Original article Remarkable anti-breast cancer activity of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines Jagannath Jadhav a , Aarti Juvekar b , Rajanikant Kurane a , Sharanabasappa Khanapure a , Rajashri Salunkhe a , Gajanan Rashinkar a, * a Department of Chemistry, Shivaji University, Kolhapur 416004, M.S., India b Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, M.S., India article info Article history: Received 27 January 2013 Received in revised form 29 March 2013 Accepted 8 April 2013 Available online 28 April 2013 Keywords: Ferrrocene 1,4-Dihydropyrimidines Ferrocenyl chalcones Amidines Anti breast cancer activity abstract A novel series of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines is synthesized by base catalyzed cyclocondensation between ferrocenyl chalcones and amidines. The structures of synthesized compounds were established on the basis of 1 H NMR, 13 C NMR, FTIR spectroscopy as well as by mass spectrometry. The compounds were evaluated for in vitro anticancer activity. The most active compounds from the series displayed GI 50 value equal to doxorubicin against the strain of human breast cancer cell line MDA-MB-435. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction The advent of ferrocene through the serependitious discovery by Pauson and Kealy in 1951 has sparked off a significant inter- disciplinary research activity [1]. The unique structure with Fe þ2 ion sandwiched between two pentahapto cyclopentadienyl ligands and three dimensional aromatic system has made ferrocene a versatile scaffold for covalent functionalization. Owing to its unique geometry, tunable redox properties and the high reactivity, ferro- cenyl compounds find wide applications in diverse areas such as catalysis [2], materials science [3], analytical sensors [4], non linear optics [5], bio-organometallic and biological chemistry [6], organic synthesis [7] and in electrochemistry [8]. The relative stability of ferrocene in biological media and low levels of in vivo toxicity of its derivatives has spurred considerable interest in the development of ferrocene based compounds for cancer therapeutics. The inclusion of ferrocene in anticancer drug design strategies received a decisive impetus as Jaouen and co-workers [9] reported on ferrocenyl an- alogs of tamoxifen viz ferrocifen (1 , Fig. 1) and hydroxyferrocifen (2, Fig. 1). In vitro cytotoxicity assays have revealed that ferrocifen is more effective than tamoxifen against both estrogen-dependent and -independent breast cancer. These findings have stimulated enormous interest in design and synthesis of new lead structures based on ferrocenyl moiety in drug discovery programs aimed at the development of potential anticancer agents [10]. It is believed that ferrocene tagged organic frameworks can provide new impetus for building structures with unprecedented attributes to probe and modulate anticancer activities. The 1,4-dihydropyrimidine (1,4-DHPM) core is ubiquitous in both naturally occurring and synthetic biologically active molecules and many of its derivatives display interesting anti-viral, anti-tumor, anti- bacterial, and anti-inflammatory activities [11,12]. In addition, they are also regarded as calcium channel blockers [13], a-adrenergic an- tagonists as well as HIV gp-120-CD4 inhibitors [14]. Recently, two prototype members of 1,4-DHPM family viz Bay 41-4109 [methyl-4- (2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1, 4-dihdro pyrimidine-5-carboxylate] (3, Fig. 1) and Bay 39-5493 [methyl-4-(2-chloro-4-fluorophenyl)-2-(-2-thiazyl)-6-methyl-1,4-di hdro-pyrimidine-5-carboxylate] (4, Fig. 1) have displayed prominent anti-hepatitis B replication activity [15]. Moreover, 1,4-DHPM de- rivatives such as 5 and 6 (Fig. 1) have been proved as selective ROCK1 inhibitors. ROCK1 is a potential therapeutic target in the treatment of cardiovascular diseases [16]. The anticancer potential of 1,4-DHPMs has been explored recently [17]. These compounds owe their anti- cancer activity to their ability to inhibit human kinesin Eg5 activity. * Corresponding author. Tel.: þ91 231 260 9169; fax: þ91 231 2692333. E-mail addresses: [email protected], [email protected](G. Rashinkar). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.04.021 European Journal of Medicinal Chemistry 65 (2013) 232e239
