Kamal 2013

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1. Introduction

2. Imidazothiazole derivatives

3. Chalcone derivatives

4. Imidazothiazole--chalcone

conjugates

5. Expert opinion

Review

The design and developmentof imidazothiazole--chalconederivatives as potential

anticancer drugsAhmed Kamal, Methuku Kashi Reddy & Arutla ViswanathCSIR-- Indian Institute of Chemical Technology, Division of Organic Chemistry,

Hyderabad, India

Introduction: Imidazothiazole derivatives have long been therapeutically

used for the treatment of various diseases. In recent years, the imidazothia-

zole and chalcone moieties have emerged as important pharmacophores in

the development of antitumor agents. Imidazothiazole--chalcone conjugates

can be accessed by covalently binding these two powerful pharamacophore

units. These conjugates are known to exhibit a wide range of biological

properties, including anticancer, antimicrobial, anti-inflammatory andimmunosuppressive activities. Their promising biological profile and easy syn-

thetic accessibility have triggered investigations directed at the design and

development of new imidazothiazole--chalcone conjugate derivatives as

potential chemotherapeutics.

Areas covered:The present review focuses on recent reports of the syntheses

and anticancer properties of various imidazothiazoles, chalcones and

imidazothiazole-linked chalcone conjugates. Furthermore, the authors discuss

the structure--activity relationships (SAR) of imidazothiazoles and chalcones

and their conjugates as new antitumor agents, as well as in vitro and in vivo

evaluation, clinical use and their future therapeutic applications.

Expert opinion: A large number of imidazothiazoles, chalcones and a new

series of imidazothiazole--chalcone conjugates possess potent anticancer activ-

ity that could be further developed as drug candidates. Imidazothiazole-based

conjugates could also display synergistic effect, and still there is a need to use

the drug combinations permitting lower dose and development of new

generation of drugs. Despite encouraging observed results for their response

to tumors in clinical studies, full characterization of their toxicity is further

required for their clinical usage as safe drugs for the treatment of cancer.

Keywords:anticancer activity, chalcones and imidazothiazole--chalcone conjugates and

chemotherapeutic agents, imidazothiazoles

Expert Opin. Drug Discov. (2013) 8(3):289-304

1. Introduction

Despite decades of continual effort, cancer is a leading cause of death worldwide,claiming more than 20% of affected patients annually[1]. TheRoll Back Cancerini-tiative, recently established by WHO, aims to combat the disease through effectiveglobal partnership and cooperation. It is estimated that there will be more than13 million deaths caused by cancer around the world in 2030 [2]. The past centuryhas demonstrated that cancer can be effectively treated with surgery, chemotherapyand radiotherapy. These treatment strategies, when used either alone or in combina-tion, can significantly impact tumor growth and even produce cures. For many solidtumors, as in colon cancer, improved methods for early diagnosis and combination

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therapies have had an important impact on survival rate.However, once the tumor has metastasized, treatmentbecomes more complicated. Even in such cases, current treat-ment strategies can relegate cancer to more of a chronic dis-ease. Still, significant challenges remain for specific cancer

types, such as glioblastoma, in which a combination of earlydetection, surgery, chemotherapy and radiotherapy cannotextend the survival for more than couple of years [3].

Currently, combination chemotherapy with drugs ofdifferent mechanisms of action is one of the methods that isadopted to treat cancer. Alternatively, a single drug which

incorporates two pharmacophores with different modes ofaction may be employed for treatment. In recent years therehas been growing interest in the design of ligands that couldact in a specific manner on more than one target. The devel-opment of such hybrid molecules not only lowers the risk ofdrug--drug interaction in comparison to cocktails but alsocould enhance the efficacy as well as improve the safety aspectsin relation to the drugs that interact on a single target [4-6]andone such example is of bleomycin [7].

2. Imidazothiazole derivatives

The chemistry as well as the biological activity of imidazo

[2,1-b]thiazoles and their derivatives has recently attractedconsiderable attention. The imidazo[2,1-b]thiazole systemconstitutes the core unit of the well-known antihelminthicand immunomodulatory agent levamisole which is 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole [8]. Levamisole(marketed as the hydrochloride salt under the trade nameErgamisol) is an antihelminthic and immunomodulatorbelonging to a class of synthetic imidazothiazole derivatives,discovered at Janssen Pharmaceutica in 1966. Levamisole hasbeen used in humans to treat parasitic worm infections andhas been studied in combination with other forms ofchemotherapy for colon cancer, melanoma and head andneck cancer [9,10].

