109

Chapter 3 Photochemical Transformations of

Talotrexin and Xipamide

110

Introduction

The dated interest of photochemists in the properties of the electronically excited

states of compounds of pharmaceutical use has been rapidly increasing during the last

decade 1,2. This has been motivated by photobiological reasons, connected to the

increasing number of cases of drug induced photosensitization disorders such as

photomutagenic, photocarcinogenic, photoallergy and phototoxicity 3,4. The

generation of an adverse photosensitivity response can be postulated to involve one or

more of the pathways namely singlet oxygen formation, an electron or hydrogen

transfer could lead to the formation of free-radical species, a covalent photobinding to

biomolecules and photoproduct in decomposition reaction 5-7. In general it immerse

that phototoxicity is strictly related to Photoreactivity 8,9. As the number and variety

of phototoxic compounds is large so emphasis should be given on those

photosensitizing drug whose molecular mechanism of photosensitization is still

unknown.

Photoinduced electron transfer reactions in drugs receiving considerable attention

recently from a more fundamental photochemical standpoint and many reactions such

as cycloadditions, cycloreversions, oxygenations and photodegradation of drugs have

been documented 10. Photoinduced electron-transfer reaction is one of the most

elementary chemical processes and plays important roles in many photosensitization

phenomena 11. Photoinduced electron transfer (PET) process can be described as

electrons are not bound equally strongly in all atoms and molecules. Some have

greater affinity for the electron than others. Electron rich systems which can readily

give up an electron are called donors (D). Correspondingly, electron deficient units

which have the ability to pick up an electron are referred to as acceptors (A). By

111

absorption of light of suitable wavelength, molecules (especially those containing

chromophoric groups) can be induced to undergo transition from the ground to the

excited electronic state. Molecules in the excited electronic state are generally very

reactive. They are capable of giving up (or taking in) an electron if efficient acceptor

or donor units are available in the neighbourhood 12. Thus, it is worthy to stress that

studies performed on drugs bearing either simple or complex chromophoric group.

The study of photochemistry of these drugs will make remarkable contributions to the

broad area of the molecular mechanisms of drug photosensitization which might be

relevance to understand the in vivo photobiological effects and help to prevent the

undesirable side effects of photosensitizing drugs before it introduces in clinical

therapy or products made available in the market.

With this interest herein we have investigated the photochemistry of talotrexin and

xipamide under different reaction conditions.

[A] Photochemical Electron Transfer Reactions of Talotrexin

[B] Photoinduced Electron Transfer Photodegradation of Phototoxic Diuretic

Drug Xipamide

112

Section [A]

Photochemical Electron

Transfer Reactions of Talotrexin

113

[A] Photochemical Electron Transfer Reactions of Talotrexin

Folic acid antagonists, often called antifolates, are cytotoxic drugs 13 used as

antineoplastic,14 antimicrobial,15 anti-inflammatory 16 and immune-suppressive 17

agents. Antifolates are compounds commonly used to treat various forms of cancer

such as breast cancer, head and neck cancer, bladder cancer, acute lymphocytic

leukemia, non-Hodgkin’s lymphoma, choricarcinoma, and osteogenic sarcoma 18.

They are also being used in the treatment of non-cancerous diseases such as malaria,19

bacterial infections,20 psoriasis and rheumatoid arthritis 21. They act as antitumor

agents by suppressing the effects of folic acid and its derivatives on cellular

processes22,23. Nearly 50 years after their first use as anticancer agents, the antifolates

remain a diverse and growing class of drugs with great promise and potential for

improving our ability to treat a broad range of human diseases. Although they are

very useful but they can produce photosensitizing disorders such as photomutagenic,

photocarcinogenic and photoallergy 24,25.

Talotrexin (PT-523, Na-(4-amino-4-deoxypteroyl -Nd-hemiphthaloyl- L-ornithine)) is

a newer antifolate and potent antagonist of dihydrofolate reductase (DHFR).