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European Journal of Medicinal Chemistry 65 (2013) 232e239
Remarkable anti-breast cancer activity of ferrocene taggedmulti-functionalized 1,4-dihydropyrimidines
Jagannath Jadhav a, Aarti Juvekar b, Rajanikant Kurane a, Sharanabasappa Khanapure a,Rajashri Salunkhe a, Gajanan Rashinkar a,*aDepartment of Chemistry, Shivaji University, Kolhapur 416004, M.S., IndiabAdvanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, M.S., India
a r t i c l e i n f o
Article history:Received 27 January 2013Received in revised form29 March 2013Accepted 8 April 2013Available online 28 April 2013
Keywords:Ferrrocene1,4-DihydropyrimidinesFerrocenyl chalconesAmidinesAnti breast cancer activity
0223-5234/$ e see front matter � 2013 Elsevier Mashttp://dx.doi.org/10.1016/j.ejmech.2013.04.021
a b s t r a c t
A novel series of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines is synthesized by basecatalyzed cyclocondensation between ferrocenyl chalcones and amidines. The structures of synthesizedcompounds were established on the basis of 1H NMR, 13C NMR, FTIR spectroscopy as well as by massspectrometry. The compounds were evaluated for in vitro anticancer activity. The most active compoundsfrom the series displayed GI50 value equal to doxorubicin against the strain of human breast cancer cellline MDA-MB-435.
� 2013 Elsevier Masson SAS. All rights reserved.
1. Introduction
The advent of ferrocene through the serependitious discoveryby Pauson and Kealy in 1951 has sparked off a significant inter-disciplinary research activity [1]. The unique structure with Feþ2
ion sandwiched between two pentahapto cyclopentadienyl ligandsand three dimensional aromatic system has made ferrocene aversatile scaffold for covalent functionalization. Owing to its uniquegeometry, tunable redox properties and the high reactivity, ferro-cenyl compounds find wide applications in diverse areas such ascatalysis [2], materials science [3], analytical sensors [4], non linearoptics [5], bio-organometallic and biological chemistry [6], organicsynthesis [7] and in electrochemistry [8]. The relative stability offerrocene in biological media and low levels of in vivo toxicity of itsderivatives has spurred considerable interest in the development offerrocene based compounds for cancer therapeutics. The inclusionof ferrocene in anticancer drug design strategies received a decisiveimpetus as Jaouen and co-workers [9] reported on ferrocenyl an-alogs of tamoxifen viz ferrocifen (1, Fig. 1) and hydroxyferrocifen (2,Fig. 1). In vitro cytotoxicity assays have revealed that ferrocifen is
more effective than tamoxifen against both estrogen-dependentand -independent breast cancer. These findings have stimulatedenormous interest in design and synthesis of new lead structuresbased on ferrocenyl moiety in drug discovery programs aimed atthe development of potential anticancer agents [10]. It is believedthat ferrocene tagged organic frameworks can provide newimpetus for building structures with unprecedented attributes toprobe and modulate anticancer activities.
The 1,4-dihydropyrimidine (1,4-DHPM) core is ubiquitous in bothnaturally occurring and synthetic biologically active molecules andmanyof its derivatives display interesting anti-viral, anti-tumor, anti-bacterial, and anti-inflammatory activities [11,12]. In addition, theyare also regarded as calcium channel blockers [13], a-adrenergic an-tagonists as well as HIV gp-120-CD4 inhibitors [14]. Recently, twoprototype members of 1,4-DHPM family viz Bay 41-4109 [methyl-4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoro-2-pyridinyl)-6-methyl-1,4-dihdro pyrimidine-5-carboxylate] (3, Fig. 1) and Bay 39-5493[methyl-4-(2-chloro-4-fluorophenyl)-2-(-2-thiazyl)-6-methyl-1,4-dihdro-pyrimidine-5-carboxylate] (4, Fig. 1) have displayed prominentanti-hepatitis B replication activity [15]. Moreover, 1,4-DHPM de-rivatives such as 5 and 6 (Fig.1) have been proved as selective ROCK1inhibitors. ROCK1 is a potential therapeutic target in the treatment ofcardiovascular diseases [16]. The anticancer potential of 1,4-DHPMshas been explored recently [17]. These compounds owe their anti-cancer activity to their ability to inhibit human kinesin Eg5 activity.
