", where the bonding

interactions prevail through non covalent bonding. The host component is

defined as an organic molecule or ion, whose binding sites converge in the

complex and the guest component, is defined as any molecule or ion

whose binding sites diverge in the complex. Non covalent bonding is

critical in maintaining the three-dimensional structure of large molecules,

such as proteins and is involved in many biological processes in which

large molecules bind specifically but transiently to one another. Here the

host and guest involved exhibit molecular complementarity. However

when the interaction between the host and the guest becomes so specific,

such that the discrimination of a particular guest molecule among a

number of guest molecules is achieved by the host molecule, it is the case

of „molecular recognition‟. Crown ethers, cyclodextrins, calixarenes,

porphyrins etc are different macrocyclic host molecules or receptors that

can bind different guest molecules in different cases, such as the cations,

anions and also neutral molecules. Inclusion phenomenon chiefly

describes the type of interaction whereby some large guest is embodied

within the cavity of the host molecule, examples can be cited of the

complexation of fullerenes by means of bisporphyrins or calixarenes.

In self-assembly, molecular structures of a defined geometry add

complementary molecular components, becoming ever-larger arrays

without guidance or management from an outside source (other than to

provide a suitable environment). The molecules are directed to assemble

through non covalent interactions. Self-assembly may be subdivided into

intermolecular self-assembly (to form a supramolecular assembly), and

intramolecular self-assembly (or folding as demonstrated by foldamers

http://en.wikipedia.org/wiki/Noncovalent_bonding

http://en.wikipedia.org/wiki/Host-guest_chemistry


and polypeptides). Molecular self-assembly also allows the construction of

larger structures such as micelles, membranes, vesicles, liquid crystals,

and is important to crystal engineering.

The interactions involved in supramolecular chemistry are predominantly

intermolecular where the different type of interactions such as H-bonding,

pi-pi stacking, hydrophobic interactions etc play their part with their

effects varying from system to system. Though each interaction is very

weak, yet their combination produces thermodynamically stable

structures, which is the essence of Supramolecular chemistry.

Supramolecular chemistry continues its expansion to include

understanding and mimicking biological processes, molecular recognition,

molecular self-assembly, catalysis, materials and medicinal chemistries,

but also dynamic covalent chemistry. In particular, efforts are recently

devoted to the synthesis of molecular machines that function through

host–guest recognition. Such systems are designed to achieve a specific

function and considerable efforts are currently focused on the construction

of molecular switches and devices in which external stimuli are used to

induce molecular motion. Therefore, the design of molecular systems

capable of controlled molecular-level motion has become an area of

growing interest, and a key issue in this field concerns the so-called

molecular tweezers, clips and clefts. The application of the underlying

principles of supramolecular chemistry is envisazed in various fields,

starting from sensors, biosensors to optoelectronics, drug delivery and

many others. In a word, it is sufficient to mention that the field of

Supramolecular chemistry will be not only promising but also extensively

challenging in the coming days. The words of J. M .Lehn seem

particularly apt for conclusion. “Supramolecular chemistry embodies the

vol 1, 2014 10

creative power of chemistry. By its very essence, by its ability to create

and through the beauty of its objects, chemistry is an art as well as a

science. Indeed, it fashions entire new worlds that do not exist before they

are shaped by the hand of the chemist, just as matter, shaped by the hand

of the sculptor, becomes a work of art”.


Organotin Compounds – A Short Review on the Nature of

Bonding and Other Related Properties

Moumita Sen Sarma *

Introduction

The Chemistry of tin has been the subject of extensive research in the last

few decades. Tin in the form of a metal and its alloys were known to the

ancient people and have greatly affected the course of human history. Tin

(atomic number, 50; relative atomic mass 118.70) is an element of group

14 of the periodic table, together with C, Si, Ge and Pb. Tin exists in three

allotropic modifications and it can form a variety of inorganic and

organometallic compounds. These two classes of compounds have

different chemical and physical properties, which make them suitable for

different applications in industry, agriculture and elsewhere. Tin as a

metal, either as such, or in the form of its alloys and chemical compounds,

has an astonishing amount of usefulness. Characteristically, in majority of

its applications, only small amount of tin is needed to see its effect. This is

generally true for organotin compounds, which during the past few

decades have developed into extremely useful industrial commodities. Tin

is unsurpassed by any other metal in the multiplicity of its applications.

These involve such widely divergent fields as stabilizers for polyvinyl

chlorides, industrial catalysts, industrial and agricultural biocides, wood

preservatives and anti-fouling agents to mention only the most important

applications.

* Assistant Professor, Department of Chemistry, Fakir Chand College,

Diamond Harbour, South 24 Parganas, Pin- 743331


vol 1, 2014 12

Organotin compounds are defined as those that contain at least one

carbon-tin covalent bond, the carbon atom being part of an organic group.

The compounds contain tetravalent tin centres and are classified as mono-,

di-, tri- and tetraorganotin (IV)s, depending on the number of alkyl (R) or

aryl (Ar) moieties. The anion is usually a chloride, fluoride, oxide,

hydroxide, a carboxylate or thiolate.

The first chemist to report the existence of “organic bodies of tin” as they

were then known seems to have been E. Frankland. This paper was

devoted largely to the reaction which occurred when ethyl iodide and zinc

were heated together in a sealed tube. The behaviour of ethyl iodide in

contact with metallic tin, at elevated temperatures (150 to 200oC) was also

studied. Frankland later showed that the crystals obtained by the reaction

of EtI with Sn at elevated temperatures (Eq.1) were of diethyltin diiodide.

2EtI + Sn Et2SnI2 ………… (1)

Bonding in organotin compounds

Tin has 5s2, 5p

2 electronic configuration in its valence shell and therefore,

two oxidation states i.e., +2 and +4 (due to „inert s-pair effect‟) are

possible. The ground state for tin is a 3P state, derived from s

2p

2

configuration. In this state, there are only two unpaired electrons and a

covalence of two would be expected. But the tetra-covalent state occurs

much more frequently than the divalent state. The four-covalent state is

derived from the sp3,

5S state of the tin, which is not the ground state but

the first excited state.


Essentially, most of the organometallic tin compounds are of the Sn(IV)

type . The marked increase in the stability of R4Sn compounds over R2Sn

compounds demonstrates the effect of increased hybridization. The

stability (to heat & oxygen) of organotin derivatives in tetravalent states is

reflected in the vast amount of growing literature about them. By contrast,

their bivalent derivatives are much less stable, but these are also beginning

to attract attention particularly with sterically demanding ligands {e.g.

CH(SiMe3)2} and -bonding ligands. These bulky ligands stabilize the

compounds in low-coordination geometry, as the congested environment

around the metal hinders polymerization due to steric factors. For

example, tin(II) cyclopentadienyl, (C5H5)2Sn is a well-established

compound with tin in the (+2) oxidation state.

Reactivity of organotin compounds

The tetraalkyl and aryl compounds of main group 14 elements differ from

the corresponding derivatives of these elements in neighbouring groups

because of their relatively low reactivity. This difference in behaviour is

more because of kinetic than thermodynamic factors.

Within group 14, the reactivity of M-C bond in tetraalkyl and aryl

increases progressively from Si to Pb as

bond energy decreases in the same sequence

expansion of the coordination number of the metal (M) becomes

easier with increasing atomic size and decreasing difference

between np and nd orbitals.

Si(C2H5)4 Ge(C2H5)4 Sn(C2H5)4 Pb(C2H5)4

Decreasing M-C bond energy

Decreasing thermal stability

vol 1, 2014 14

The electronegativity of tin change with its oxidation number. Tin(II)

compounds are generally more ionic than tin(IV) compounds .

The general characteristic pertaining to increase in electropositive

character with increase in atomic number in a group is also strikingly

pronounced among the metals of group 14. Therefore, the Sn-C bond

should be polar since tin is electropositive with respect to carbon and is

represented by Cδ-

-Snδ+

. The polarization of Cδ-

-Snδ+

bond makes tin atom

more electrophilic and carbon atom attached to tin more nucleophilic. This

enhances the reactivity of organotin moieties both towards electrophiles as

well as nucleophiles. Reaction of alkyltin chlorides with the appropriate

nucleophiles gives the alkyltin alkoxides, amides, thioalkoxides,

carboxylates etc. The presence of these electronegative groups on tin

renders the metal susceptible to coordination by Lewis bases and simple

tetrahedral four-coordination is an exception rather than the rule in such

cases.

Organotin compounds can undergo Grignard type reactions particularly

with carbonyl containing substrates. For instance, allyltin compounds will

add across the C=O bond of aldehydes in a manner analogous to that of

Grignard reagent.

Et3SnCH2CH=CH2 + RCHO RCH(OSnEt3)CH2CH=CH2 …….(2)

Due to low polarity of C-Sn bond, as in tetraalkyl and aryl derivatives of

tin, these are not actually hydrolyzed by water. Hydrolysis however, may

be brought about by increasing pressure and temperature and using

catalysts such as acid or alkalis which attack „C‟ or „Sn‟. A rather unusual

feature of the organotin compounds is the ionization of some of the R3SnX

and R2SnX2 compounds in water .The extremely ready hydrolysis of a


fluorocarbon-tin bond in perfluorophenyl trimethyltin has been partly

ascribed to the increased susceptibility of tin to nucleophilic attack. The

hydrolysis is catalyzed by halide ion.

There is substantial evidence that the d orbitals of the elements of group

14, other than carbon are used in dπ-pπ bonding. A simple example

illustrates this phenomenon. With the four acids of the type p-

R3MC6H4COOH, where M=C, Si, Ge or Sn, C is the most electronegative

and should enhance the acid strength to the greatest extent. But, it is found

that M=C compound shows the lowest acid strength, indicating that dπ-pπ

bonding is operative in the other three metal compounds. The tendency to

use„d‟ orbitals in bonding decreases from Si to Sn, since in (GeH3)2S and

(GeH3)2O, the Ge-S-Ge and Ge-O-Ge appear to be highly bent whereas in

(SiH3)2O, the Si-O-Si bond angle is around 150oC. However, the

possibility of dπ-pπ bonding in Sn cannot be completely ignored, atleast

with elements of higher atomic numbers, e.g., Cl, Br, I, etc. This is

supported by the higher values of Sn-Cl stretching frequencies in certain

tin compounds and Sn–O frequency in (Ph3Sn)2O.

Reactions of the general type:

Sn-C Sn-A C-BA B

are of utmost significance in both theoretical and practical studies in

organotin chemistry. Although the reactivity of tin-carbon bonds depends

on molecular environment, they are susceptible to attack by a wide variety

of reagents so that A-B in the above equation may be a halogen, mineral

acid, carboxylic acid, thiol, phenol, alcohol, metallic or non-metallic

halide, alkali & alkali metal etc. Tin-carbon bond cleavage not only

vol 1, 2014 16

involves electrophilic attack at „C‟ but also nucleophilic assistance at the

Sn atom.

Among organometallic main group compounds, organotin compounds are

quite unique in possessing reasonably labile tin-carbon bonds. While

compounds containing Sn-allyl bonds are the most labile, those containing

Sn-benzyl and Sn-phenyl substituents are sufficiently reactive. The Sn-

alkyl bond cleavage is the most difficult to accomplish and occurs under

relatively harsh conditions. Even among Sn-alkyl compounds those

containing Sn-methyl cleavage are the most documented. In contrast,

those involving Sn-butyl cleavage are very few. The current state of

knowledge of these Sn-C cleavage reactions allow these compounds to be

utilized extensively as synthons. In view of this, it is expected that in

addition to organotin halides, oxides and hydroxide compounds containing

Sn-alkyl, Sn-benzyl, Sn-phenyl or Sn-allyl bonds will also be very useful

as reactants in synthetic procedures for the construction of rings, cages and

clusters.