Andreani et al. studied a series of imidazo[2,1-b]thiazoleand benzimidazo[2,1-b]thiazole guanyl hydrazones that areactive against various cancer cell lines. Besides, imidazo[2,1-b]thiazoles are well-known compounds and many deriv-atives of this fused ring system have been evaluated for poten-tial biological activity. The 6-substituted imidazothiazole andbenzimidazothiazole guanylhydrazones (1) have been reportedto exhibit an antiproliferative effect on the cell cycle, apoptosisand mitochondria [11]. Moreover, 3-(5-imidazo[2,1-b]thiazo-lylmethylene)-2-indolinones (2) are potent antitumor agentsand their ability to inhibit cellular proliferation was mediatedby cell cycle arrest at the G2/M phase, accompanied by inhi-

bition of ornithine decarboxylase (ODC), the limitingenzyme of polyamine synthesis, and followed by inductionof apoptosis [12]. The effect of the guanyl hydrazoneof 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]-thiazole-5-carbaldehyde (3) was investigated, and it was foundto be an inhibitor of Complex III of the mitochondrial respi-ratory chain and could induce apoptosis in the cell linesHT29 and HL60 [13]. Later the same group reported a seriesof imidazothiazole guanylhydrazones by varying the substitu-tions on the thiazole ring of the imidazothiazole skeleton. Theantiproliferative effect of compound 4 was associated with a

Article highlights.

. The advantage of conjugates/hybrids derived from twoor more pharmacophore moieties over conventionalapproaches in cancer chemotherapy are highlighted. Therecent reports on imidazothiazoles, chalcones and

imidazothiazole--

chalcone conjugates as potentialanticancer agents are described.

. Imidazothiazoles are well-known compounds and manyderivatives of this fused ring system have beenevaluated for potential biological activity particularly forantitumor activity. Moreover, structurally modifiedimidazothiazole scaffold is an important core unit ofwell-known antihelminthic andimmunomodulatory agents.

. Chalcone constitute an important building block for alarge number of clinical drugs that possess a variety ofbiological activities, including anticancer, anti-inflammatory, immunomodulatory and antibacterialactivities. In addition they also exhibit antiprotozoan,trypanocidal, leishmanicidal, antimalarial activities and

modulation of P-gp-mediated multidrug resistance.Chalcone-based analogues are the most effectivecompounds exhibiting tubulin-binding activity in humanbreast, ovarian and gastric cancer HGC-27 cell lines andalso show considerable antiproliferative effects.

. Biaryl-based chalcones synthesized by sequentialKnoevenagel reaction and microwave-assisted Suzukicoupling showed good anticancer and NF-kB nucleartranslocation inhibition activities. Anticancer activities ofchalcone-based compounds may be a result of itsinhibitory activities against the NF-kB signaling pathways.

. It focuses on the structural modifications of theimidazothiazoles and chalcones, including the designand synthesis of imidazothiazole--chalcone conjugates asantitumor agents. SAR of imidazothiazoles, chalconesand their conjugates their in vitroand in vivo screening

results and their future therapeutic applicationsare discussed.

. Imidazothiazole--chalcone conjugates were accessible viaClaisen--Schmidt condensation of appropriatelysubstituted acetophenones by treatment withimidazothiazole aldehydes in basic media. All theconjugates showed significant anticancer activity andG0/G1-phase cell cycle arrest, downregulation ofG1-phase cell cycle regulatory proteins, such as cyclin D1and cyclin E1, and upregulation of CDK4. Moreover,these compounds elicit the characteristic features ofapoptosis such as enhancement in the levels of p53,p21 and p27, suppression of NF-kB and upregulationof caspase-9.

. Future applications and scope of such imidazothiazoles,

chalcones and imidazothiazole--

chalcone conjugatestoward the treatment and prevention of cancer arebrought out.

This box summarizes key points contained in the article.

A. Kamal et al.

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block in cell cycle progression, with accumulation of cells inthe G2/M phase and with a marked reduction in the mito-chondrial transmembrane potential DYm and a decrease inthe intracellular ATP content [14]. However, the most activecompound (5) of this series follows a different mechanismwhich is not known. A series of 6-nitrophenyl-substituted

imidazothiazole guanylhydrazone derivatives have also beenexamined for the anticancer activity. Compounds 6, 7 and 8exhibited significant antitumor activity; however, compound8showed cytotoxicity by acting as a CDK-1 inhibitor [10].