Talotrexin (1) combines characteristics of both the classical and non classical

antifolates 26. Talotrexin (1) has demonstrated enhanced antitumor activity in a broad

spectrum of cancer models by targeting the enzyme DHFR to prevent DNA synthesis

in tumor cells and inhibit tumor growth 27. Preclinical studies suggest that talotrexin

(1), as compared to methotrexate, the most widely used antifolate, enters into cells up

to 10 times more efficiently and demonstrates 10 to 100-fold more potency in

overcoming polyglutamation, a well-established mechanism of antifolate resistance 28.

It belongs to the family of drugs called photosensitizing agents 29. Interest in the

114

photoreactivity of talotrexin (1) arises from the clinical and pharmacological reports

of toxic effects associated with the use of this drug 30. The aim of this study is to

contribute to the knowledge of the photochemical process involved in the

photodegradation of talotrexin (1) and the possible implications in the

phototosensitizing activity. Herein we have elucidated the photochemical behavior of

the novel antifolate drug talotrexin (1) under both aerobic and anaerobic conditions in

UV-A light. Photolysis of talotrexine (1) resulted in the formation of three

photodegradation products, identified as (2), (3) and (4) from their spectral (IR, 1H-

NMR, 13C-NMR, Mass spectra) properties (Scheme-3A.1).Photoproducts are

presumably produced by photoinduced electron transfer (both inter and intra

molecular) mechanism.

Experimental

Chemicals

All chemicals used were of analytical grade. Pure talotrexin (1) was obtained from

varda Biotech (P) Ltd India. Riboflavin was purchased from Sigma Aldrich (India).

Apparatus

Photochemical reactions were carried out in quartz fitted immersion well

photochemical reactor equipped with 400W medium pressure mercury vapour lamp

with continuous supply of water. IR spectra were recorded as KBr discs on a Perkin

Elmer model spectrum RXI. 1H-N M R and 13C-NM R Spectra were recorded on a

Bruker Avance DRX-300 Spectrometer using TMS as internal standard and DMSO as

solvent. High resolution mass spectra were determined with a VG-ZAB-BEQ9

spectrometer at 70 e V ionization voltage. Column chromatography was performed on

115

silica gel 60 (70-230 mesh); thin layer chromatography (TLC) was carried on Merck

silica gel 60 F 254 (0.2 mm thick plates).

General Photoirradiation procedure

An aqueous solution of talotrexin (1) was stirred for 1 h before irradiation and was

kept bubbling during the irradiations. The course of reaction was monitored by thin

layer chromatography on pre-coated silica gel TLC plates using chloroform- methanol

(98:7) mixture. After the completion of reaction (when desired conversions have

reached) the solvent was removed in a rotary evaporator and products were purified

by silica gel column chromatography.

Irradiation of talotrexin under aerobic condition

An aqueous solution of talotrexin (1) (170 mg, 0.30 mM) with riboflavin (Rib) as a

photosensitizer under aerobic condition was irradiated for 3 h. After following the

steps described in general photoirradiation procedure, 2, 4-diaminopteridine-6-

carboxalic acid (2, 53 mg) was obtained as main product with a trace amount of 2-((4-

(4-aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic acid (3, 35 mg) as detected

on TLC.

2, 4-diaminopteridine-6-carboxalic acid (2):

Yield: 53 mg (31%) HRMS calcd.For(M+) C7H6N6O2 206.1615 found 206.1601;

IR(KBr) 1595, 2600, 3450 cm-1; 1H-NMR (DMSO, , ppm): 10.9 (s,1H,COOH), 8.59

(s,1H, H-7), 5.30 (s, 4H, 2NH2); 13C-NMR (DMSO, , ppm): 165.6 (COOH), 161.4

(C-2), 155.7 (C-8a), 155.4 (C-4), 146.4 (C-7), 143.8 (C-6), 122.7 (C-4a); Ms:m/z: 206

(M+), 161(M+-45).