Structure of organotin compounds

Tin(II) compounds are mostly bent, pyramidal or distorted (due to the

presence of a stereochemically active lone pair of electrons which does not

participate in bonding and occupies a position directed away from the

strongly bonded coordination sites). The structural chemistry of tin(IV)

compounds reflects the relative simplicity of the electronic configuration

in this oxidation state and is dominated by regular bond arrangements:

tetrahedral, trigonal bipyramidal and octahedral depending on the

coordination number. Tin(IV) is remarkable in its capacity to expand its


coordination number from four (which is found in most simple organotin

compounds like the simple tetraalkyls and tetraaryls) to five, six or seven .

In organotin derivatives of the type RnSnX4-n (n = 1 to3), where X is an

electronegative group (e.g. halide or carboxylate etc.), the Lewis acid

strength of tin is increased and subsequently the Lewis bases form

complexes with higher coordination number. The compounds R3SnX

usually yield five-coordinate complexes R3SnXL which are approximately

trigonal bipyramidal, and the compounds R2SnX2 and RSnX3 usually form

six-coordinate complexes R2SnX2L2 and RSnX3L2 which areapproximately

octahedral. The groups X, however, by virtue of the unshared electron

pairs which they carry, can themselves act as Lewis bases resulting in

intermolecular self-association to give dimers, oligomers, or polymers.

Nature of the ligands and the steric demands of R, X and L are the factors

influencing the self-association. If R or X carries a functional substituent

Y beyond the -position, intramolecular coordination can occur leading to

the formation of monomers with 5-, 6-, 7-, or 8- coordinated tin . In fact,

even, coordination number 7 which was once regarded an oddity no longer

remains to be so given the appropriate type of ligand to interact with the

metal; double-armed bis(semicarbazone) and bis(thiosemicarbazone)

ligands derived from pyridine belong to this class .

Applications of organotin compound

Non-biological applications

A major development in recent years has been the increasing use of

organotin reagents and intermediates in organic synthesis, exploiting both

their homolytic and heterolytic reactivity. Another important use of

organotin compounds is in the stabilization of PVC. Many organotin

vol 1, 2014 18

compounds are used as homogeneous catalysts in industry. Also, several

organostannosiloxanes have been shown to be extremely versatile

catalysts for transesterification reactions.

Biological applications

Organotin compounds have found a variety of applications in agriculture

and medicine. The first organotin compounds to reach commercialization

in agriculture (in the early 1960s) were triphenyltin acetate (Brestan*,

Hoechst A.G.) and triphenyltin hydroxide (Duter*, Philips Duphar, N.V.)

both of which are used widely. Aquatic organisms such as algae,

crustaceans, fish and mollusks are sensitive to tri-n-butyltin, triphenyl and

tricyclohexyltin compounds leading to the incorporation of these

triorganotin units in anti-fouling paints for marine transport vessels.

Organotin compounds are also used extensively as preservatives of wood

and as agricultural fungicides and insecticides, and in medicine they are

showing promise in cancer therapy and in the treatment of fungal

infections. Organotin compounds with coordination number greater than

four are significant for their biological activity and interesting structures.

Along with this their potent antitumour activity has led many researchers

to investigate them as effective antitumour agents. A large body of

literatures is now available.

References

1. Encyclopedia Britannica, 15th

Ed., 1974, Vol.18, 426.

2. Frankland, E. J. Chem. Soc., 1849, 2 , 263.

3. Frankland, E. Phil. Trans. 1852, 142, 417.

4. Frankland, E. Liebigs Ann. Chem. 1853, 85, 329.


5. Weiss, R. W. (Ed.) Organometallic compounds, 2nd

Ed.,

Springer-Verlag, New York, 1967, Vol. 2, 158.

6. Cotton, F. A. Wilkinson, G. Advanced Inorganic Chemistry, 2nd

Ed., Inter Science Publishers, New York, 1967.

7. Poller, R. C. The Chemistry of Organotin Compounds, Logos

Press, London, 1970.

8. Neumann, W. P. The Organic Chemistry of Tin, Wiley, London,

1970.

9. Sawyer, A. K. (Ed.) Organotin Compounds, Marcel Dekker Inc.,

New York, 1971; 1972, Vols.1&2; Vol.3.

10. Zuckerman, J. J. (Ed.) Organotin Compounds: New Chemistry and

Applications, ACS, Washington, D.C. 1976.

11. Davies, A. G.; Smith, P. J. ‘Tin’, in: Comprehensive

Organometallic Chemistry, Wilkinson, G. (Ed.), Pergamon Press,

Oxford, 1982, Vol. 2, 519.

12. Blunden, S. J.; Cusack, P.A.; Hill, R. The Industrial Use of Tin

Compounds, Royal Society of Chemistry, London, 1985.

13. Evans, C. J.; Karpel, S. Organotin Compounds in Modern

Technology, Elsevier, Amsterdam, 1985.

14. Evans, C. J. in: Smith, P. J. (Ed.) Chemistry of Tin, Blackie

Academic and Professional, London, 1998, 442.

15. Molloy, K. C. Bioorganotin Compounds, in: F.R. Hartley (Ed.),

The Chemistry of Metal-Carbon Bond, John Wiley and Sons,

London, 1989, Vol.5, 46.

16. Mehrotra, R. C. ; Singh, A. Organometallic Chemistry-A unified

Approach, 2nd

Ed., New Age International (P) Ltd. Publishers,

New Delhi, 2000.

17. Davies, A. G. Organotin Chemistry, Wiley-VCH, Verlag, GmbH

& Co., KGaA, Weinhem, 2003.

18. Crowe, A. J. Appl. Organomet. Chem. 1987, 1, 143.

19. Crowe, A. J. Appl. Organomet. Chem. 1987, 1, 331.

20. Saxena, A. K.; Huber, F. Coord. Chem. Rev. 1989, 95, 109.

21. Gielen, M. Coord. Chem. Rev. 1996, 151, 41.

22. Nath, M.; Pokharia, S.; Yadav, R. Coord. Chem. Rev. 2001, 215,

99

23. Beckman, J.; Jurkschat, K. Coord. Chem. Rev. 2001, 215, 267

vol 1, 2014 20

24. Chandrasekhar, V.; Nagendran, S.; Baskar, V. Coord. Chem. Rev.

2002, 235, 1.

25. Pellerito, L.; Nagy, L. Coord. Chem. Rev. 2002, 224, 111.

26. Chandrasekhar, V.; Gopal, K.; Sasikumar, P.; Thirumoortii, R. L.;

Pellerito, L.; Nagy, L. Coord. Chem. Rev. 2005, 249, 1745.


Formula for the Wiener Index of n-polyphenacene Systems

Piyali Ghosh *

Abstract

Formula for the determination of Wiener Index of n-polyphenacene

systems where n numbers of phenyl rings are attached in linear fashion is

derived. The formula so developed has been expressed in matrix product

form and in analytical form also. The analytical formula requires only the

value of n i.e. the number of phenyl rings present in polyphenacene

systems. Such formula has general applicability for the calculation of

Wiener Index for a large number of polyphenacene systems for any n

value.

Key Words

Wiener Index; n-polyphenacene; analytical formula

Introduction

Quantitative Structure-Activity Relationship (QSAR) and Quantitative

Structure-Property Relationship (QSPR) studies [1-3] are active areas of

chemical research that focus Structure-dependant chemical behavior of

molecules. Topological indices [4,5] are graph invariants and are found to

be very useful for searching molecular database, selecting compounds for

molecular drug screening and drug designing, modeling drug receptor sites

[6] and also predicting the properties like toxicities of chemical

compounds etc.

* Department of Chemistry, M.U.C. Women’s College, Burdwan-713104


vol 1, 2014 22

2n+1 2n+1

3 4 4 4 4 4 3

3 4 4 4 4 4 3

Wiener Index of Graph

Wiener index (W) is one of the oldest and also common topological

descriptor of molecular structure and is based on the distance matrix; for a

graph G it is equal to the sum of the shortest distances between all pairs of

vertices of G and is expressed [7] as

jiji vv

i

vv

ji vDvvdw )(2

1),(

,

(1)

Method of determination for the Wiener Index of n-polyphenacene

Figure-1: Fragmentation of n-polyphencene using symmetry planes

Fragmentation of n-polyphencene using plane of symmetry is shown in

Figure-1. In this figure only four phenyl rings are shown but actually „n‟

numbers of phenyl rings are present here. According to graph theoretical

method we obtain three fragments which are given below

Figure-2


When n-phenacene is fragmented using horizontal plane as shown in

Figure-3 two linear chains are obtained each consists of (2n+1) vertices if

n number of phenyl rings are present. Similarly considering the

fragmentations by other symmetry planes we obtain the last two linear

graphs as shown in Figure-2.

Figure-3

Thus using graph theoretical approach we can write the expression of

Wiener index (W) for n-phenacene as follows

2n+1

2n+1

vol 1, 2014 24

2

1

(2 1) 2 [3 ( 1)4][3 ( )]n

r

W n r n r

.......... (2)

Equation (2) can be written in matrix product form also and it is given

below

TABnW 2)12( 2 , T stands for transpose .......... (3)

In above equation (3) A and B are the two matrices of the form given

below

A ]4)1(3[ r and B )](3[ rn

Equation (2) can be farther calculated (replacing r by 1, 2, 3…n.) to obtain

the analytical formula

24 4 1 2[16 ( 1) / 2 16 ( 1)(2 1) / 6

16 ( 1) / 2 4 3]

W n n n n n n n

n n n

.......... (4)

After simplification of equation (4) we obtain the following form

15206016 23 nnnW .......... (5)

The formula to determine the Wiener index for n-polyphenacene is given

in above equation (5).

Conclusion

The formula has been used to generate the Wiener index for any poly-

phenacene systems. This index can be correlated to some important

physic-chemical properties of polyphenacene compounds. The Wiener

indices of thorn trees, stars, rings and rods have been presented by

Bonchev and Klein [8].


References

1. Randić, M. J. Am. Chem. Soc. 1975, 97, 6609.

2. Randić, M. J. Am. Chem. Soc. 1992, 9, 97.

3. Balaban, A. T. (Eds.), Topological Indices and Related

Descriptors in QSAR and QSPR, Gordon and Breach Science

Publishers, The Netherlands, 1999.

4. Klein, D. J.; Randić, M. (Eds.), Mathematical Chemistry, VCH,

Weinheim, 1990.

5. Gutman, I.; Polansky, O. E. Mathematical Concepts in Organic

Chemistry, Springer-Verlag, New York, 1986.

6. Johnson, M. A.; Maggiora, G. M., Concepts and Applications of

Molecular Similarity, Wiley Interscience, New York, 1990.

7. Wiener, H. J. Am. Chem. Soc. 1947, 69, 17.; J. Phys. Chem. 1948,

52, 1082.

8. Bonchev, D.; Klein, D. J. Croat. Chem. Acta. 2002, 75, 613.

vol 1, 2014 26

Nanotechnology in Medicine

Prajnamoy Pal *

Nanomedicine involves utilization of nanotechnology for the benefit of

human health and well-being. The use of nanotechnology in various

sectors of therapeutics has revolutionized the field of medicine where

nanoparticles of dimensions ranging between 1-100nm are designed and

used for diagnostics, therapeutics and as biomedical tools. Conventional

drugs suffer from major limitations of adverse effects occurring as a result

of non-specificity of drug action and lack of efficacy due to improper or

ineffective dosage formulation. Designing of drugs with greater degree of

cell specificity improves efficacy and minimizes adverse effects.

Nanotechnology is being applied extensively to provide targeted drug

therapy, diagnostics, tissue regeneration, cell culture, biosensors and other

tools in the field of molecular biology. Various nanotechnology platforms

like fullerenes, nanotubes, quantum dots, nanopores, dendrimers,

liposomes, magnetic nanoprobes and radio controlled nanoparticles are

being developed.

The major factors influencing the treatment outcome in a patient are the

efficacy and safety profile of the drug more so when used for cancer

chemotherapy. These drugs have poor cell specificity and high toxicity

like bone marrow suppression, gastric erosion, hair loss, renal toxicity,

* Associate Professor, Department of Chemistry, Fakir Chand

College, Diamond Harbour, South 24 Parganas, Pin- 743331



Cardiomyopathy and several effects on other systems. Similarly treatment

for diabetes faces challenges with the route of delivery and inadequate

glycaemic control.