Among the synthesized compounds 9, 10 and 11 have alsoshowed significant growth inhibition against a broad rangeof cancer cell lines and the cytotoxicity of these compoundsis associated with early damage to mitochondria (Figure 1).

Recently a new series of substituted 3-(5-imidazo[2,1-b]-thiazolylmethylene)-2-indolinones have been reported as anti-cancer agents. Among these, compounds12,13and14exhibitgrowth inhibition in submicromolar range [15]. Mechanisticstudies of these compounds revealed that the tubulin effects

were relatively modest and the apoptosis in the HT-29 cellswas accompanied by caspase activation and phosphatidylserineexternalization. Interestingly, the most potent compounds 15and 16 strongly inhibited the activation of the kinase Aktand also exhibited prominent anticancer activity. Furthermechanistic studies in colon adenocarcinoma (HT-29) cellline revealed that these compounds are capable of blockingcells in M phase without interfering with microtubuledynamics (Figure 2) [16,17].

Buttar et al. [18] examined a series of imidazole--vinyl--pyrimidine derivatives as anticancer agents. Inphospho-Tie-2 cell-based ELISA assay, compounds 17and 18 exhibited IC50 of 2.9 and 0.33 M, respectively.Compound17 showed reasonable selectivity in a large panelof kinase assays, only inhibiting three other enzymes with anIC50 of < 10 M (p38, 1.6 M; Flt-4, 5.5 M; KDR,7.0 M). In contrast to Tie-2, this compound (17) was inac-tive in vascular endothelial growth factor receptors (VEGFr)and p38 cellular assays and showed better oral exposure in amouse cassette dosing experiment (Cmax= 0.29 M followinga 1 mg/kg dose). Parket al. demonstrated the synthesis andanticancer activity of a series of imidazo[2,1-b]thiazole deriv-atives. Theirin vitroantiproliferative activities against A375Phuman melanoma cell line and NCI-60 cell line panel weretested. Compounds 19, 20 and 21 showed superior activity

than sorafenib against A375P cell line [19]. Among them,compounds20 and 21 exhibited selectivity toward melanomacell lines than for other cancer types (Figure 3).

Recently, a series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (22a -- h) [20] have been synthesized byC-arylation of 2-arylimidazo-[2,1-b]benzothiazoles usingpalladium acetate as catalyst in this laboratory, and the result-ing compounds were evaluated for their anticancer activity.Compounds22a,22eand22h exhibited good antiproliferativeactivity, with GI50 values in the range of 0.19 -- 83.1 M.Compound 22h showed potent anticancer efficacy against

60 human cancer cell lines, with a mean GI50 value of0.88 M. This compound also induced cell cycle arrest inthe G2/M phase and inhibited tubulin polymerizationfollowed by activation of caspase-3 and apoptosis. A high-throughput tubulin polymerization assay showed that thelevel of inhibition for compound 22h is similar to that of

combretastatin A-4 (CA-4). Molecular modeling studies alsosupported a favorable binding of compounds 22a, 22eand22hto the colchicine-binding pocket of tubulin (Figure 4).

3. Chalcone derivatives

Chalcone scaffolds, such as 1,3-diaryl-2-propen-1-ones, areprominent secondary metabolite precursors of flavonoidsand isoflavonoids in plants [21]. Structurally, they may be con-sidered as open-chain flavonoids in which the two aromaticrings are joined by a three-carbon a,b-unsaturated carbonylsystem. Chalcones (23) are easily synthesized by the (E)-selectivecondensation reaction of acetophenones with substituted

benzaldehydes. They display a broad spectrum of pharmaco-logical effects that include anticancer [22-26], anti-inflamma-tory [27,28], immunomodulatory [29,30]and antibacterial [31,32]activities; in addition they also exhibit antiprotozoan [33],trypanocidal [34], leishmanicidal [35], antimalarial [36,37]activities and modulation of P-glycoprotein (P-gp)-mediatedmultidrug resistance [38]. Many chalcone-based compoundshave shown promising anticancer therapeutic efficacy for themanagement of human cancers. Different research groupshave synthesized various chalcone derivatives and screenedthem for their in vitro anticancer activity against a numberof cancer cell lines. Changes in their structure have offered ahigh degree of diversity that has proven useful for the develop-ment of new medicinal agents having improved potency andlesser toxicity.