116

2-((4-(4-aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic acid (3):

Yield: 35mg (20%) HRMScalcd. For (M+) C20H21N3O6 399.3972 found 399.396; IR

(KBr) 3410, 3050, 1725, 1680 cm-1; 1H-NMR (DMSO, , ppm): 8.12 (m, 2H, H-2 &

H-6 of benzoic acid), 7.98 ( m, 1H, H-1 of amino benzamido), 760 (m, 1H, H-4 of

benzoic acid), 7.47(m, 2H, H-3& H-5 of benzoic acid), 6.80 (m, 2H, H-2 & H-6 of

amino benzamido), 6.34 (m, 2H, H-3 & H-5 of aminobenzamido), 4.46 (t, 1H, H-4

of carboxy butyl), 4.0 (2H, NH2), 3.20 (t, 2H, H-1 of carboxy butyl), 1.78 (m, 2H, H-

3 of carboxy butyl), 1.55 (m, 2H, H-2 of carboxy butyl); 13C-NMR (DMSO, ,

ppm):174.5 (COOH of carboxy butyl), 170.4 ( COOH of benzoic acid), 168.3 (COOH

of carbamoyl group), 146.8 (C-4 of aminobenzamido), 133.7 ( C-4 of benzoic acid),

130.4 (C-2 & C-6 of benzoic acid), 129.2 ( C-1 of benzoic acid), 129.6 (C-2 &C-6 of

aminobenzamido), 128.6 ( C-5 of benzoic acid), 128.2 (C-6 of amino benzamido),

127.8( C-1 of amino bezamido), 115.8 (C-3 & C-5 of amino benzamido), 53.4 (C-4 of

carboxybutyl), 48.8(C-1 of carboxy butyl), 28.4 (C-3 of carboxy butyl), 21.9 (C-2 of

carboxy butyl); MS: m/z: 355(M+), 310 (M+-45).

Irradiation of talotrexin under anaerobic condition

An aqueous solution of talotrexin (1) (170 mg, 0.30 mM) under anaerobic condition

was irradiated for 4 h. After following the steps described in general photoirradiation

procedure, 2, 4-diamino-6-(hydroxymethyl) pteridine (4, 47 mg) was obtained as

main photoproduct with a trace amount of (3), as detected on TLC.

117

2, 4-diamino-6-(hydroxymethyl) pteridine (4):

Yield: 47 mg (28%) HRMS calcd. For (M+) C7H8N6O 192.178 found 192.174; IR

(KBr) 3585, 3450, 1595cm-1; 1H-NMR (DMSO, , ppm): 8.54 (s, 1H, H-7), 5.30 (s,

4H, 2NH2), 4.79 (s, 2H, 6CH2OH), 2.0 (s,1H, 6CH2OH); 13C-NMR (DMSO, , ppm):

162.3 (C-2), 155.4 (C-4), 153.7(C-6), 149.4 (C-8a), 144.8(C-7), 124.1(C-4a), 65.0

(CH2OH); Ms: m/z: 192 (M+), 175(M+-17), 161 (M+-31).

Results and discussion When an aqueous solution of talotrexin (1) was irradiated with medium pressure

mercury vapour lamp in an immersion well type photo reactor under aerobic condition

gave 2, 4-diaminopteridine-6-carboxalicacid (2) and trace amount of 2-((4-(4-

aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic acid (3). When irradiation

was carried out under anaerobic condition 2, 4-diamino-6-(hydroxymethyl) pteridine

(4) was obtained along with the trace amount of (3) (Scheme-3A.1). The spectral

features correlated to the assigned structure of the main photoproducts and were done

in comparison with the spectra of the starting drug. The 1H-NMR spectrum of

photoproduct (2) showed signals similar to those of parent drug talotrexin, except for

the proton signals of 2-((4-(4-aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic

acid moiety. A new signal that appeared at 10.9 ppm was assigned to the proton of

newly generated -COOH group at C-6 that resulted by the cleavage of C-N bond of

the 4(2, 4-diaminonpteridin-6yl) methyl) amino moiety in the starting drug. The 13C-

NMR spectrum of photoproduct (2) also showed signals similar to those of talotrexin

except for the carbon signals of 2-((4-(4-aminobenzamido)-4-carboxy butyl)

carbamoyl) benzoic acid moiety. A new signal that appeared at 165.6 ppm was

assigned to the carbon of –COOH group present at C-6.