Development of newer drug delivery systems based on nanotechnology

methods is being tried for conditions like cancer, diabetes, fungal

infections, viral infections and in gene therapy. The main advantages of

this modality of treatment are targeting of the drug and enhanced safety

profile. Nanotechnology has also found its use in diagnostic medicine as

contrast agents, fluorescent dyes and magnetic nanoparticles.

Liposomes discovered in mid 1960s were the original models of

nanoscaled drug delivery devices. They are spherical nanoparticles made

of lipid bilayer membranes with an aqueous interior but can be unilamellar

with a single lamella of membrane or multilamellar with multiple

membranes. They can be used as effective drug delivery systems. Cancer

chemotherapeutic drugs and other toxic drugs like amphotericin and

hamycin, when used as liposomal drugs produce much better efficacy and

safety as compared to conventional preparations. Immunoliposomes are

liposomes conjugated with an antibody directed towards the tumour

antigen. The antibody can be conjugated to the surface of a stealth

liposome, the polyoxyethylene coating of a stealth liposome or on the

surface of a non-stealth liposome. These immunoliposomes when injected

into the body, reaches the target tissue and gets accumulated in its site of

action. This reduces unwanted effects and also increases the drug delivery

to the target tissue, thus enhancing its safety and efficacy.

vol 1, 2014 28

Nanopores consist of wafers with high density of pores (20 nm in

diameter). The pores allow entry of oxygen, glucose and other products

like insulin to pass through. However, it does not allow immunoglobulin

and cells to pass through them. Nanopores can be used as devices to

protect transplanted tissues from the host immune system, at the same

time, utilizing the benefit of transplantation.

Fullerenes, a carbon allotrope, also called as “bucky balls” were

discovered in 1985. The Buckminster fullerene is the most common form

of fullerene measuring about 7Å in diameter with 60 carbon atoms

arranged in a shape known as truncated icosahedrons. It resembles a

soccer ball with 20 hexagons and 12 pentagons and is highly symmetrical.

Fullerenes have the potential to stimulate host immune response and

production of fullerene specific antibodies. Animal studies with C60

fullerene conjugated.

Carbon nanotubes discovered in 1991 are tubular structures like a sheet of

graphite rolled into a cylinder capped at one or both ends by a buckyball.

Single walled nanotube has an internal diameter of 1-2 nm and multi-

walled nanotube has a diameter of 2-25 nm. Cell specificity can be

achieved by conjugating antibodies to carbon nanotubes with fluorescent

or radiolabelling. Entry of nanotubes into the cell may be mediated by

endocytosis or by insertion through the cell membrane. Amphotericin B

nanotubes have shown increased drug delivery to the interior of cells

compared to amphotericin B administration without nanotubes. The

efficacy of amphotericin B nanotubes was greater as an antifungal agent

compared to amphotericin B alone and it was effective on strains of fungi

which are usually resistant to amphotericin B alone. Further, there was


reduced toxicity to mammalian cells with amphotericin B nanotubes. The

ability of nanotubes to transport DNA across cell membrane is used in

studies involving gene therapy. It was observed that carbon nanotubes,

except acetylated ones, when bonded with a peptide produce a higher

immunological response compared to free peptides. This property can be

used in vaccine production to enhance the efficacy of vaccines. Further, it

was also found that compounds bound to nanotubes increase the efficacy

of diagnostic methods like ELISA. These can also be used for designing of

biosensors owing to property of functionalization and high length to

diameter aspect ratio which provides a high surface to volume ratio.

Quantum dots are nanocrystals measuring around 2-10nm which can be

made to fluorescence when stimulated by light. Their structure consists of

an inorganic core, the size of which determines the colour emitted, an

inorganic shell and an aqueous organic coating to which biomolecules are

conjugated. The biomolecule conjugation of the quantum dots can be

modulated to target various biomarkers. Quantum dots can be used for

biomedical purposes as a diagnostic as well as therapeutic tool. These can

be tagged with biomolecules and used as highly sensitive probes.

Quantum dots can also be used for imaging of sentinel node in cancer

patients for tumour staging and planning of therapy. This method can be

adopted for various malignancies like melanoma, breast, lung and

gastrointestinal tumours.

Nanoshells were developed by West and Halas at Rice University as a new

modality of targeted therapy. Nanoshells consist of nanoparticles with a

core of silica and a coating of thin metallic shell. These can be targeted to

desired tissue by using immunological methods. This technology is being

vol 1, 2014 30

evaluated for cancer therapy. Nanoshells were developed by West and

Halas at Rice University as a new modality of targeted therapy.

Nanoshells consist of nanoparticles with a core of silica and a coating of

thin metallic shell. These can be targeted to desired tissue by using

immunological methods. This technology is being evaluated for cancer

therapy. Nanoshells can also be embedded in a hydrogel polymer

containing the drug. After directing the

nanoshells to the tumour tissue by immunological methods, with an

infrared laser, these can be made to get heated up, melting the polymer

and releasing the drug at the tumour tissue. Targeting the drug release

avoids the toxicity of cancer chemotherapy drugs. Nanoshells are currently

being investigated for micro metastasis of tumours and also for treatment

of diabetes.

Cancer therapeutic drugs can be incorporated into nanoscaled bubble like

structures called as nanobubbles. These nanobubbles remain stable at

room temperature and when heated to physiological temperature within

the body coalesce to form microbubbles. These have the advantages of

targeting the tumour tissue and delivering the drug selectively under the

influence of ultrasound exposure. This results in increased intracellular

uptake of the drug by the tumour cells. It also provides an additional

advantage of enabling visualisation of the tumour by means of ultrasound

methods. Liposomal nanobubbles and microbubbles are also being

investigated for their role as effective non-viral vectors for gene therapy.

Nanobubbles are also being tried as a therapeutic measure for removal of

clot in vascular system in combination with ultrasound, a process called as

sonothrombolysis. This method has advantages of being non-invasive and

causing less damage to endothelium.


Paramagnetic nanoparticles are being tried for both diagnostic and

therapeutic purposes. Diagnostically, paramagnetic iron oxide

nanoparticles are used as contrast agents in magnetic resonance imaging.

These have a greater magnetic susceptibility than conventional contrast

agents. Targeting of these nanoparticles enables identification of specific

organs and tissues. Magnetic microparticle probes with nanoparticle

probes have been used for identification of proteins like prostate specific

antigen. Magnetic nanoprobes are used for cancer therapy. Iron

nanoparticles coated with monoclonal antibodies directed to tumour cells

can be made to generate high levels of heat after these accumulate in their

target site by means of an alternating magnetic field applied externally.

This heat kills the cancer cells selectively.

Nanosomes are being developed for treatment of various tumours, in

particular CNS tumours. Silica coated iron oxide nanoparticles coated with

polyethylene glycol and affixed with targeting antibody and contrast

elements like gadolinium are used to access specific areas of brain

involved with tumour. Targeting aids in binding the nanoparticle

specifically to the tumour cells and the contrast elements helps in better

detection with magnetic resonance imaging. Subsequent treatment with

laser can destroy the cells loaded with these nanoparticles by the heat

generated by iron oxide particles by absorbing the infrared light.

Nanosomes can also be integrated with a photocatalyst which produces

reactive oxygen species when stimulated by light and destroy the target

tissue. This method has advantage over conventional drugs in being much

safer without the adverse effects of cancer chemotherapy drugs and also

the absence of development of drug resistance. Nanosomes are being

vol 1, 2014 32

developed to integrate more and more components in it for flexibility of its

applications.

Dendrimers are nanomolecules with regular branching structures. The

number of branching determines the size of the dendrimer which can be

controlled. The branches arise from the core in shape of a spherical

structure by means of polymerisation. This results in formation of cavities

within the dendrimer molecule which can be used for drug transport. The

ends of the dendrimer molecule can be attached with other molecules for

transport. These molecules give the dendrimers various functional

applications. This extended nanodevice has potential applications in

cancer chemotherapy as a mode of targeted drug therapy. Dendrimers can

be used for gene therapy where these can replace conventional viral

vectors. Dendrimer based drugs are being tried for antiretroviral therapy.

Respirocytes are hypothetical artificial red blood cells are nanodevices

which can function as red blood cells but with greater efficacy. These have

higher capacity to deliver oxygen to tissues, supplying 236 times more

oxygen per unit volume than natural red blood cells. These devices have

sensors on the surface which can detect changes in the environment and

the onboard nanocomputer will regulate the intake and output of the

oxygen and carbon dioxide molecules.

Microbivores83 are hypothetical structures which function as white blood

cells in the blood stream designed to trap circulating microbes. They are

expected to have greater efficacy than cellular blood cells in phagocytosis.

The microbivores surface is arranged with processes which can extend in

length and secure the microbe which gets in contact with it. The microbe


will be gradually maneuvered to the ingestion port and undergoes the

process of morcellization and enzymatic degradation.

Regulatory issues play a major role in the development of

nanoformulation drugs. These include, the type of nanodrug produced and

the various regulatory requirements that the manufacturers must follow

during the manufacturing of nanodrugs. A nanoformulation of a drug

which is based on a previously approved drug in microformulation can

undergo a shorter approval pathway by means of abbreviated new drug

application if bioequivalence can be demonstrated to its microformulation

drug. However, if bioequivalence cannot be demonstrated, it would

necessitate approval of all the stages of new drug application. Further,

when a nanodrug is designed as a new chemical entity, the evaluation

procedure becomes more stringent.

Nanoparticles, as a result of their extreme microscopic dimension, which

gives unique advantage, have potential hazards similar to particulate

matter. These particles have the potential to cause varied pathologies of

respiratory, cardiovascular and gastrointestinal system. Intratracheal

instillation of carbon nanotube particles in mice, has shown that carbon

nanotubes have the potential to cause varied lung pathologies like

epitheloid granuloma, interstitial inflammation, peribronchial

inflammation and necrosis of lung. The toxicity produced by carbon

nanotube was found to be greater than that produced by carbon black and

quartz. Nanoparticles can enter the central nervous system either directly

through axons of olfactory pathway or through systemic circulation that

C60 fullerene can cause oxidative stress and depletion of GSH in brain in

fishes by entering through the olfactory bulb. Involvement of olfactory

vol 1, 2014 34

bulb in humans is possible in case of inhalational exposure. Nanoparticle

mediated delivery can in future provide a means of alternate route,

circumventing the blood brain barrier. However, this can also result in the

inflammatory reactions in the brain which needs to be evaluated. The

toxicity of nanoparticles can also be extrapolated to gastrointestinal

system, resulting in inflammatory bowel diseases. The toxicity of

nanoparticles may be related to its ability to induce release of pro-

inflammatory mediators resulting in inflammatory response and organ

damage. If ingested, the nanoparticles can reach the circulation and reach

different organs and systems and possibly result in toxicity. These have

been studied in vitro and in animal models and the effect on human system

is difficult to extrapolate from such studies. Their use in humans require

further research and much needed caution.

Reference

1. Surendiran A.; Sandhiya S.; Pradhan S. C.; Adithan C. Novel

applications of nanotechnology in medicine. Ind. J. Med. Res.

2009, 130, 689, and references therein.


Solvation Dynamics

Rana Karmakar *

Solvation dynamics generally refers to the reorientation of the solvent

molecules around a solute dipole instantly created in a polar solvent. In the

fluorescence study the solute refers to the fluorescence probe molecules

that are weekly polar or nonpolar in the ground state but become highly

dipolar upon excitation. Some typical fluorophores normally used for the

study of solvation dynamics are shown in Fig. 1. Instantaneous excitation

of the probe molecule with an ultra-short laser pulse disturbs the

equilibrium arrangement of solvent dipoles around the probe molecule.