Introduction of various substituents into the two arylrings is also a subject of interest because it provides usefulstructure--activity relationship (SAR) conclusions that helpin preparing pharmacologically active chalcones. Many suchsubstituted chalcones have shown potent anticancer activities.Lawrenceet al.and Duckiet al.have reported the synthesis oftrimethoxy-substituted chalcones [39,40]24and25, that possesspotent anticancer activity and bind strongly to tubulin at a siteshared with, or close to, the colchicine-binding site [41,42]. Theanticancer activity and tubulin binding property of these chal-

cones is comparable with CA-4. The IC50value of compoundSD400 (3) against the K562 human chronic myelogenousleukemia cell line is 0.21 nM, whereas CA-4 shows the IC50to be 2.0 nM. Compound 24 inhibits cell growth at low con-centrations (IC50, P388 murine leukemia cell line 2.6 nM)and shares many structural features common to othertubulin-binding agents [43]. Interestinglya-methyl chalcone(25) is more cytotoxic than compound 24, which bears ahydrogen atom at the same site [44]. Presently, phosphateprodrugs of compounds 24 and 25 are under preclinicalevaluation as shown in Figure 5.

Design and development of imidazothiazole--chalcone derivatives as potential anticancer drugs

Expert Opin. Drug Discov. (2013) 8(3) 291

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The anticancer activity of chalcones is believed to be aresult of their binding to tubulin and preventing it frompolymerizing into microtubules. Tubulin is a protein thatexists as a heterodimer of two homologousa- andb-subunits.

Many molecules based on a chalcone scaffold have been syn-thesized to improve their biological profile, including theircapability as sequence selective DNA interactive and cross-linking agents. However, trihydroxychalcone (26) represents

1 32 4

5 76

9 1110

8

N

N

HN

N

N

HN

S

OCH3

NO2Cl

H3CO

N

NS

H

N

OCH3

H3CO

O

N

N

N

HN

S

NH2

OCH3

OCH3

NH

N

N

N

HN

S

NH2

NO2

Cl

H3CCH

3

NH

N

NN

N

HN

S

NO2

NH2

ClH3C

NH

N

N

N

HN

S

NO2

NH2

Cl

NH

N

N

N

HN

S

NH2

NO2

O2N

NH

N

N

N

HN

S

NH2

NO2

NHN

N

N

HN

S

NH2

NO2

Cl

NH

N

N

NS

HN

NH2

OCH3

NO2

Cl

H3CO

NH

N

N

N NS

HN

NH2

H3C

H3C

NH

Figure 1. Recent advances on structural modifications of imidazothiazoles and their derivatives.

12

15 16

13 14

H

NO

N

NS

CH3H3C

H3CO

H

N O

N

N NS

H3CO

OCH3

H

NO

N

NS

H

N O

N

NS

CH3H3C

Cl

H

NO

HO

N

NS

CH3

H3C

Figure 2. Chemical structures of antitumor imidazothiazole derivatives.

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a new class of tyrosinase inhibitors [45]. Some of the naturalchalcones are found in a variety of plant sources. These natu-ral compounds have served as valuable leads for further designand synthesis of more active analogues. Further, a variety oftrimethoxy acetophenone-derived chalcones (27 -- 30) havebeen synthesized by different groups and evaluated for theircytotoxicity[46-49]. These compounds show promising activityagainst different cancer cell lines (Figure 6).

Natural and synthetic chalcones have shown to possessstrong antiproliferative effects in both primary and establishedovarian cancer cells[50]and in gastric cancer HGC-27 cells[51].The majority of the naturally occurring chalcones containeither hydroxyl (-OH) or methoxy (-OCH3) substituents inboth the aromatic rings [52]. Naturally occurring licochalcone

A (31), a chalcone derivative found in the licorice root, hasbeen associated with a wide variety of anticancer effects.Recent studies have shown that these chalcones induce apo-ptosis in a variety of cell types, including breast cancers [53,54].

Xanthohumol (32) is the most abundant prenylated chalcone

in hop cones (Humulus lupulusL) and exhibits an interestingspectrum of pharmacological effects. Besides its remarkableantiproliferative activity against different cancer cell lines [55],xanthohumol also exhibits apoptotic [56] activity as well aschemopreventive effects [57,58]. Furthermore, several in vitrostudies substantiated effects on enzymes and transcription fac-tors that are involved in the genesis of cancer [59,60]. Isoliquir-itigenin (33) demonstrated significant chemopreventiveactivities against lung, breast, prostate and colorectal can-cers [61]. Flavokawain A (34) suppresses bladder tumor growthat a dose of 50 mg/kg of body weight in a mouse xenograftmodel (Figure 7) [44].