118

The 1H-NMR spectrum of photoproduct (4) showed signals similar to those of parent

drug talotrexin except for the proton signals of 2-((4-(4-aminobenzamido)-4-carboxy

butyl) carbamoyl) benzoic acid moiety. A new signal that appeared at 2.0 ppm was

assigned to the proton of newly generated –CH2OH group at C-6 that resulted by the

cleavage of C-N bond of the 4(2, 4-diaminonpteridin-6yl) methyl) amino moiety in

the starting drug. In 13C NMR spectrum of photoproduct (4) the signals of 2-((4-(4-

aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic acid moiety did not appear as

they were in the starting drug.

The mechanism of the formation of different talotrexin (1) photoproducts is depicted

in scheme-3A.2 and 3A.3. Under aerobic condition the formation of photoproducts

can be rationalized as when an aqueous solution of talotrexin (1) with riboflavin as a

photosensitizer was irradiated, triplet excited state of riboflavin (Rib) was formed.

Subsequently triplet excited state of riboflavin (Rib) accept an electron from

talotrexin and resulting the formation of corresponding radical ions, riboflavin radical

anion (Rib . _ ) and talotrexin radical cation (talotrexin +. ). Talotrexin radical cation

then undergo a loss of electron followed by deprotonation yield an enamine which on

hydrolysis gave 2-((4-(4-aminobenzamido)-4-carboxy butyl) carbamoyl) benzoic acid

(3) and an aldehyde and aldehyde finally oxidized due to aerial oxidation to gave

photoproduct (2, 2,4-diaminopteridine-6-carboxalic acid) (Scheme-3A.2). In

anaerobic condition photoexcited talotrexin undergo intramolecular electron transfer

to form radical ion pair which after hydrolysis gave photoproduct 2, 4-diamino-6-

(hydroxymethyl) pteridine (4) and 2-((4-(4-aminobenzamido)-4-carboxy butyl)

carbamoyl) benzoic acid (3) (Scheme-3A.3).

119

Talotrexin(1)

N

N N

NH2N

H2N

NH2CH2OH N

RO

H

(2)

(3)

NHO

COOH

R =COOH

N

N N

NN

H2N

NH2 NH

OR

H

CN

N

N

N NH2

NH2O

HO

H2N

NR

O

H

(4)

(3)

hvO2

hvRiboflavin (Rib)

Scheme-3A.1

120

Rib

Rib*1

Isc

Rib3 *

N

N N

NN

H2N

NH2 NH

OR

H

N

N N

NN

H2N

NH2 NH

O

HRib

N

N N

NN

H2N

NH2 NH

OR

H2O

N

N N

NH2N

H2N

NH2NH

OR

CHOoxidation

N

N N

N

H2N

NH2COOH

(1)

(2)

Rib= Riboflavin

-e/-H+

hv

R

(3)

Scheme-3A.2

121

N

N N

NN

H2N

NH2

N

N N

NN

H2N

NH2

N

N N

NH2N

H2N

NH2CH2OH

Intramolecular electron transfer

NH

O

N RO

NR

O

N

N N

NN

H2N

NH2 NR

O

*

H20hydrolysis

R

Talotrexin(1)

(4) (3)

H

H

H

H

H

H

hv

Scheme-3A.3

122

Photoproduct 2, 4-diamino-6-(hydroxymethyl) pteridine (DHP) exhibits a phototoxic

effect caused by oxidation of biomacromolecules through photoinduced electron

transfer 31.

In conclusion, the present results have shown that talotrexin is photolabile under both

aerobic and anaerobic condition with UV light. Under aerobic condition talotrexin

under goes photodegradation by photoinduced inter molecular electron transfer

mechanism and under anaerobic condition it photochemically transformed through

intra molecular electron transfer mechanism. Hence the study describes that electron

transfer may play a significant role in photosensitizing effects of talotrexin. The

observed photodegradation behavior of photosensitizing talotrexin under both aerobic

and anaerobic condition may be of relevance to the in vivo photobiological effect of

drug. On the basis of obtained results, it would seem advisable to avoid intense

exposure to artificial and natural UV light during therapy and in all stages of drug

development process, handling and storage.