The solvent molecules reorient themselves around the newly created

dipole and the time taken for the rearrangement of the solvent molecules

to form a new equilibrium configuration around the excited probe

molecule is referred to as the relaxation time of the solvent. This

relaxation time obviously depends on the viscosity, the molecular structure

of the solvent and the temperature of the medium. In conventional solvents

at room temperature the excited state equilibrium is reached prior to

emission because the solvent relaxation times are typically less than 100

ps whereas the emission decay times are of the order of a few

nanoseconds.




vol 1, 2014 36

Fig. 1. Typical fluorescence probe molecules used for the study of

solvation dynamics

However, the relaxation times become much slower in a viscous solvent

and in proteins or in membranes. In these cases, the emission occurs

during the solvent relaxation and this results in a time-dependent shift in

the emission spectra. This phenomenon is pictorially shown in Fig. 2.


Fig. 2. Time-dependent Stokes shift

Time-dependent Stokes shifts are measured from the time-resolved

emission spectra (TRES), which are usually constructed by an indirect

procedure starting with the measurement of a series of time-resolved

decays monitoring 15 – 20 wavelengths across the entire steady state

emission spectrum. A wavelength dependent intensity decays are

observed as a general case. The solvation dynamics is evaluated by

monitoring the time dependence of the solvation correlation function,

C(t), defined as1

0

ttC

where, )0( , )(t and )( are the peak frequencies of the TRES at

time zero, at an intermediate time (t) and at infinite time after excitation

respectively. The longitudinal relaxation time of the solvent, L, is an

exponential decay function of C(t) with time, so that C(t) = exp(-t/L).

However, experimentally found C(t) functions are multi-exponential in

nature and hence, an average solvation time <L> is reported, where

n

i

iiL a1

. The simple continuum theory equates the

vol 1, 2014 38

longitudinal relaxation time, L, with much slower Debye relaxation

time, D according to the following equation.

DDD

c

cL

nn

22

0 12

12

2

2

where,

and 0 (<0) are the infinite-frequency and low-frequency

dielectric constant of the solvent. c is the dielectric constant of the

cavity containing the probe molecule. The equation is often simplified

assuming = n2, where n is the refractive index & replacing 0 by

static dielectric constant, .

Relaxation processes in polar and nonpolar solvents

The relaxation processes in conventional solvents are usually faster due

to very fast reorientation of the solvent molecules. Using ultrafast time

resolution of the order of few femto-seconds and exact time zero

calculation, Maroncelli and coworkers2 showed that in major class of

solvents where specific interaction like hydrogen bonding is

unimportant, the solvation times are in the sub picosecond time scale at

room temperature. The result can be well explained using non-specific

theories of solvation dynamics. The linear correlation between

experimentally observed average relaxation time and longitudinal

relaxation time, L as predicted by simple continuum theory, depends

primarily on the nature of solute-solvent interaction and temperature of

the medium. Deviation from the above can be accounted for

considering molecular nature of the solvent, translational contribution

to the solvent relaxation and specific hydrogen bonding ability of the

protic solvents.


High pressure solvation dynamics

The effect of enhanced pressure on solvation dynamics of coumarin

153 in different alcohol has been studied by Hara and coworkers.3 They

observed a good correlation between the average solvation time and the

longest longitudinal relaxation time of the alcohol used as the solvent.

A similar observation was made by Huppert and coworkers while

studying the solvation dynamics of coumarin 480 in ethanol at much

higher pressure.4 In atmospheric pressure ethanol shows usual

monomeric relaxation process with a relaxation time of 35 ps. With

gradual increase in pressure (> 0.5 Gpa) the solvation becomes

biexponential in nature. A typical biphasic solvation time of 110 ps and

500 ps, with an average relaxation time of 410 ps was observed at a

pressure of 1.55 Gpa. This slow dynamics has been explained on the

basis of liquid-solid phase transition of ethanol in this high pressure.

On the contrary, in solid phase, relaxation occurs at a relatively faster

rate with an average time of 360 ps. The faster relaxation process in

solid crystalline alcohol is ascribed to rapid reorientation of the ethanol

molecule in vicinity of the fluorescence probe.

Hara and coworkers observed a faster solvation rate of C153 in aqueous

Triton X-100 micelle with increase in pressure.5 At enhanced pressure,

a weakening of hydrogen bonding interaction at the Stern layer of the

micelle is believed to result in an increased mobility of the water

molecules, resulting a shorter relaxation time.

Solvation dynamics in confined environment

The relaxation in pure water is biexponential nature with an ultrafast

relaxation time of 126 fs and a relatively slower one, 880 fs.6

vol 1, 2014 40

According to Fleming et al., the faster component arises due to

intramolecular vibration of the water molecule and the slower one for

the librational motion. Interestingly, the presence of a slow component

(of few nanoseconds) with significant amplitude has been reported by

Bhattacharyya et al. for water present in a confined environment such

as in micelles, cyclodextrin, polymer-surfactant aggregates, protein and

DNA. In all cases, two types of water molecules have been assigned,

unbound or free and bound with the macromolecules by strong

electrostatic interaction or hydrogen bonding. The former one is

responsible for the faster component whereas the slow relaxation time

arises due to the latter.7

Solvation dynamics in ionic salt solution

Chapman and Maroncelli uses large number of metal perchlorate and

halide salts and studied those in a number of non-aqueous solvents with

different polarity. Their observations suggest an excitation wavelength

dependent solvation rate. The solvent response functions could be

extracted either by single exponential or bi exponential decay function

depending on the salt concentration. The ionic solvation is rather slow

(few nanoseconds) when compared with that in conventional solvents.

A profound effect of the solvent polarity and charge to size ratio of the

cation has been observed. Considering the faster rotational rate of the

probe molecule relative to spectral relaxation, a slow activated

exchange between ions and solvent molecules in the first solvation

shell of the probes is attributed to the slow dynamics in these media.


Solvation dynamics in high temperature molten salts

A slow solvation dynamics, similar to that in ionic salt solution, was

observed by Huppert and coworkers in several solids and in molten

tetra alkyl ammonium salts.8 In all cases, the solvation process occurred

in two different time scales (picosecond and nanosecond). The average

relaxation time in molten salt was found relatively slower than that

observed in pure solvent or electrolyte solutions. According to Huppert

et al., the fast component of the dynamics is due to the translational

motion of the smaller species, the anion and the slower one is due to the

larger cation. Both the solvation times were found to be dependent on

the cation size and the chosen probe molecule.

Solvation dynamics in room temperature ionic liquids

The solvation dynamics in these media are bi exponential in nature, in

all cases consisting of a short and a long component. The average

solvation time, which is found to depend on the probe molecule used

and viscosity of the medium, lies in the nanosecond time scale. Based

on the observed results, the fast initial response of the bi-phasic

dynamics is attributed to the motion of the relatively smaller species,

the anions, while the slow component originates from the collective

motion of the cations and the anions.9, 10

References

1. Bagchi, B.; Oxtoby, D. W.; Flemming, G. R. Chem. Phys.

1984, 86, 257.

2. Horng, M. L.; Gardecki, J. A.; Papazyan, A.; Maroncelli, M. J.

Phys. Chem. 1995, 99, 17311.

vol 1, 2014 42

3. Kometani, N.; Kajimoto, O.; Hara, K. J. Phys. Chem. A. 1997,

101, 4916.

4. Molotsky, T.; Koifman, N.; Huppert, D. J. Phys. Chem. A.

2002, 106, 12185.

5. Hara, K.; Kuwabara, H.; Kajimoto, O. J. Phys. Chem. A. 2001,

105, 7174.

6. Jimenez, R.; Fleming, G. R.; Kumar, P. V.; Maroncelli, M.

Nature 1994, 369, 471.

7. Bhattacharyya, K. Acc. Chem. Res. 2003, 36, 95.

8. Bart, E.; Meltsin, A.; Huppert, D. J. Phys. Chem. 1994, 98,

10819.

9. Karmakar, R.; Samanta, A. J. Phys. Chem. A 2002, 106, 4447.

10. Karmakar, R.; Samanta, A. J. Phys. Chem. A. 2002, 106, 6670.


Chemistry of the Brain in Depression and its Relation to the

Immune System

Sanjukta Chaudhuri *

Abstract

The brain is the most mysterious and understudied part of human anatomy.

Ever since the evolution of the human race, it has been the prerogative of

the humans to find out everything they can about themselves and the

world around them. 20th and 21st century saw many breakthrough events

in brain research. It is now established that the brain functions by using

many charged particles, called neurotransmitters, whose presence or

absence or balance determines how a person perceives and thinks as well

as conducts and carries out all the voluntary and involuntary functions

throughout his lifetime. Depression is one of the leading causes of

disability nowadays and is mainly the outcome of chemical imbalance in

the brain. It has a close relationship with stress and immune system.

Key words

Depression, neurotransmitters, immunity, cytokines

Introduction

The World Health Organization (WHO), states that depressive disorder is

the fourth leading cause of disease and disability in the world, and is

expected to rank second by the year 2020.

* Assistant Professor, Department of Zoology, Fakir Chand College,



vol 1, 2014 44

This disease however remains under-recognized and most of the time goes

untreated (WHO, 2000). For the affected person, it causes major

psychological setback that diminishes the quality of life. It is the second

leading cause of disability (Murray and Lopez, 1996). Depression is also

associated with an increased mortality in today‟s world due to suicide,

murders, accidents, and heart diseases. The symptoms of depression can

range from mild to severe, and can be associated with anxiety and

agitation. In the Diagnostic and Statistical Manual Of Mental Disorders,

(Fourth Edition, Text Revision), the diagnosis of depression or major

affective disorder (MAD), requires the experience of major depressive

episodes that are defined by at least five of the following symptoms for a

minimum of 2 weeks duration: loss of interest, depressed mood,

appetite/weight disturbance, sleep disturbance, psychomotor change, loss

of energy, worthlessness/guilt, difficulty in concentration, recurrent

thoughts of death/suicide (DSM-IV, 2000; ICD-10, 1992). The occurrence

of depression is double fold in relatives of depressed people; this suggests

a genetic basis of the disease (Nemeroff, 1998). From the initial idea that

depression was caused by „disturbances‟ in the „chemical equilibrium‟ of

the brain, the mass of research has developed into a complicated theory

which involves several neural networks, neuronal plasticity and

neurotransmitters (Castren, 2005).

What triggers depression?

Depression or Major Affective Disorder (MAD) affects the dynamic

connectivity among the neuroanatomical structures of brain that regulate

mood and stress response (FIG-1). Limbic structures like, hippocampus,

amygdala, and nucleus accumbens, have bidirectional connections with

cortical areas, anterior cingulated cortex and ventromedial prefrontal


cortex (VMPFC). It is believed that disrupted connectivity between limbic

areas and rostral integrative prefrontal cortex (RIPFC), results in disturbed

and incomplete feedback regulation of limbic functions. As a result, dorsal

cognitive/executive network is hypoactive and on the other hand,

hyperactive limbic areas continuously stimulate the hypothalamus, finally

leading to neuroendocrine dysregulation and sympathetic hyperactivity

(Anand et al, 2005; Whittle et al, 2005). According to neurobiological

studies, anxiety is very closely associated with depression. This is

supported by the fact that stress hormone levels (cortisol in man and

corticosterone in rat), are elevated in depressed individuals. Stress induced

depression is caused by the Hypothalamic-Pituitary-Adrenal axis (HPA-

axis). Stress results in glucocorticoid release and corticotrophin releasing

hormones (CRH) and cytokines (TNF, IL-1, IL-6). In MAD, disruption of

serotonin (5-HT), dopamine (DA), and norepinephrine (NE) transmission

impair the regulatory feedback loops that seem to “turn off” the stress

response. Sympathetic over reactivity results in activation of immune

system and release of cytokines (Raison et al, 2006).

Depression and immunity in human beings

a) Occurrence of depression: Depression is one of the major disorders of

mood. With 21% women and 13% men suffering from major depression

worldwide, this is second leading basis for disability (Murray and Lopez,

1996). The interaction of genes with a given environment leads to

depression. Environmental stress, heredity and change in biological

rhythm can trigger depression in individuals who possess the genes for

depression (Nestler et al, 2002).

vol 1, 2014 46

b) Different types of depression and immunological changes: Psychiatrists

often encounter an unrepresentative sample of patients. Some patients are

severely ill and some may suffer from mild mood swings. That is the

reason why depressive disorders have been classified into different

categories, so that proper diagnosis and treatment could be done. Table-1

lists different types of depression along with their symptoms.