Kumaret al. [62]have synthesized and reported indolyl chal-cones (35) that are very potent and selective anticancer agentswith IC50values 0.03 and 0.09 M, against PaCa-2 cell line.Lawrence et al. [63] reported a new chalcone derivative (36)which possesses good anticancer activity (Figure 8).

Curcumin, a polyphenolic natural compound (37) derivedfrom dietary spice turmeric, possesses diverse pharmacologicaleffects, including anticancer, anti-inflammatory, antioxidantand antiangiogenic activities [64,65]. A series of chalconedimers has been reported as potent inhibitors of variouscancer cells at very low concentrations. Compound 3,5-bis(2-fluorobenzylidene)-4-piperidone (38, also known asEF24) is the first synthetic analog of curcumin [66]. Other

analogues, 3,5-bis(benzylidene)-4-piperidones (39, alsoknown as CLEFMA and compound 40) [67] have beenadvanced as synthetic analogs of curcumin with anticancerand anti-inflammatory properties (Figure 9).

The cyclic chalcone analogues, E-2-arylmethylene-1-inda-nones, E-2-arylmethylene-1-tetralones and E-2-arylmethy-lene-1-benzosuberones have been synthesized and theircytotoxicities determined against different cancer cell lines.

Among these cyclic chalcones, compounds 41a, 41b, 42aand 42b have shown potential anticancer activity againsthuman cancer cell lines. These compounds inhibit RNA and

17

20 21

18 19

N

N

N

NS

NH2N

N

N

NS

NH2

O

NH

HN

N

N

N

N

S

HO

O

NH

HN

N

N

N

N

S

OH

HO

O

N

N

NHN

NH

HN

N

S

CF3

H3CO

Figure 3. Structures of imidazothiazole conjugates.

SN

N

R

H3CO

22 a h

22a R = 4-hydroxy-3-methoxy benzyl22b R = 2,4-dimethoxy benzyl22c R = 2,6-dimethoxy benzyl22d R = 3,4,5-trimethoxy benzyl22e R = 3 thiophenyl22f R = 3 pyridinyl22g R = 3 pyrazinyl22h R = 3 naphthyl

Figure 4. Biologically active 3-substituted-2-phenylimidazo

[2,1-b]benzothiazoles.



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protein syntheses and induced apoptosis which are likelymajor mechanisms whereby cytotoxicity is mediated [68].The active compound 41b in these cyclic chalcones affectsthe mitochondrial function as well as causes mitochondrialDNA damage. Compound 42b also shows good activity intargeting Alzheimers disease by inhibition of AChE-induced

Ab aggregation (Figure 10) [69].Valdameri et al. [38] have synthesized a series of chalcone

derivatives (43 -- 46) that play a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent

O

A B

23 Basic chalcone scaffold 25 SD40024

O

A B

H3CO

H3CO

OCH3

OCH3

OH

O

A

B

H3CO

H3CO

OCH3

OCH3

OH

Figure 5. Structures of potential anticancer chalcones.

27 2826

HO

OCH3OH

OH

O

H3CO

H3CO

OCH3

OH

O

H3CO

H3CO NO2

OCH3

O

3029

H3CO

H3CO

OCH3

OCH3

B(OH)2

OH3CO

H3CO

OCH3

OCH3

O

Figure 6. Some chemical structures of trimethoxy acetophenone-derived chalcones.

O

OHOHHO

O

OHHO H3CO

O

OHHO OCH3

OOH

H3CO OCH3OCH3

31 Licochalcone A

33 Isoliquiritigenin 34 Flavokawain A

32 Xanthohumol

Figure 7. Chemical structures of naturally occurring chalcones with apoptosis-inducing ability.

O

N

OCH3

OCH3

O

OCH3

OCH3

OCH3

NH

36 MDL35

Figure 8. Structures of anticancer chalcones.