Fig. 1. Pharmacologically important ferrocene and 1,4-DHPM based compounds.
J. Jadhav et al. / European Journal of Medicinal Chemistry 65 (2013) 232e239 233
Human Eg5 has been an interesting drug target for the developmentof cancer chemotherapeutics as it plays a vital role in mitosis byestablishing the bipolar spindle, the inhibition of which leads tomitotic arrest and cell death. Because of interesting biological prop-erties and several degrees of structural diversity, development ofnovel methods for synthesis of 1,4-DHPMs as well as new analogs isan intensively investigated field of utmost importance.
Based on these precedents, we sought to construct hybrid mo-lecular architectures by combining ferrocene and pyrimidinepharmocophores. We envisioned that resultant conjugates by vir-tue of the presence of critical structural features might serve as aprototype for new drugs that could be used in anticancer research.In continuation of research work related to applications of ferro-cene [18], we report herein synthesis and in vitro anti breast canceractivity of novel ferrocene tagged multi-functionalized 1,4-dihydropyrimidines.
R"N
R'
N
R
R"
NH
NH
R'Fe
Fe
O
R+
Scheme 1. Retrosynthetic analysis of ferrocene tagged multi-functionalized 1,4-DHPMs.
2. Results and discussion
The initially planned retrosynthesis of ferrocene tagged multi-functionalized 1,4-DHPMs is depicted in Scheme 1 and is based oncyclocondensation between chalcones and amidine. This conver-gent route was envisaged to be highly significant due to easyaccessibility of large number of structurally diverse ferrocenylchalconeswhich can be easily prepared by reacting acetyl ferrocenewith large variety of commercially available aryl aldehydes underbasic conditions [19]. In addition, we hypothesized that use ofsubstituted benzamidines that have already displayed promisingbiological activities [20] will offer a valuable addendum in biolog-ical profile.
To test the validity of our disconnection approach, a preliminarysurvey of reaction conditions was conducted using 1-ferrrocenyl-3-phenyl-2-propen-1-one (a prototype ferrocenyl chalcone) and N-o-tolylpicolinamidine (Table 1). Our initial studies focused on scrutiny
of bases required for cyclocondensation. A series of experimentswere conducted using various bases in different solvents. The use ofsodiummetal in isopropanolwas found to bemost efficient catalyticsystem as it afforded the desired 6-ferrocenyl-4-phenyl-2-pyridin-2-yl-1-o-tolyl-1,4-dihydropyrimidine in 80% yield within 3 h underreflux conditions (Table 1, entry 1). The use of inorganic bases suchas NaOH and KOH showed remarkably poor catalytic activity as thecorresponding productwas obtained in a scarce yield alongwith theformation of undesired tarry material after prolonged reaction time(Table 1, entries 2e5). On the other hand, the use of Na in ethanolfurnished the anticipated product in moderate yield (Table 1, entry5). Thus, use of sodium in IPAunder refluxconditionswas selected asoptimal reaction conditions for further studies.
After the optimization of reaction conditions, we evaluated thescope of the protocol by reacting structurally diverse ferrocenylchalcones with different amidines (Scheme 2). The results aresummarized in Table 2. In general, the corresponding ferrocenetagged multi-functionalized 1,4-DHPMs were obtained in good toexcellent yields in all the investigated cases. No significant elec-tronic effects were observed for the electron donating as well aselectron withdrawing substituents on phenyl ring in ferrocenylchalcones. It was interesting to observe that Na/IPA catalytic systemis tolerant to a halogen substitution on the phenyl ring thusproviding a handle for additional synthetic manipulation via crosscoupling chemistry.
a All products were characterized by IR, 1H and 13C NMR spectroscopy as well as by mass spectrometry.b Isolated yields after chromatography.
J. Jadhav et al. / European Journal of Medicinal Chemistry 65 (2013) 232e239234
The structures of all the ferrocene tagged multi-functionalized1,4-DHPMs were elucidated on the basis of 1H NMR and 13C NMRspectroscopy as well as by FTIR and mass spectrometry. The spec-tral data is in agreement with the proposed structures. All thesynthesized compounds are air and moisture stable for severalweeks without any decomposition and are soluble in normalorganic solvents.