TABLE - 1

TYPE OF DEPRESSION SYMPTOMS

Recurrent Unipolar

depression or Major

Affective Disorder (MAD)

(DSM-IV, 2000; ICD-10,

1992)

Episodes of depression vary in length, severity,

impairment.

Depressed mood for more than 2 weeks.

All 7 symptoms of depression.

Often associated with anxiety.

Presence of somatic depressive symptoms like

feeling sick, weight loss, headache etc.

Dysthymia

(DSM-IV, 2000; ICD-10,

1992)

Mild depression, often more than 2 months but not

exceeding 2 years.

2 of the 7 general symptoms of major depression.

No evidence of unequivocal major depression

during 1st 2 years.

Recurrent brief depression

(DSM-IV, 2000; ICD-10,

1992)

Depression lasting for less than 2 weeks.

Similar to Recurrent unipolar depression.

Often occur every month.

Seasonal Affective

Disorder (SAD)

(DSM-IV, 2000)

3 episodes of mood disturbance in 3 separate years

with at least 2 or more episodes consecutive years.

Mixed Anxiety Depressive

Disorder (MADD)

( ICD-10, 1992)

Both anxiety and depression symptoms are present.

Bipolar Affective Disorder

(BAD)

(DSM-IV, 2000)

Distinct period of elation following depression.

7 symptoms of depression.

Symptoms of mania- Over activity, Talkativeness,

Flight of ideas, Inflated self-esteem, Decreased

sleep, Distractibility, Indiscreet behavior with poor

judgment (sexual, financial).


In people suffering from depression or affective disorder, the cognitive

and emotional responses to any given stressful situation is exaggerated, so

these people are more stressed in comparison to their normal counterparts.

Chronic stress is encountered during depression and it brings about

simultaneous enhancement and suppression of the immune response by

modifying cytokine secretion patterns (Marshall et al, 1998). It has been

shown in many researches that depressed people are more susceptible to

infection than nondepressed ones (Herbert and Cohen, 1993; Miller et al,

1994; Bachen et al, 1995). Depression is associated with

immunodeficiency. Natural killer cell activity (NKCC) and number

seemed to decrease in patients suffering from depression (Adler et al,

2008). Reiche et al (2004) reported that decreased NKCC and cytotoxic T

cell, lead to tumor formation during depression. Mitogenic response to

Con-A and PHA is reduced in people suffering from depression. Increased

IL-1β and IL-6 secretion by blood mononuclear cells were also found to

be associated with depression (Maes, 1995). Mark et al (2003) reported

that hormone therapy, antidepressive drugs (AD), immunomodulators can

act on the depression-immune pathways to improve cellular immunity.

In Animals

a) Different animal models: There are many methods with which animals

are depressed under laboratory conditions; e.g., Forced Swim Test (FST) ,

Learned Helplessness (LH), Open Field (OF), and Conditioned Defensive

Burrowing (CDB) ( Pare et al.,1994), Tail Suspension (TST) (Porsolt et al,

2001). Genetically developed strains of rodents, such as Flinders Sensitive

Line (FSL) or Fawn Hooded (FH) are also used in laboratories (Braw et al,

2006; Simmons and Broderick, 2005). The most commonly used models

vol 1, 2014 48

are FST, OF, MS, and TST. Sometimes Olfactory Bulbectomised (OB)

rats are also used as animal model of depression, since OB rats exhibit

similar behavioral and immunological characteristics of depressed rats

(Song and Leonard, 2005). In his review article about FST and TST,

Porsolt et al (2001), stated how both the methods are useful in screening

depressed rats and how application of antidepressants can normalize the

behavioral changes due to depression. Cryan et al (2002) also gave useful

information regarding animal models of depression in their review article.

The affective symptoms in humans are not wholly reflected in rats, but

neuroendocrine responses, psychomotor activities, cognitive changes,

disturbances in sleep and appetite in rats are considered for depression

studies.

b) Physiological changes: There are marked physiological changes in

depressed rats as reported by many researchers. These changes include

behavioral changes like low intake of food and water resulting in weight

reduction (Dunn and Swiergiel, 2005), reduced psychomotor activity as

seen in FST, TST, OFT, etc. Sometimes fever is also associated with

depression (Levay et al, 2006). However, most of the physiological

changes are due to neural or endocrine dysfunction associated with

depressive disorders.

c) Immune changes:

i) Certain immune changes are associated with depression. The available

literature on depression induced immune changes in rat model is not

exhaustive. It shows that during depression few parameters of immunity

are suppressed while others are stimulated. Studies in cellular immunity,

as reported by many scientists, show that in depressed rats neutrophil


percentage increases whereas lymphocyte percentage decreases (Connor et

al, 1998). Decrease in Neutrophil phagocytosis (Song et al, 1994) and

Natural Killer Cell Activity (NKCC) (Levay et al, 2006) was also

reported. Decrease in mitogen induced lymphocyte proliferation was

demonstrated by using Phytohemagglutinin or PHA (Connor et al, 1998)

and increase in lymphocyte proliferation was induced by using Concavalin

A or ConA (Levay et al, 2006). It was also found that the depressed rats

were susceptible to infection (Breveik et al, 2006). Change in humoral

immunity was also reported in depressed rats; cytokine transformation

factor or TNF levels were altered. Increased TNF-β and decreased TNF-α

levels were associated with depressed rats (Breveik et al, 2006). The level

of corticosterone (CORT) was elevated in all these experiments suggesting

the probable involvement of HPA-axis in bringing about those immune

and behavioral changes during depression. The immune changes are

confusing because PHA induced lymphocyte proliferation decreases while

that of ConA induced increases in rats in two different studies (Connor et

al, 1998; Levay et al, 2006). Similar experiments in humans showed that

in depression both PHA and ConA invoke reduced mitogenic response

(Herbert et al, 1994; Bachen et al, 1995).

ii) Over the years depression was treated by developing antidepressive

drugs (AD). In rats, application of AD, reduce and sometimes completely

recover the behavioral changes due to depression (Connor et al, 1998;

Song et al, 1994; Kitamura et al, 2002). Reduction or recovery of

depression is a good indicator of AD activity (as clearly reflected in

behavioral studies using FST, TST, OF etc.). The immune changes in

depression should, theoretically, be normalized along with the recovery of

behavioral parameters by the use of AD. So, efforts were also made to

vol 1, 2014 50

study AD induced immune recovery by some workers. The changes of

immune parameters during depression are recovered by the use of AD.

The following immune changes have been reported to be recovered: PHA

induced depressed lymphocyte proliferation (Connor et el, 1998, by

Desipramine), increased TNF-α levels (Breivik et al, 2006, by Tianeptine),

decrease of phagocytic activity of neutrophil (Song et al, 1994, by DMI

and lithium chloride), and decrease of T-lymphocyte (Basso et al, 1993, by

Imipramine). Depressed hypersensitivity type-IV, increased tumor

formation, and increased periodontal infection were also normalized

(Basso et al, 1993; Basso et al, 1992; Breivik et al, 2006). Some

parameters like percentage of neutrophill and lymphocyte remained

unchanged by AD administration (Connor et al, 1998). CORT level also

remained unaltered i.e. high in all the antidepressant treated groups, even

though the behavioral and immune changes are near normal. This data

points to the fact that there must be other factors responsible in depression

induced immune response apart from HPA-axis and stress hormone.

iii) The components of limbic system such as hippocampus, amygdala,

cingulate gyrus (Drevets, 1998; Davidson, 2003; Swanson, 1987) and

other areas such as the brain stem nuclei locus ceruleus (LC) (Bracha et

al, 2005) and Raphae nucleus (RN) (George J. Siegel, ed. 1999) are the

areas regulating depression. LC mediates sympathetic effects during stress

through release of NE and thereby stimulation of HPA-axis. Experiments

involving manipulation of different brain areas show that hippocampus,

amygdala (Brooks et al, 1982; Cross et al, 1982; Pan and Long, 1993),

hypothalamus (Carlson and Felten, 1989; Hass and Schauenstein,1997),

BNST (Jurkowski et al, 2001), medial septum (Labeur et al, 1991;Zach et

al, 1999) are primarily responsible for immune changes brought about by


CNS. Some areas of brain involved in immunemodulation, therefore, are

common with the areas causing depressive behavior. Although, CORT

remains unaltered even after antidepressant use (Song et al, 1994; Connor

et al, 1998; Levay et al, 2006), some immune and behavioral changes are

normal.

Theories of Depression

There are mainly four basic hypotheses that are used to explain the neural

basis of depression.

a) Glucocorticoid hypothesis states that, HPA-axis is involved in

depression. Normal response to stress seems to activate hypothalamus to

secrete CRF, which in turn activates pituitary to secrete ACTH, and finally

ACTH causes adrenal cortex to secrete glucocorticoid. A long term high

levels of glucocorticoid during chronic stress can damage hippocampal

cells and normal feedback inhibition in the hippocampus is disrupted.

Thus some of the serotonergic neurons could be destroyed. (Arborelius et

al, 1999). Some serotonergic changes due to depression may be the result

of hypersecretion of cortisol, the stress hormone. Increased ACTH levels,

elevated plasma and urinary cortisol are indicators of depression.

Exogenous administration of ACTH leads to a greater release of cortisol in

depressed people, suggesting state-dependant oversensitive adrenal gland.

Treatment with CRF seems to correct the symptoms (Nemeroff, 1998).

b) Monoamine hypothesis proposes the interaction of monoamine (MA)

neurotransmitters such as serotonin (5-HT; 5 hydroxytryptamine),

dopamine (DA), and nor-epinephrine (NE; also known as nor adrenaline)

in the brain. Many reviews indicate that hypofunctioning of

vol 1, 2014 52

monoaminergic neurons in brain lead to depression (Caldecott-Hazard and

colleagues, 1991; Morgan et al., 1994; Willner, 1995). A close study by

Sulser (1989) has led to the discovery that, 5-HT and NE modulate each

other. This forms the basis of many antidepressant drugs. Antidepressants

are either Monoamine Oxidase Inhibitors (MAO-Is), which prevent the

monoamines from being destroyed, or, Monoamine Reuptake Inhibitors

(SSRIs and SNRIs), which prevent reuptake of monoamines by the

presynaptic neurons. Both types of drugs finally increase the amount of

monoamines available for the postsynaptic neurons. Depression seems to

be associated with decreased neurotransmission at post-synaptic receptors

and many antidepressants act on this site (Nemeroff, 1998; Nestler et al,

2002).

c) Neurotropic hypothesis implies that deficiency of neurotropic factors,

like Brain Derived Neurotropic Factor (BDNF), could be responsible for

loss of dendritic spines a well as branches. Chronic stress seems to reduce

BDNF and treatment with antidepressant can increase BDNF. (Vaidya et

al, 1999).

d) Immune hypothesis a current hypothesis states that cytokines like

Interleukin-1 might be involved in depression (Smith, 1991; Dantzer et al,

1999; Charlton, 2000). It was found that administration of IL-1 induces

sickness behavior very similar to depressive behavior (Kent et al, 1992;

Smith, 1991).

Most accepted theory of depression is, however, the monoamine theory.

During neurotransmission in brain monoamine neurotransmitters (NT)

such as serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are


released into the synaptic cleft from storage vesicles present in the pre-

synaptic neuron. The NTs then bind to their respective receptors on the

post-synaptic neuron, thereby transferring the signal. If the concentration

of NT available for the post-synaptic neuron is lower, then depression

occurs (Nestler et al, 2002). Some cytokines (e.g. IL-1, IL-6, TNF-α) are

also involved in the regulation of monoaminergic transmission during

depression (Berkenbosch et al, 1987; Sapolsky et al,1987; Adler et

al,2008). Immune system is altered in humans (Herbert et al, 1994;

Bachen et al, 1995; Reiche et al, 2004) and animals in depression (Song et

al, 1994; Connor et al, 1998; Levay et al, 2006; Breveik et al, 2006).

Immune system and depression are sometimes linked together via HPA-

axis. Hormones like glucocorticoids are increased in stressed animals and

in turn cause depression (Blalock, 1989; Haddad et al, 2002).