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and selective breast cancer resistance protein (BCRP) inhibi-tors (ATP-binding cassette sub-family G member 2,

ABCG2) with low cytotoxicity were investigated among alibrary of chalcones derivatives (1,3-diarylpropenones), byevaluating their inhibitory effect on the transport of mitoxan-trone, a known ABCG2 substrate. Six compounds producingcomplete inhibition with IC50 values < 0.5 M and highselectivity for ABCG2 were identified. The number and posi-tion of methoxy substituents appeared to be critical for both

ABCG2 inhibition and cytotoxicity. The best compounds,with potent inhibition and low toxicity, contained an N-

methyl-1-indolyl (44) or a 6-hydroxyl-2,4-dimethoxy-1-phenyl (43) moiety (A-ring) possessing two methoxy groupsat positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxysubstitution contributed to inhibition at positions 3 and 5,but had a negative effect at position 4, and where as 3,4,5-tri methoxy substitution on the B-ring markedly increasedcytotoxicity and hence, not preferable (Figure 11).

Juvale et al. [70] have synthesized chalcones (47 -- 49) andbenzochalcones with different substituents (such as OH,OCH3, Cl) on ring A and B of the chalcone structure. Allsynthesized compounds were tested by Hoechst 33342

accumulation assay to determine inhibitory activity in

MCF-7 MX and MDCK cells expressing BCRP. The com-pounds were also screened for their P-gp and multidrugresistance-associated protein 1 inhibitory activity in the cal-cein AM accumulation assay and were found to be selectivetoward inhibition of BCRP. Substituents at position 2 and4 on chalcone ring A were found to be essential for activity;additionally there was a great influence of substituents onring B. Presence of 3,4-dimethoxy substitution on ring Bwas found to be optimal, while presence of 2- and 4-chlorosubstitution also showed a positive effect on BCRP inhibition.BCRP/ABCG2 belongs to the ATP-binding cassette family oftransport proteins. BCRP has been found to confer multidrugresistance in cancer cells. The development of potent and spe-cific BCRP inhibitors is important as a strategy to overcomeresistance due to BCRP overexpression (Figure 12).

Zuo et al. [71] have synthesized a series of biaryl-basedchalcones that were designed as a combination of the naturalchalcone and biphenyl moieties, by sequential Knoevenagelreaction and microwave-assisted Suzuki coupling. Sulforhod-amine B assay was performed to evaluate the cell viabilityinhibitory abilities of these compounds against five cancercell lines (A549, CNE2, SW480, MCF-7 and HepG2) fromdifferent tissues. Their nuclear factor-kB (NF-kB) nucleartranslocation inhibitory activities were further investigatedby high content analysis-based assay. Most of the compounds

showed moderate-to-strong anticancer and NF-kB nucleartranslocation inhibition activities. Compounds 50 and 51exhibit potent inhibitory activities toward CNE2 cell growthwith some extent of selectivity to other cell lines, suggestingthat these compounds (50 and 51) could serve as leads fornovel anti-NPC drug discovery. Furthermore, severalcompounds, such as 52, 53, 54 and 55, were found to bepotent leads against different cancer cell lines (Figure 13).

Mielcke et al. [72] have synthesized quinoxaline-derivedchalcones and evaluated their anticancer activity againsthuman glioma cell lines. Eight synthetic quinoxaline-derived

O ClCl

O

O

N

OH

O

NH

F FOOH

OCH3

HO

H3CO

OH

O

OCH3

CH3

H3CO

NHO OH

37 Curcumin

39 CLEFMA 40

38 EF24

Figure 9. Structures of potential anticancer bischalcones.

41a

42a 42b

41b

O

OCH3

O

CH3

N

O

O NO2

Figure 10. Structures of potent anticancer cyclic chalcones.



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chalcones, structurally based on the selective PI3Kg inhibitorAS605240, were evaluated for antiproliferative activity andviability inhibition using glioma cell lines of human and ratorigin (U-138 MG and C6, respectively), at different concen-trations and time periods of incubation. The results reveal thatfour chalcone derivatives (56a--d), possessing methoxy groupson the A ring, inhibited either cell proliferation or viability, ina time- and concentration-dependent manner, with an efficacy

greater than that seen for the positive control (AS605240).Flow cytometry analysis demonstrated that incubation ofC6 cells with compound56bled to G1 phase arrest, indicatingan interference with apoptosis. It is noteworthy thatcompound 56b also inhibits Akt activation, allied to thestimulation of ERK MAP kinase (Figure 14).