123

Section [B]

Photoinduced Electron Transfer

Photodegradation of Phototoxic Diuretic

Drug Xipamide

124

[B]Photoinduced Electron Transfer Photodegradation of Phototoxic Diuretic

Drug Xipamide

Diuretics are among the most widely used clinical agents and their discovery was a

great success of both synthetic organic chemistry and pharmacology, 32 with most of

these agents being discovered in the late 50s and 60s. Right from the beginning of

research in this field, it was clear that many compounds incorporating SO2NH2 groups

showed great pharmacological activity 33. Diuretic agents are drugs that increase the

renal excretion of water and solutes (mainly sodium salts). The main purposes of

diuretic therapy are to decrease fluid volume of the body and to adjust the water and

electrolyte balance 34. Diuretics are drugs broadly used in clinical practice mainly in

the treatment of hypertension and in different kinds of edema 35. Diuretics may be

classified according to their chemical structure, mechanism, primary site of action in

the nephron and their diuretic potency in thaiazide and non thiazide 36. Non thiazide

diuretic drugs are widely used as antihypertensive agents in clinical treatment,37 but

these drugs are also well known to exhibit phototoxic, photomutagenic and

photocarcinogenic properties, often causing undesirable side effects when patients are

exposed to light, especially at UV-A wavelengths 38.

Xipamide (4-Chloro-5-sulfamylsalicyloyl-2’, 6’-dimethylamilide, 5) is a potent non-

thiazide diuretic with a greater natriuretic effect than the thiazides and a less abrupt

onset and longer duration of action than furosemide 39,40. It is an effective

antihypertensive drug, appears to be a more effective diuretic than the thiazides and

may cause a lower potassium loss relative to sodium excretion than these drugs 41,42.

Xipamide (5) offers a suitable alternative to other diuretics in the treatment of patients

with mild to moderate hypertension and of patients with oedema due to a variety of

125

causes 43,44. It belongs to the group of diuretics, which have been considered as doping

substances since 1986 45. In recent years, diuretics have been abused in sport to reduce

body weight in order to qualify for a lower weight class and to manipulate urine to

avoid a positive result in doping tests 46. The most frequently reported side effects of

xipamide (5) include mild upper gastrointestinal symptoms, anorexia or nausea, and

tiredness and fatigue 47. Dizziness (often postural) and vertigo have also occurred

infrequently and were probably related to the extent of reduction in blood pressure.

Xipamide (5), like the thiazide and 'loop' diuretics, causes net potassium loss, but this

has varied according to the country of investigation 48. There have been occasional

reports of considerable decreases in serum potassium to concentrations as low as 2.2

mmol/L and of symptomatic hypokalaemia 49. As might be expected, xipamide (5) has

caused small increases in average blood urea and serum urate concentrations in some

studies, and occasional increases in blood glucose and of plasma lipids in diabetic

patients 50. Despite their excellent therapeutic activity xipamide (5) induces

phototoxicity as a significant side effect 51,52. Herein we present an overview of the

photochemical properties of xipamide. Evidence about the fragmentation modes and

the intermediates occurring is discussed. A rationalization of the photoreactivity of the

drug molecules is an important step in the understanding of the photodegradative

paths occurring in biological environments and in the correlation between structural

characteristics and phototoxicity. In the present study we have elucidate the

photochemical behaviour of the phototoxic diuretic drug xipamide (5) under

anaerobic conditions in presence of both electron donor and acceptor in UV-A light.

Photolysis of xipamide (XIP, 5) resulted in the formation of two major

photodegradation products, identified as (6) and (7) from their spectral (IR, 1H-NMR,

126

13C-NMR, Mass spectra) properties. Photoproducts are presumably produced by

photoinduced intermolecular electron transfer mechanism.

Experimental

Chemicals

All chemicals used were of analytical grade. Pure xipamide was obtained from Taj

Pharmaceuticals Ltd. India.N, N-dimethylaniline (DMA) and 1, 4-dicyanonaphthalene

(DCN) were purchased from Sigma Aldrich (India).