Glucocorticoids may influence immune system and is one of the causes of

immune changes in depression. Several areas of the brain are involved in

depression, such as, hippocampus (HPC), raphae nucleus (RN), locus

ceruleus (LC), limbic area (LA), etc (Anand et al, 2005; Whittle et al,

2005). All these areas have different monoaminergic transport systems.

The balance between different MAs and their receptors, together with the

endocrine system, determine normal psychomotor activity. The

monoamines, cortisol/corticosterone and cytokines may modulate each

other‟s function. The immune changes occurring during depression has

been explained on the basis of higher circulating levels of cortisol or

corticosterone. However, antidepressive drugs may ameliorate the

psychological component of depression along with the recovery of some

suppressed immune parameters, when the cortisol or corticosterone level

remains high (Connor et al, 1998 and 2000). Thus, it appears cortisol or

corticosterone may not be the only cause of immune suppression and

vol 1, 2014 54

higher sensitivity to inflammatory response in depression. There are

several reports that central neural areas such as hypothalamus (HPTH),

amygdala (AM), hippocampus (HPC), are able to modulate the immune

system through HPA-axis and autonomic activity in spleen and lymph

glands (Hori et al, 1995). Some of these areas are also considered as

neural centres involved in depression. However, the role of the central

neural areas affected in depression may be responsible for the immune

changes in depression.

Discussion

Depression induced immune changes may be mediated through several

neural centres of the brain which are common sites for regulation of

immune system and psychological state. These neural areas may regulate

the immune system through autonomic nervous system (ANS) and

neuroendocrine axis. Several works have reported that autonomic

innervation to spleen and lymph glands, is important for changes of

immune activity (Irwin, 1994). Hence, depression and immunity are

closely related due to their common biochemical pathway sharing.

Treatments of mental depression should be more non-invasive, so that any

chemical dysregulation in the immune system does not occur. Also,

similarly, while treating a physical ailment, utmost caution and a sound

knowledge of the patient‟s mental health is to be taken in account, so as to

avoid future complications.

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vol 1, 2014 62

Controlled Drug Delivery in Chemotherapy Using

Polymeric Drug Carriers

Suchandra Biswas *

Introduction

The problems of Chemotherapy and related toxic side effects cannot be

limited to any Nation. Intravenously administered chemotherapy have

limited effectiveness, since only a small amount of the systemic blood

flow is directed to the target (for example in cancerous tissues), only a

fraction of the total dose reaches the site [1]. The remainder of the dose is

distributed throughout healthy organs and tissues, leading to a variety of

undesirable side effects ranging from neutropenia to cardiomyopathy

[2,3]. Many chemotherapeutic drugs have also been reported to show very

rapid plasma clearance, leading to short target exposure times [4].

Using controlled drug delivery in a non-toxic biodegradable matrix, the

toxicity and side effects of the internationally accepted potent drugs can

be reduced to a great extent. Optimal therapy of a disease requires the

efficient delivery of active drugs to the tissues or organs that need

treatment. Pharmacological activity and therapeutic efficacy are known to

depend upon the concentration of the drug reaching the ailing tissue cells

at a constant level and within a therapeutically effective dose range for as

long as the treatment requires.

* Assistant Professor, Department of Chemistry, Bankim Sardar

College, P.O. – Tangrakhali, South 24 Parganas, Pin – 743329.



However, the availability of drug molecules to the cells is governed by a

sequence of Pharmacokinetic processes - release, absorption, distribution

and elimination. The potential benefits that a controlled release drug

delivery system may bring to us can be appreciated by a consideration of

prolonged and efficient delivery of therapeutically effective doses, patient

compliance and localization of therapy.

Polymeric drug carrier

A model for pharmacologically active polymer drug carriers has been

developed (Figure-1). Here, four different groups are attached to a

biodegradable polymer backbone. One group is the pharmacon or drug,

the second is a spacing group, the third is a transport system and the

fourth is a group to solubilize the entire biopolymer system. The transport

system for these soluble drug carriers can be made specific for certain

tissue/cells with targeting moieties such as pH sensitive group or receptor

active components such as antibody-antigen recognition [5-11]. They

afford a high degree of compatibility and stability to many drugs. A wide

variety of polymers are required to fit many applications. [12-15]

Figure -1: A Model for Polymeric drug carrier

vol 1, 2014 64

In the polymeric drug delivery system, three kinds of polymers are used

water soluble, biodegradable and non-water soluble-non biodegradable.

Water-soluble drugs are used for the short-term (Several hours to several

days) drug delivery. Polymers used are of different types like

polyethylene glycol, polyethylene imine, polyacrylic acid, chitosan.

Biodegradable polymers are used for long-term drug delivery. In the third

generation of polymeric drug delivery system, non-degradable polymers

are used. Hydro gels are used in oral delivery of drugs and as devices in

rectal, vaginal and buckle delivery of drugs.

Biodegradable polymers have been widely used in biomedical

applications because of their known biocompatibility and

biodegradability. Biodegradation is a natural process by which organic

chemicals in the environment are converted to simpler compounds,

mineralized and redistributed through elemental cycles such as carbon,

nitrogen and sulphur cycles. Polymers within this group retain their

properties for a limited period of time and then gradually degrade into

soluble molecules that can be excreted from the body. Biodegradable

polymers are preferred for drug delivery applications, since the need for

surgical removal of the depleted device is eliminated. Although the

number of biodegradable polymers is large, only a limited number of

polymers are suitable for drug delivery applications. Suitable candidates

must not only be biodegradable but also fit the high prerequisites of

biocompatibility. In addition, a polymer should ideally offer

processability, sterilizability, and storage stability if it is to be useful for

biomedical applications. The greatest advantage of degradable polymers

is that they are broken down into biologically acceptable molecules that

are metabolized and removed from the body via normal metabolic

pathways. However, biodegradable materials do produce degradation by-


products that must be tolerated with little or no adverse reactions within

the biological environment. Some of the important biodegradable

polymers used in drug delivery are listed below in Table -1

Table -1: List of Polymers used in Drug Delivery

Polymers Structures

Polyesters

Polyanhydrides

Polyamides

Phosphorous based

polymers like

Polyphosphorazenes

Polycaprolactones

Polysaccharides like

chitosan

vol 1, 2014 66

Mechanism for controlled drug release

A diverse range of mechanisms [16] have been developed to achieve

controlled release of drugs using polymers. This diversity is a necessary

consequence of different drugs imposing various restrictions on the type of

delivery system employed. For example, a drug that is to be released over

an extended period in a patient‟s stomach where the pH is acidic and

environmental conditions fluctuate widely will require a controlled release

system very different from that of a drug that is to be delivered in a

pulsatile manner within the blood system. An important consideration in

designing polymers for any controlled release mechanism is the fate of the

polymer after drug release. Polymers that are naturally excreted from the

body are desirable for many controlled release applications. These

polymers may be excreted directly via the kidneys or may be biodegraded

into smaller molecules that are then excreted.

Most drug molecules need to be dissolved in the aqueous environment of

the patient and freely diffuse within that media before they can act on their

target receptors. Polymeric devices that achieve temporal controlled

release protect drug molecules from this aqueous living environment for

preprogrammed periods of time. This protection can involve delaying the

dissolution of drug molecules, inhibiting the diffusion of the drug out of

the device, or controlling the flow of drug solutions. Polymers employed

to delay drug dissolution aim to slow the rate at which drug molecules are

exposed to water from the aqueous environment surrounding the drug

delivery system. This may be achieved by a polymer coating or matrix that

dissolves at a slower rate than the drug. In diffusion-controlled release,

drug molecule diffusion within an aqueous solution is inhibited by the

insoluble polymer matrix in which drug molecules must travel through


tortuous pathways to exit the device. Polymer chains such as those in a

cross-linked hydrogel form the diffusion barrier. The barrier to diffusion

can be decreased by swelling of the hydrogel, for example, which creates

voids in the gel structure. Such hydrogels may also benefit from

bioadhesive characteristics which allow them to reside within the

gastrointestinal tract for extended time periods. Polymers used for

diffusion-controlled release can be fabricated as either matrices in which

the drug is uniformly distributed or as a rate-limiting membrane that

protects the drug reservoir from the living environment. Devices that

control the flow of drug solutions sometimes utilize osmotic potential

gradients across semipermeable polymer barriers to generate pressurized

chambers containing aqueous solutions of the drug. This pressure is

relieved by the flow of the solution out of the delivery device. The rate of

flow is controlled because flow is restricted to fluid transport through a

micrometer scale to larger diameter pore or pores. Many temporal

controlled release devices use the above mechanisms to provide sustained

release of drug at a constant rate. Another form of temporal controlled

release is responsive drug delivery in which drug is released in a pulsatile

manner only when required by the body. Much work in this area has as its

eventual goal the delivery of insulin to diabetics. Insulin requirements

fluctuate throughout the day as patient food intake and activity change

blood glucose levels. Current insulin formulations require repeated

injections daily and careful control of glucose intake. Responsive drug

delivery hopes to revolutionize insulin therapy with the design of systems

that release insulin in response to increased blood glucose levels. In

general, responsive drug delivery systems have two components: a sensor

that detects the environmental parameter that stimulates drug release and a

delivery device that releases drug. For diabetes treatment, responsive drug

vol 1, 2014 68

delivery systems have been proposed that use the enzyme glucose oxidase

as the sensor. When blood sugar levels rise, glucose oxidase converts

glucose to gluconic acid resulting in lowered pH. This pH decrease is then

used as the signal for insulin release. Release is achieved by pH-sensitive

polymers that either swell or degrade in acidic environments. The concept

of responsive drug delivery can be used for any drug therapy in which a

sensor and delivery device can be coupled. Signals that have been

employed to trigger drug release include the following: magnetic signals

in which magnetic beads are distributed within a polymer matrix and

cause a rearrangement of that matrix when a magnetic field is applied;

electrical signals in which pore size, permeability, and other factors are

controlled by electrically stimulated polymer swelling; ultrasonic signals

in which the intensity, frequency, and duration of ultrasound increase for

both nondegradable and biodegradable polymeric systems; pH systems in

which ionizable groups within polymer gels control polymer chain

interactions; and temperature systems in which thermosensitive hydrogels

swell and collapse in response to temperature variations.

A review of different drug delivery systems developed

Delivery of drug by means of controlled release technology began in

1970 and has continued to expand so rapidly that there are now numerous

products in the market. Extensive research efforts are being made to

improve both the polymers and the processes as well as to apply them to

the controlled release of a wide variety of pharmaceutical products

[17,18]

Encapsulation of phthalocyanines in biodegradable polysebasic anhydride

nano particle has been developed by Ng and Wu et. al. for photo dynamic


therapy (PDT) for cancer treatment. The treatment involves

administration of photosensitive drug, which has a high affinity to

malignant tissues. It unlashes singlet oxygen as the predominant

cytotoxic agent when excited by the light of appropriate wavelength and

power. Among the various photosensitizers, phthalocyanines have been

found to be highly promising. Owing to their strong Q-band absorption at

the red visible region (700 nm) these pigments can be excited at longer

wavelength than photofrin, which is the first clinically, approved

photosensitizer. This optical property allows a deeper penetration of the

light into tissues. A novel series of co-polymers of Zn (II) phthalocyanine

and sebasic anhydride which are common building block of

biocompatible and biodegradable polymers have been prepared. The

degradation pattern has been seen in alkaline pH. The result shows that

this biocompatible polymer based colloidal system is potentially useful

for delivery and release of photosensitizer in PDT [19-21].