Vogelet al. [73]have synthesized and evaluated the cytotox-icity, antioxidative and anti-inflammatory activity and the

OOH R2

4B

6RR

A

R

4

6

2

43 R = OCH3 44 1-Indolyl-3-phenylpropenones

45 3-Indolyl-1-phenylpropenones 46 1,3-Diindolyl-propenones

O2

64R1

H3CN

O

H3C H3CN N

O2

46H3C

NH3CO

OH3C

Figure 11. Chemical strucutres of the indole chalcones.

O

A

16

5

4

3

2

23

4

5B

16

O

A

16

5

4

3

2

23

4

5B

1

6

47 48

O

A

16

5

4 3

2

23

4

5B

1 6

49

Figure 12. Structures of benzo chalcones as breast cancer agents.

F

O

OCH3

F

H2N

O

OH

OCH3

H2N OCH

3

OH

OF

N

H2N

H3CO

H3CO

OCH3

OCH3

O

50

52

F

H2N

O

OH

OCH3

54 55

F

O

OCH3

OCH3

51

53

Figure 13. Chemical structures of antitumor biphenyl-based chalcones.

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influence of A-ring modifications on the pharmacologicaleffect of a new series of chalcones. These chalcones weredesigned by the combination of the B-ring fragments of heli-chrysetin, xanthohumol, xanthohumol C and xanthohumol

H with ferulic or caffeic acid moieties on A ring. Com-pounds57 and 58, both Phase II metabolites of xanthohumolin rats, and compound 59, a related synthetic chalcone,exhibit cytotoxic activity against HeLa cells with an IC50valueof 7.3 0.4 M (Figure 15).

A new class of chalcone hybrids were synthesized by Clai-sen--Schmidt condensation and tested for their cytotoxicactivity against PC-3 (prostate cancer), HT-29 (colon cancer),B-16 (mouse macrophages) and NCI-H460 (lung cancer) celllines. All the new hybrid chalcones exhibited moderate-to-excellent selectivity toward PC-3 cell lines [74]. Some of thecompounds,60a, 60b and 60c(IC50= 8.4, 7.9 and 5.9 M),showed significant activity against PC-3 cell line (Figure 16).

Singhet al. [75]have prepared a series of novel 1,2,3-triazoletethered b-lactam-chalcone bifunctional hybrids via clickchemistry approach utilizing azide--alkyne cycloadditionreactions. These triazole derivatives were then evaluated asanticancer agents against four human cancer cell lines. Thepresence of a cyclohexyl substituent at N-1 ofb-lactam ringand methoxy substituents, preferably at ortho position onring A and para position on ring B on chalcones markedlyimproved the anticancer profiles of the synthesized scaffolds.The most potent of the test compounds (61aand 61b) exhib-ited IC50 values of < 1, 67.1, < 1 and 6.37 M against

A-549 (lung), PC-3 (prostate), THP-1 (leukemia) and

Caco-2 (colon) cell lines, respectively (Figure 17).NF-kB is a transcription factor that regulates inflammation,immunity, apoptosis, cell proliferation and differentiation ofthe cells after binding to DNA and activating gene transcrip-tion [76]. NF-kB is a dimer of five possible subunits: RelA(p65), p50, p52, c-Rel and RelB, and the p65:p50 heterodimeris the predominant form [77]. NF-kB is bound to an inhibitoryprotein (IkB-a) in the cytoplasm, when it is in an inactiveform. Numerous extracellular stimuli, including bacteria,viruses, inflammatory cytokines, growth factors, ultraviolet(UV) and oxidative stress cause the phosphorylation of the

inhibitory protein IkB-a by IkB kinase (IKK) and subse-quently the ubiquitination and degradation of IkB-a byproteasome to release NF-kB. The released NF-kB migratesinto the nucleus to bind with DNA and activate the trans-

cription of inflammatory and other target genes, includingCOX-2, inducible NO synthase, cyclin D1 and Bcl-2 [78].

In cancer treatment, some of the chemotherapeutic drugsthat induce apoptosis lose their activities because they activateNF-kB to induce cancer cell proliferation, which brings che-moresistance to cancer cells [79]. NF-kB inhibition can restorethe capability of chemotherapeutic agents to repress cancercells inducing apoptosis. IKK inhibitors prevent phosphoryla-tion of IkB-a, and proteasome inhibitors inhibit degradationof IkB-a, precluding NF-kB activation. Both are essentialsteps for NF-kB activation. Therefore, anticancer activitiesof chalcone-based compounds may be a result of its inhibitoryactivities against the NF-kB signaling pathways [80]. In fact,quite a few chalcone-based compounds (62 -- 65) [81-83] havebeen reported to inhibit the NF-kB signaling pathway, andsome of them are shown in Figure 18.