The UVevis absorption spectra of all the synthesized com-pounds were measured in methanol (Fig. 2) and the optical char-acteristics are summarized in Table 3. The studies revealed that theabsorption peaks of ferrocene tagged multi-functionalized 1,4-DHPMs were different from precursor ferrocenyl chalcones as theformer display peaks in the range 270e318 nm due to pep* tran-sitions of the ferrocene chromophore while latter exhibit the samein the range 487e517 nm [21]. The hypsochromic shift observedmay be attributed to the disturbance in enone system of ferrocenylchalcones during the cyclo-condensation with amidines. In addi-tion, the less intensity absorption peaks in the region 450e550 nmwere also observed. These peaks may be assigned to the metal toligand charge transfer (MLCT) transitions from Fe to either anti-bonding or nonbonding orbitals of Cp rings.
A tentative mechanism for the formation of ferrocene taggedmulti-functionalized 1,4-DHPMs is depicted in Scheme 3. Thereaction is likely to proceed via sodium isopropoxide induced 1,4-nuclepohilic addition of amidine on ferrocenyl chalcone. Anintramolecular displacement leads to nucleophilic additionfurnishing cyclized intermediate. Under experimental reactionconditions, the cyclized intermediate loses water forming thefinal product.
NNH
NH
R'
O
R
Fe+
1 2
Scheme 2. Na/IPA catalyzed cyclocondensatio
All the synthesized ferrocene tagged multifunctionalized 1,4-DHPMs (3aej) were evaluated for their in vitro cytotoxicity in hu-man breast cancer cell line MDA-MB-435 by employing the sulfo-rhodamine B (SRB) assay method [22]. The results are described inTable 4. It is worthy of note that all the compounds except 3hejwere significantly cytotoxic against MDA-MB-435 compared to thestandard drug tested, i.e. Doxorubicin, with the concentration ofthe drug that produced 50% inhibition of cell growth (GI50) rangingfrom 17.4 to 152.9 mM.With regard to anticancer activity, 3b and 3cturned out to be the most attractive since they demonstrated thelowest GI50 values of 18 and 17.4 mM respectively in the cell lineexamined which was almost equal to the standard anticancer agentDoxorubicin (18.4 mM).
3. Conclusion
In summary, we have developed a reliable and generallyapplicable approach for the synthesis of a novel series of ferrocenetagged multi-functionalized 1,4-DHPMs from easily accessibleferrocenyl chalcones and amidines. The structures of all thecompounds were established on the basis of analytical and spec-tral data. The synthesized compounds were evaluated for theirin vitro anticancer activities against the strain of human breastcancer cell line MDA-MB-435. The compounds 3b and 3c with aGI50 values 18 and 17.4 mM respectively were found to be the mostactive. We believe that reported protocol offers scope for exten-sion to variety of other substrates to form products that mightserve as an interesting alternative in endemic area of anticancerresearch.
N
NN
R
R'
Fe
Na Metal
IPA, 80-90 OC
3
n of ferrocenyl chalcones with amidines.
Table 2Synthesis of ferrocene tagged multi-functionalized 1,4-DHPMs.a
a All products were characterized by IR, 1H and 13C NMR spectroscopy as well as by mass spectrometry.b Isolated yields after chromatography.
J. Jadhav et al. / European Journal of Medicinal Chemistry 65 (2013) 232e239236
4. Experimental part
4.1. General
1H NMR and 13C NMR spectra were recorded on a Brucker AC(300MHz for 1H NMR and 75MHz for 13C NMR) spectrometer usingCDCl3 as solvent and tetramethylsilane (TMS) as an internal stan-dard. Infrared spectra were recorded on a PerkineElmer FTIRspectrometer. The samples were examined as KBr discsw5% w/w.Mass spectra were recorded on a Perkin Elmer Flexar SQ 300 LCMS.Elemental analyses were performed on EURO EA3000 vectromodel. Melting points were determined on MEL-TEMP capillarymelting point apparatus and are uncorrected. Precoated aluminumsheets (silicagel 60 F254, Merck Germany) were used for thin-layerchromatography (TLC) and spots were visualized under UV light. Allthe ferrocenyl chalcones [19] and benzamidines [20] were
synthesized following the literature procedure. All other chemicalwere obtained from local chemical; suppliers and were usedwithout further purification.