Robert Lu developed phospho lipid-sub micro emulsion as carrier system

for new cholesterol based compounds for targeted delivery to cancer

cells. Low density lipoprotein (LDL) and high-density lipoprotein (HDL)

are the natural carriers of cholesteryl esters in the body. Certain human

and animal tumor has been shown to have elevated LDL receptor activity

primarily because the rapidly dividing cancer cells need higher amount of

cholesterol to build new cell membrane. The elevated LDL receptor has

also been used in colon, kidney and liver tumors. To utilize LDL as a

drug carrier for preferential drug delivery to cancer cells, cholesteryl

esters of carbonates has been synthesized by Lu. This compound mimics

the native cholesteryl ester present in the core of LDL for drug targeting

and can be potentially used for boron neutron capture therapy (BNCT) of

cancers. It is an important requirement to have about 20μg of 10

B per gm

vol 1, 2014 70

of cell to achieve successful BNCT. All the tests were carried on Rat 9L

glioma cell (cancer-infected cell) in vitro [22].

In number of publications chitosan has been used as polymer matrix for

control release of drug. Chitosan is polysaccharide derived from chitin by

alkaline deacetylation. Chitosan nano particles were first prepared in

1997 by Alonso et. al. and was used in nasal delivery of insulin in rabbits.

Lim et.al. reported the release of insulin from chitosan-insulin in presence

of different enzyme [23].

Several self-regulating insulin delivery devices have been coupled with

insulin release to construct artificial pancreas systems. One of the

approaches is based on immobilizing glucose oxidase (GOX) in a pH

sensitive hydrogel, which is used as the insulin-release controller. GOX

catalyses the oxidation of glucose to gluconic acid. This reaction

generates a localized pH change, which causes a volume change in the

pH-sensitive hydro gel, release of the entrapped insulin, GOX has been

immobilized on a wide variety of polymers and hydro gel [24-26].

Conclusion

Polymer drug targeting to a specific biological site is an enormous

advantage in drug delivery because only those sites involved are affected

by the drug. This precludes the transport throughout the body, which can

elicit serious side effects. Ideally, a targetable drug carrier is captured by

the target cell to achieve optimum drug delivery while minimizing the

exposure to the host. However, the ultimate fate of drugs and their

metabolites is a major concern. If they are not cleared in a reasonable

time, they could lead to undesirable side effects. If the sizes of polymeric

drug carriers are greater than 40,000 daltons, they could accumulate in


the host with the potential of future unwanted effects. The future of

success of biodegradable polymer based formulation will primarily

depend on pledge of pharmaceutical and biotechnology industries to

development of this technology. Although many advances have been

made, much work still remains before proteins can be tamed as useful

molecules for efficient drug delivery systems

References

1. Dowell, J. A.; Sancho, A. R.; Anand, D.; Wolf. W.

Noninvasive measurements for studying the tumoral

pharmacokinetics of platinum anticancer drugs in solid tumors.

Adv. Drug Deliv. Rev. 2000, 41, 111.

2. Crawford, J.; Dale, D. C.; Lyman, G. H. Chemo-therapy-

induced neutropenia: Risks, consequences, and new directions

for its management. Cancer 2004, 100, 228.

3. Wallace, K. B. Doxorubicin-induced cardiac

mitochondrionopathy. Pharmacol Toxicol 2003, 93,105.

4. El-Kareh, A. W.; Secomb, T. W. A mathematical model for

comparison of bolus injection, continuous infusion, and

liposomal delivery of doxorubicin to tumor cells. Neoplasia,

2000, 2, 325.

5. Brand, C. et. Al. Bio act Comp. Polymer. 1989, 4, 269.

6. Muzzarelli, R. A. et. al. J. Bio act Comp. Polymer. 1990, 5,

396.

7. Dumitrin, S. et. al. J. Bio act Comp. Polymer. 1988, 3, 243.

8. Ringsdorf, H. J. Polymer Sc. 1975, 51, 135.

9. Larsen, C. Adv. Drug Delivery Rev. 1989, 3, 103.

10. Duncan, R. et. al. J. Bio act Comp. Polymer. 1988, 3, 4.

11. Flanagen, P. A. et. al. J. Bio act Comp. Polymer. 1990, 5, 151.

vol 1, 2014 72

12. Ganderton, D. in Drug Delivery Systems, Johnsten, P. et. al.

(Ed), Ellis Harwood Publisher, Chichester,UK, 1987.

13. Heller, J. Critical Reviews in Therapeutic Drug Carrier

Systems, S. D. Bruk (Ed) CRC Press, Fl, 1984 (Vol. I), 38.

14. Pitt, C. G. In Biodegradable Polymers as Drug Delivery

Systems, Longer, R. et. al. (Ed) MD, NY 1990, Vol. 45, 71.

15. Kormeyer, R. W. et. al. J. Control. Rel.1984, 1, 89.

16. Uhrich, K. E. Chem. Rev. 1999, 99, 3181.

17. Donaruma, L. G.; Vogl, O. (Eds.), Polymeric Drugs. AP NY,

1978.

18. Ottenbriten, R. M. in Anti-cancer and Interferon, MD NY,

1984.

19. Fu, J.; Li, X.; Ng, D. K. P.; Wu, C. Langmuir. 2002, 18(10),

3843.

20. Bonnet, R. Chemical Aspect of Photodynamics, Gordon and

breach, Amsterdam, 2000.

21. (a) Allen, C. M.; Sharman; van Lier, J. E. J. Porphyrins

Phthalocyanins. 2001, 5, 161.

(b) Urizzi, P.; Allen, C. M.; Langlois, R.; Ouellet, R.; La

Madeleine, C.; van Lier, J. E. J. Porphyrins Phthalocyanines.

2001, 5, 154.

22. Lu, D. R. J. Phamaceutical Sc. 2002, 91(6), 1405.

23. Lim, L. Y. et. al. J. Pharmaceutical Sc. 2002, 91(6), 1396.

24. Design and evaluation of polymeric ocular drug delivery

system for controlled release of tetracycline HCl, K.M.

College of Pharmacy, Department of Pharmaceutics,

Uthangudi, Madurai-525107.

25. Rajan, N. S. M. G.; Jayaprakash, S.; Somnath, S. Indian

Journal of Pharmaceutical Sciences. 2001, 63(6), 526.

26. Podual, K.; Doyle III, F. J.; Peppas, N. A. J. Controlled

Release. 2000, 67, 9.


Recent Applications of Iodine in Organic Synthesis

Tapas Kumar Mandal *

Introduction

Iodine is shown to be an effective catalyst in organic synthesis. Last ten

years have witnessed a remarkable growth and development in the use of

iodine in organic synthesis, both as a Lewis acid catalyst and as a reagent.

Iodine has been explored as a powerful catalyst for various organic

transformations such as cross-Aldol condensation, conjugate addition

reaction, Hantzsch pyrimidine synthesis, Suzuki-Miyaro coupling,

esterification reaction, transesterification reaction, acetylation reaction,

protection and deprotection reaction, Diels-Alder reaction, Friedel-Crafts

reaction and various cyclization reactions. Besides its use due to its Lewis

acidity, it is also used as an electrophilic regents and mild oxidiging agent.

Iodine has been attracting much attention since its discovery1a

in 1811by

French chemist Bernard Courtois (1777-1838). The element occurs

primarily in sea water and in solids formed when seawater evaporates. It is

the heaviest of the commonly occurring halogens. Iodine‟s chemical

properties are similar to those of the lighter halogens above it, viz.,

fluorine, chlorine and bromine but its physical properties are very

different. It is one of the most striking and beautiful of all elements.




vol 1, 2014 74

As a solid, it is a heavy, grayish-black, metallic-looking material. Iodine

dissolves only slightly in water (0.33gL-1

at 25ºC). But it dissolves in

many other liquids to give distinctive purple solutions. Iodine has several

advantages over the vast majority of the other Lewis-acid catalysts,

especially the metallic catalysts. Its catalytic potential is intriguingly

broad; it is a water-tolerant, relatively cheap and environmentally friendly

catalyst. Another distinctive feature of iodine is its high catalytic activity

in dilute solutions, under highly concentrated reaction conditions (HCRC)

as well as under solvent free reaction conditions (SFRC). The latter

reaction conditions are particularly important in terms of green chemistry;

they contribute to waste- and health-hazard minimization and cost

efficiency.

About two-thirds of all iodine and its compounds are used in sanitation

systems or in making various antiseptics and drugs. Iodine is also used to

make dye, photographic film and specialized soaps. But it is used as a

reagent and mostly as a catalyst in industry as well as in laboratory. The

Lewis acidity1b

of iodine comes from the consideration of the electronic

structure of this molecule. Iodine has the electronic structure

5σ25σ

2*5π

45σ

25π

4*5σ*. This shows iodine has an empty 5σ*orbital which

is anti-bonding. When iodine is dissolved in a solvent S having a lone pair

of electrons or when contact comes with molecules containing N, O, S,

etc. having lone pair of electrons, it forms a charge transfer complex (CT

complex) with donor molecules. This is accompanied by the partial

charge-transfer of an electron lone pair from the donor to iodine, resulting

the Lewis acidity of the molecules.

The Lewis acid promoted organic reactions were carried out as early as

1890, and they still play important roles in modern organic chemistry.


O

+ ArCHO

O

ArArI2, CH2Cl2

( )n ( )n(Ref. 2a)

I2, No solvent

(Ref. 2b)

Molecular iodine has received considerable attention in organic synthesis

because of its low cost, non-toxicity and ready availability. The mild

Lewis acidity associated with iodine has enhanced its use in organic

synthesis. Owing to numerous advantages associated with this eco-

friendly element, iodine has been explored as a powerful catalyst for

various organic transformations. In the following Sections the author

presents some applications of iodine reported in the literature during last

ten years.

Result and Discussion

Cross-Aldol Condensation Reaction

Cross-Aldol condensation of aromatic aldehydes with cyclic ketones is an

important synthetic reaction for the preparation of α,α'-bis(benzylidene)-

cycloalkanones. These benzylidene derivatives are intermediates for

synthesis of various pharmaceuticals, agrochemicals and perfumes. Das et

al.2a

first reported that molecular iodine efficiently catalyses the two

component cross-aldol condensation of aromatic aldehyde and cyclic

ketones in CH2Cl2 at room temperature affording α,α'-

bis(substituted)benzylidene in high yield (Scheme 1). The same

observation was reported by Pasha et al.2b

under stirring in solvent free

condition in good to excellent yield (85-94%).

vol 1, 2014 76

Scheme 1

Dehydration of Alcohols

Iodine has been shown to be an efficient catalyst for transforming of

alcohols to alkenes under solvent free conditions. In presence of 5% of

iodine, tertiary alcohols underwent dehydration forming the corresponding

alkenes3. Secondary and primary alcohols under the same conditions gave

corresponding ethers.

Scheme 2

Ren et al.4a

converted benzylic and aliphatic alcohols into nitriles in

the presence of a twofold excess of iodine in aqueous NH4OAc. The

same transformation could also be accomplished in aqueous NH34b

using an excess of I2 or with TBHP4c

and a catalytic amount of I2.

Scheme 3


Esterification Reaction

Transesterification of esters with alcohols have been accomplished

using molecular iodine. Ramalinga and co-workers5 reported that

iodine acts as a Lewis acid catalyst for transesterification of simple

esters with different alcohols including tertiary alcohols and sterically

hindered primary and secondary alcohols in refluxing condition

(Scheme 4). Simultaneous esterification and transesterification

reactions can also be reported using iodine.

Scheme 4

Etherification

Rostami et al. 6successfully converted primary, secondary, tertiary

aliphatic, benzylic alcohols and phenols into the corresponding

tetrahy-dropyranyl ethers by using iodine.

R1COOR2 + R3OHI2

RefluxR1COOR3 + R2OH

vol 1, 2014 78

Scheme 5

Cleavage of Ethers

Yadav et al.7

were cleaved ethers with iodine in the presence of

aromatic or aliphatic acyl chlorides, and the corresponding esters

(Scheme 6) were formed in high yield at ambient temperature;10

mol % of I2 and a nine-fold excess of ether relative to acyl chloride

were used. Later, it was found that much less iodine was necessary

and that the reaction time could be significantly reduced. Ring

opening of THF with benzoyl chloride was also very efficient with

iodine, below 1 mol

Scheme 6

Iodine was shown to catalyze the transformation of epoxides to

thiiranes8 using NH4SCN in MeCN; acid-sensitive protecting

groups, e.g., THP or TBDMS unaffected during the process.