Apparatus

Photochemical reactions were carried out in quartz fitted immersion well

photochemical reactor equipped with 400W medium pressure mercury vapour lamp

with continuous supply of water. IR spectra were recorded in KBr discs on a Perkin

Elmer model spectrum RXI. 1H-NM R and 13C-NM R Spectra were recorded on a

Bruker Avance-DRX-300 Spectrometer using SiMe4 as internal standard and CD3OD

as solvent. High resolution mass spectra were determined with a VG-ZAB-BEQ9

spectrometer at 70 e V ionization voltage. Column chromatography was performed on

silica gel 60 (70-230 mesh); TLC was carried on Merck silica gel 60 F 254 (0.2 mm

thick plates).

General Photoirradiation procedure

A solution of xipamide (XIP, 5) in methanol was stirred for 1 h before irradiation and

was kept bubbling during the irradiations. The course of reaction was monitored by

thin layer chromatography on pre-coated silica gel TLC plates using chloroform-

acetone (9:1) mixture. After the completion of reaction (when desired conversions

have reached) the solvent was removed in a rotary evaporator and products were

purified by silica gel column chromatography.

127

Irradiation of xipamide in presence of electron donor

Methanolic solution of xipamide (XIP, 5) (295, 0.8 mM) in presence of electron

donor, N, N- Dimethylaniline (DMA) 53 was irradiated for 5 h. After following the

steps described in general photoirradiation procedure, 2-choloro-5-((2, 6-

dimethylphenyl) carbamoyl)-4-hydroxy benzene sulfonic acid (6) was obtained as a

major photoproduct which exhibited the following spectral properties.

2-choloro-5-((2, 6-dimethylphenyl)carbamoyl)-4-hydroxy benzene sulfonic acid (6):

Yield: 105 mg (35.59%); HRMS calcd. For (M+) C15H14ClNO5S 355.7934 Found

355.7930; IR (KBr) 3592, 3294, 3100, 1715, 1601, 1345 cm-1; 1H-NMR (CD3OD, ,

ppm): 8.36 ( s,1H, H-6), 8.0 (s, 1H, NH), 7.19 ( s, 1H, H-3), 6.83 ( d, 2H, H-3 & H-5

of phenyl), 6.74 (m, 1H, H-4 of phenyl), 4.9 (s, 1H, OH), 2.34 (d, 6H, 2 CH3 of

phenyl); 13C-NMR (CD3OD, , ppm): 163.9, 136.9, 136.4, 134.5, 133.9, 126.2, 124.1,

119.1, 118.0, 15.3; MS:m/z: 355 (M+), 338 (M+-17), 320 (M+-35).

Irradiation of xipamide in presence of electron acceptor

Methanolic solution of xipamide (XIP, 5) (295, 0.8 mM) in presence of electron

acceptor, 1, 4-dicyanonaphthalene (DCN), 54 was irradiated for 4 h at 254 nm. After

following the steps described in general photoirradiation procedure, 4-hydroxy-N-(2,

6-dimethylphenyl)-2-hydroxy-5- sulfamoylbenzamide (7) was obtained as a major

photoproduct which exhibited the following spectral properties.

128

4-hydroxy-N-(2, 6-dimethylphenyl)-2-hydroxy-5-sulfamoylbenzamide (7):

Yield: 110 mg (37.2%) HRMScalcd. For (M+) C15H16N2O5S 336.3629 Found

336.3625;IR (KBr): 3592, 3310, 3294, 3100, 1715, 1601, 1345 cm-1; 1H-NMR

(CD3OD, , ppm): 8.26 (s, 1H, H-6), 8.0 ( s, 1H, NH), 6.84 (d, 2H, H-3 & H-5 of

phenyl), 6.74 (m, 1H, H-4 of phenyl), 6.64 (s, 1H, H-3), 4.98 (s, 2H, 2OH), 2.35 (d,

6H, 2CH3), 2.0 (s, 2H, NH2); 13C-NMR (CD3OD, , ppm): 164.5, 163.9, 156.8, 134.4,

134.1, 126.2, 124.1, 123.1, 114.0, 112.5, 103.9, 15.3; MS:m/z: 336 (M+), 319 (M+-

17).