4.2. General procedure for the synthesis of ferrocene tagged multi-functionalized 1,4-dihydropyrimidines (3aej)
A mixture of sodium metal (69 mg, 3 mmol) in isopropanol(25 ml) was refluxed for 30 min. Amidine (1 mmol) and ferrocenylchalcone (1 mmol) were sequentially charged into reaction flask atintervals of 30 min. The reaction mixture was heated under refluxconditions for 3e5 h. After completion of the reaction as monitoredby thin layer chromatography (TLC), the reaction mixture waspoured into ice-water and extracted with ethyl acetate (3 � 25 ml).The combined organic layers were washed with brine, dried overanhydrous Na2SO4 and concentrated under reduced pressure to
N
NN
R
R'
Fe
N
NN
R
OH
H
R'
Fe
NNH
NH
R'
O
N
NN
R
R'
Fe
O
R
Fe
+NaOPr
H..Na + IPA
..
-H2O
Scheme 3. Proposed mechanism of Na/IPA catalyzed cyclocondensation of ferrocenylchalcones with benzamidines.
Table 4In vitro cytotoxicities of ferrocene tagged multi-functionalized 1,4-DHPMs againsthuman breast cancer cell line MDA-MB-435.a
Compound LC50b TGIc GI50d
3a >157.1 138.8 63.2
-0.5
0
0.5
1
1.5
2
2.5
3
3.5
220 320 420 520 620
Ab
so
rb
an
ce
Wavelength
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
Fig. 2. UVevis absorption spectra of 1,4 DHPMs in methanol.
J. Jadhav et al. / European Journal of Medicinal Chemistry 65 (2013) 232e239 237
give crude residue which was purified by column chromatographyover silica gel using hexane/ethyl acetate (4:1 v/v) to afford thepure compound.
Tumor cells (human breast cancer cell line MDA-MB-435) weregrown in tissue culture flasks in growth medium (RPMI-1640 with2 mM glutamine, pH 7.4, 10% fetal calf serum, 100 mg/mL strepto-mycin, and 100 units/mL penicillin) at 37 �C under the atmosphereof 5% CO2 and 95% relative humidity employing a CO2 incubator.The cells at subconfluent stage were harvested from the flask bytreatment with trypsin (0.05% trypsin in PBS containing 0.02%EDTA) and placed in growth medium. The cells with more than97% viability (trypan blue exclusion) were used for cytotoxicitystudies. An aliquot of 100 mL of cells were transferred to a well of96-well tissue culture plate. The cells were allowed to grow for oneday at 37 �C in a CO2 incubator as mentioned above. The testmaterials at different concentrations were then added to the wellsand cells were further allowed to grow for another 48 h. Suitableblanks and positive controls were also included. Each test wasperformed in triplicate. The cell growth was stopped by gentlylayering of 50 mL of 50% trichloroacetic acid. The plates wereincubated at 4 �C for an hour to fix the cells attached to the bottomof the wells. Liquids of all the wells were gently pipette out anddiscarded. The plates were washed five times with doubly distilledwater to remove TCA, growth medium, etc and were air-dried.100 mL of SRB solution (0.4% in 1% acetic acid) was added toeach well and the plates were incubated at ambient temperature
J. Jadhav et al. / European Journal of Medicinal Chemistry 65 (2013) 232e239 239
for half an hour. The unbound SRB was quickly removed bywashing the wells five times with 1% acetic acid. Plates were airdried, tris-buffer (100 mL of 0.01 M, pH 10.4) was added to all thewells and plates were gently stirred for 5 min on a mechanicalstirrer. The optical density was measured on ELISA reader at540 nm. The cell growth at absence of any test material wasconsidered 100% and in turn growth inhibition was calculated. GI50values were determined by regression analysis.
Acknowledgments
Authors are thankful to ACTREC, TATA Memorial Centre forAnticancer Screening and IISC, Bangalore for spectral analysis.
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