OMeCOCl or PhCOCl

10 mol % of I2, ,rt, 120 min

R3

O

O

Cl

R3 = Me or Ph

(91-96 %)

O

Cl

MeCOCl

ClH2C CH2Cl

OAc

85 %

40mol % of I2, ,rt, 240min

Acetic acid 2-chloro-1-chloromethyl-ethyl ester


Furthermore, iodine catalyzed the ring opening of epoxides in the

presence of nucleophiles to the corresponding hydroxy

derivativesb.

Scheme 7

Protection and Deprotection of Carbonyl Group

Banik et al.9 showed that several ketals were prepared using

carbonyl compounds and ethylene glycol in the presence of iodine

(5 mol%). Aliphatic aldehydes and ketones were extremely good

substrates for this purpose. The yields with the aromatic aldehydes

and benzylic ketones were satisfactory.

Scheme 8

O

R2

R1

NH4SCN in CH3CN

10 mol % I2

R1 = H, R

2 = CH2OPh

R1 = R

2 = Ph

S

R2R

1

I2, 1-1.7 mol %

R3OH

OR3

R2

R1

OH

R1 + R

2 = (CH2)3, (CH2)4

R1 = H, R

2 = aryl, alkyl

R3 = H, alkyl, Ac

b

Thiiranesa

vol 1, 2014 80

Hu et al 10

. An extremely convenient method for deprotection of

acetals and ketals catalyzed by molecular iodine (10 mol%) in

acetone reported. The protocol achieved the deprotection of acyclic

or cyclic O,O-acetals and O,O-ketals in excellent yields within a

few minutes under neutral conditions. The double bond, hydroxyl

group, and acetate group remained unchanged, and the highly acid-

sensitive furyl, tert-butyl ethers, and ketone-oxime stayed intact

under these conditions.

Scheme 9

Conjugate Addition

Singh et al.11

reported regioselective 1,2-reduction of conjugated

α,β-unsaturated aldehydes/ ketones by using I2 and NaBH4 (

Scheme 10).

Scheme 10

O

R2

R1 NaBH4 /I2

THF, 15oC, stirring OH

R2

R1

H


R-OH + Ac2OI2, cat.

(1-10 min.)R-OAc

85-100%

Wang et al.12

reported that indole undergoes conjugate addition

with α,β-unsaturated carbonyl compounds (chalcones) by means of

alkylation of indoles in presence of catalytic amount of molecular

iodine in ethanol at room temperature to afford the corresponding

adduct in excellent yield (up to 96%) (Scheme 11). The same

observation was reported by B. K. Banik et al13

. under solvent free

condition in good yield.

Scheme 11

Acetylation Reaction

The acetylation of alcohols, phenols, amines and anilines is an important

and widely used transformation in organic synthesis. Phukan14

reported

that iodine acts as a Lewis acid catalyst for acetylation of alcohols and

phenols in a very short time by using an equivalent amount of acetic

anhydride under solvent free condition at room temperature (Scheme 12).

Scheme 12

NH

+

O

R2

R1

NH

R2

O

R1I2, EtOH

I2, Solvent

a)

b)

free

vol 1, 2014 82

Saini et al.15

also reported a one pot process for effective transformation of

aldoximes into nitriles using Zn/I2 system. Here, iodine acts as a Lewis

acid for the dehydration process (Scheme 13).

Scheme 13

Friedel–Crafts Reaction

Iodine is shown to be an efficient catalyst for the Friedel–Crafts

alkylation16

of arenes with a wide variety of aldehydes in toluene under

„open-flask‟ and mild conditions. In the presence of 10 mol % of iodine,

the reaction of arenes with aromatic aldehydes gives the corresponding

triarylmethane derivatives (TRAMs), regioselectively, in good to excellent

yields. On the other hand, a series of diarylalkane derivatives is

synthesized smoothly by reaction with aliphatic aldehydes (Scheme 14).

Scheme 14

RCH=N-OH RC NI2, Zn

CH3CN, r.t.


O

OHPh

Ph

PhNH2

NH4OAc

ArCHO

N

NPh

Ph

Ar

Ph

+

+

+

I2

EtOH

wang et al17

developed a novel molecular iodine-catalyzed benzylation of

arenes with benzyl alcohols . The reaction can be carried out under mild

conditions to afford a series of diarymethane derivatives in high yields and

good regioselectivities (Scheme 15).

Scheme 15

Synthesis of Imidazole

Kidwai and Mothsra18

synthesized 1,2,4,5-tetraarylimidazoles using

benzoin, an aromatic aldehydes, aniline and ammonium acetate in

presence of molecular iodine in excellent yield (94-98%). The Lewis

acidity of iodine makes it capable of binding with the aldehyde carbonyl

oxygen increasing the reactivity of the parent carbonyl compounds.

Scheme 16

vol 1, 2014 84

NH

O

OO ArO

O

O

O

OArCHO

NH4OAC

I2

ethanol+ + +

Iodine reacts initially with aldehyde to produce a diamino intermediate

then it condenses with benzil which is produced in situ and subsequently

elimination of water affords 1,2,4,5-tetraarylimidazoles (Scheme 16).

Hantzsch Pyrimidine Synthesis

Hantzsch 1,4-dihydropyrimidines (1,4-DHPs) and their derivatives have

gained great importance in the field of organic and medicinal chemistry

since they display a fascinating array of pharmacological properties. A

variety of 4-substituted 1,4-dihydropyrimidines was synthesized by Ko et

al19

from the reaction of different aryl or alkyl aldehydes, 1,3-

cyclohexanone, ethyl acetoacetate and ammonium acetate in presence of

catalytic amount of iodine at room temperature in ethanol (Scheme 17).

Scheme 17

Domino/Domino Knoevenagel Reaction

2-Arylquinolines are biologically active and occur in the structures of a

number of antimalarial compounds and antitumor agents. Therefore, the

developement of new synthetic approaches leading to them remains an

active research area. Lin et al20

reported that a molecular iodine-catalysed


N

R1

R2 HR3

O+

N

R3

R1

R2

I2

Benzene reflux

one pot domino reaction of imines with enolisable aldehydes afforded

various substituted quinoline in good yields (60-82%) (Scheme 18).

Scheme 18

Molecular iodine was used as a catalyst in the [3+3] cyclocoupling of

phenols and cinnamic acids which proceeds via a tandem esterification –

hydroarylation process at 120-130⁰C under solvent-free conditions.

Substituted 4-aryl-3, 4-dihydrobenzopyran-2-ones21

were obtained in good

yield (Scheme 19).

Scheme 19

Mallik et al.22

reported that cinnamylideneacetophenones underwent facile

cyclocondensation with thiophenol in dichloromethane under iodine

catalyzed condition yielding cis-2-(aroylmethyl)-4-phenylthiochromans in

very good to excellent yield. The structures of the products have been

OH

R

HO

Ar

O O O

Ar

+

20 mol % I2

120o-130oC

vol 1, 2014 86

established from their spectral data as well as X-ray crystallographic

studies on one of them (Scheme 20).

Scheme 20

Conclusion

This review focuses the versatile uses of iodine in different chemical

transformations. It specially concentrates on the utility of molecular iodine

as an effective Lewis acid catalyst, not only in performing selective

transformations but also in development of host of interesting and useful

reactions. The ever-growing relevance and concern of modern chemistry

chemistry is for the protection of the environment, solid-supported iodine

with unreduced activity could considerably contribute to green chemistry.

Although many interesting observations have not received application in

synthesis of natural products or complex molecules so far, it is expected

that in near future they will be useful in facile synthesis of many useful

target molecules.

Acknowledgements

The author takes this opportunity to express his sincere gratitude and deep

appreciation to Dr. A. K. Mallik, Professor and Former Head, Department

SH

+

Ph

OAr

H

S

PhH

HAr

O

I2

CH2Cl2, reflux

2.5-3.5 h

1 2


of Chemistry, Jadavpur University, for constructive ideas, valuable

guidance throughout the progress of this work.

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vol 1, 2014 88

11. Singh, J.; Kaur, I.; Kaur, J.; Bhallaa, A.; L. K., G. Synth. Commun.,

2003, 33, 19.

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Synlett, 2012, 23, 2459.


Stabilization of Lipophilic Drug, Curcumin within Micelles

Ummul Liha Khatun *

In recent year curcumin [having IUPAC nomenclature: 1,7-bis (4-

hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione] has received

considerable attention due to its versatile medicinal properties. Curcumin

(structure is shown in figure 1) is the major ingredient of the yellow

pigments (curcuminoids) in the Indian spice plant turmeric. A large

number of studies have shown that curcumin possesses anti-cancer, anti-

oxidant, anti-mutagenic, antibiotic, anti-viral, anti-fungal, anti-amyloid,

anti-diabetic and anti-inflammatory properties. Because of its numerous

pharmaceutical effects without side effects unlike conventional

chemotherapy drugs and its inherent non-toxicity curcumin has been the

focus of many recent biochemical investigation.

Fig. 1. Structure of Curcumin

_______________________________________________________________

* Guest lecturer, Department of Chemistry, Fakir Chand College,



vol 1, 2014 90

Two major problems regarding the application of curcumin as a drug are

the lack of bioavailability and limited stability in aqueous environments.

Low aqueous solubility of curcumin tends to aggregation and precipitation

in water, limiting its bioavailability. In addition, curcumin undergoes rapid

degradation in water and in buffer solutions due to deprotonation

producing the degradation products vanillin, ferulic acid and feruroyl

methane. Recent studies show that encapsulation of curcumin within

micelles improved clinical use of curcumin. Curcumin is intrinsically

fluorescent. The photo-physical properties and fluorescence spectra of

curcumin are very sensitive to the polarity of the medium/environment.

When free curcumin was excited at 420 nm it showed a low-intensity

broad steady-state fluorescence peak at 540 nm in aqueous solution.

When curcumin bound to micelles its steady-state fluorescence spectrum

was blue shifted to a well-defined peak at 500 nm and intensity sharply

increased. Such blue shift of the emission spectra indicates the binding of

curcumin to the hydrophobic core of the micelles. Stabilization of

curcumin within micelles was measured using the loss of the characteristic

absorption maximum at 424 nm as a marker for curcumin degradation.

Curcumin exists predominantly in keto-enol tautomeric form in a number

of solvants other than water. This keto-enol tautomeric form help

curcumin to execute excited state intramolecular hydrogen atom transfer

(ESIHT) due to the presence of strong intramolecular hydrogen bonding

between the proton donor and the acceptor atom i.e., ESIHT is a major

photophysical event of curcumin. It is also reported that the presence of

labile hydrogen as a result of ESIHT plays a role in the medicinal effects

of other naturally occurring pigments such as hypericin and hypocrellin

etc. Time-resolved fluorescence results demonstrate that ESIHT is a major


photophysical event of curcumin within micelles. Micelles-encapsulated

curcumin is well-dispersed consequently preventing aggregate formation,

thereby increasing the bioavailability significantly. Moreover, curcumin is

trapped in the hydrophobic region of the micelles where the presence of

free water molecules is limited preventing alkaline hydrolysis which is the

major mechanism for degradation. It is therefore inferred that

encapsulation of curcumin within micelles enable curcumin to exhibit its

medicinal characteristics. Apart from preventing degradation, micelles

also serve as well-defined model systems for biomembranes as well as

drug-delivery vehicle.

References

1. Leung, M. H. M.; Colangelo, H.; Kee, T.W. Langmuir, 2008, 24

(11), 5672.

2. Wang, Z.; Leung, M. H. M.; Kee, T.W.; English, D. S. Langmuir,

2010, 26 (8), 5520.

3. Adhikary, R.; Carlson, P. J.; Kee, T.W.; Petrich, J. W. J. Phys.

Chem. B, 2010, 114 (8), 2997.

4. Sahu, A.; Kasoju, N.; Bora, U. Biomacromolecules, 2008, 9 (10),

2905.

5. Barry, J.; Fritz, M.; Brender, J. R.; Smith, P. E. S.; Lee, D. K;

Ramamoorthy, A. J. Am. Chem. Soc., 2009, 131 (12), 4490.

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