Results and discussion When methanolic solution of xipamide (XIP,5) was irradiated with medium pressure

mercury vapour lamp in an immersion well type photo reactor in presence of DMA,

2-choloro-5-((2,6-dimethylphenyl)carbamoyl)-4-hydroxy benzene sulfonic acid (6)

was obtained as a major photoproduct. When irradiation was carried out in presence

of DCN, 4-hydroxy-N-(2, 6-dimethylphenyl)-2-hydroxy-5- sulfamoylbenzamide (7)

was obtained as a major photoproduct (Scheme-3B.1). The photoproducts were

isolated and identified from their spectral (IR, 1H-NMR, 13C-NMR, and Mass spectra)

properties. The assigned structures to these products well correspond to their observed

spectral properties. The formation of photoproducts have been rationalized through

photoinduced intermolecular electron transfer mechanism as given in scheme 3B.2

and 3B.3

When xipamide (XIP, 5) was irradiated in presence electron donor N, N-dimethyl

aniline (DMA), XIP reaches in excited state and in excited state it accept an electron

from N,N-dimethyl aniline to form XIP radical anion (XIP . _ ) and DMA radical

cation (DMA +. ) and in subsequent step XIP radical anion (XIP . _ ) on hydrolysis

129

yield photoproduct (6) by loosing ammonia (Scheme-3B.2). Similarly when the XIP

was irradiated in presence of electron acceptor (1,4-dicyanonaphthalene), XIP reaches

in excited state and in excited state XIP donate an electron to 1,4-dicyanonaphthalene

(DCN) to form XIP radical cation (XIP .+ ) and DCN radical anion (DCN . _ ) and in

next step XIP radical cation (XIP .+ ) on hydrolysis yield photoproduct (7) by the

substitution of chlorine by hydroxyl group and by back electron transfer (Scheme-

3B.3).

130

Cl OH

SHN

O

H2NO O

(XIP,5)

hv hvDMA(electron doner) DCN

(electron acceptor)

Cl OH

SHN

O

HOO O

(6)

HO OH

SHN

O

H2NO O

(7)

Xipamide

DMA =

NH3C CH3

N,N-dimethyaniline = DCN =

CN

CN

1, 4-dicyanonaphthalene =

Scheme-3B.1

131

Cl OH

SHN

O

H2NO O

hv

electron transfer

Cl OH

SHN

O

H2N

O O

.DMA

H2O

Cl OH

SHN

O

HOO O NH3

(XIP,5)

(6)

Cl OH

SHN

O

H2NO O

*

DMA

Scheme-3B.2

132

Cl OH

SHN

O

H2NO O

+H2O

-HCl e

HO OH

SHN

O

H2NO O

(7)

DCN

Cl OH

SHN

O

H2NO O

hv

(XIP,5)

Cl OH

SHN

O

H2NO O

*

electron transfer DCN

Scheme- 3B.3

133

To conclude, the present results have shown that in presence of both electron acceptor

and donor drug undergo photodegradation and yield 2-choloro-5-((2, 6-

dimethylphenyl) carbamoyl)-4-hydroxybenzenesulfonic (6) and 4-hydroxy-N-(2, 6-

dimethylphenyl)-2-hydroxy-5- sulfamoylbenzamide (7) as the main photodegradation

products through photoinduced intermolecular electron transfer mechanism. From the

above study it is clearly indicate that during the fragmentation of xipamide (5) in

presence of both electron donor and acceptor radical ions are generated and it is a well

known fact that radical ion is responsible for phototoxicity 55. So the phototoxicity of

xipamide (5) may possible due to these radical ions; hence the present study may find

its significance in rationalizing the phototoxicity of the xipamide. Therefore, the

obtained data confirmed that adequate light protection should be adopted for the

handling and storage of xipamide and suggest that excessive sunlight should be

avoided after the drug consumption.

134

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