In the past few years, the authors research group havesynthesized different types of chalcone conjugates and haveevaluated their biological activity. Among them, chalcone-linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugateshave shown enhanced DNA-binding affinity and promisinganticancer activity on a large number of human cancer celllines. Compounds 66a -- c and 67a -- c enhance the CT-DNA DTm values in the respective ranges of 1.7 -- 8.1Cand 1.0 -- 9.0C. Compound 66ahas been evaluated for its

in vitro activity against the standard 60 human tumor celllines, derived from nine cancer types (leukemia, non-small-cell lung, colon, CNS, melanoma, ovarian, renal, prostateand breast cancer). This compound showed good anticancerpotency in a wide spectrum of cell lines with 50% cell growthinhibition (GI50) values ranging from 0.01 to 0.40 M [84].Combining these two core pharmacophore (chalcones andDC-81) structures with modifications at A-C8/C-C2-positionof PBD ring system yielded analogues with improved efficacywhich showed promising in vitro anticancer activity rangingfrom < 0.1 to 2.92 M. These studies revealed that the triazole

56a 56b

A

OCH3

O

B A

AA

N

N

56c 56d

O

OCH3

N

N

OCH3

B

O

OCH3

N

N

OCH3

B

O

N

N

OCH3

OCH3

B

Figure 14. Anticancer quinoxaline chalcones.



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compound 68dis the most effective member of series and ithas been taken for detailed investigations [85].

A series of novel chalcone-linked imidazolones wereprepared and evaluated for their anticancer activity against apanel of 53 human tumor cell lines derived from nine differ-ent cancer types: leukemia, lung, colon, CNS, melanoma,ovarian, renal, prostate and breast. Some of these hybrids(69 -- 71) showed good anticancer activity with GI50 valuesranging from 1.26 to 13.9 M. When breast carcinoma cells(MCF-7) were treated with 10 M concentration of com-pounds TMAC, CA-4, 69 and 71, cell cycle arrest wasobserved in G2/M phase. Surprisingly, the increased concen-tration of the same compound to 30 M caused accumulation

of cells in G0/G1 phase of the cell cycle [86]. A series ofchalcone--amidobenzothiazole conjugates (72a-- kand 73a,b)

have been synthesized and evaluated for their anticanceractivity [87]. All these compounds exhibited potent activityand the IC50 of two of the more potent compounds ( 72aand 72f) against different cancer cell lines are in the range of0.85 -- 3.3 M. Flow cytometric analysis revealed that thesecompounds induced cell cycle arrest at G2/M phase in

A549 cell line leading to caspase-3-dependent apoptoticcell death. The tubulin polymerization assay (IC50 ofcompound 72a is 3.5 M and compound 72f is 5.2 M)and immuofluorescence analysis showed that these com-pounds effectively inhibit microtubule assembly at both

OCH3

OCH3

OH

A

O

HO

B

O

OH

OH OH

OOCH3

HOO

O

OCH3

OH

A

O

HO

B

57 58 59

Figure 15. Chemical structures of pharmacological effective chalcones.

OOPhPh

N

N

Cl

O

OPhPh

N

N

O

O

OCH3

60a 60b

OPhPh

N

N

O

O

O2N

60c

Figure 16. Different chalcones exhibiting antitumor activity.

61a

O

O

N

N

N

NO

OCH3

BA

H3CO

61b

O

O

N

N

N

NO

OCH3

OCH3

BA

H3CO

Figure 17. Structure of lead compound and target hybrid compounds.

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molecular and cellular levels in A549 cells. Further, annexinstaining also suggested that these compounds induced celldeath by apoptosis. Moreover, docking experiments haveshown that they efficiently interact and bind with tubulin pro-tein. Overall, this investigations demonstrated that the chalco-ne--amidobenzothiazole conjugates are promising anticanceragents with potent apoptotic-inducing activities via targetingtubulin (Figure 19).

4. Imidazothiazole--chalcone conjugates

Some of the recent advances in the development of anticanceragents involve structural modification of chalcones to improvetheir bioavailability and to study the role of various substitu-ents on the aryl rings [88]. In addition, heterocyclic derivativesof chalcones wherein the B ring is replaced by a heterocyclehave been systematically investigated. Imidazothiazoles are

66a n = 166b n = 266c n = 3

68a i n = 1 3

68d n = 3

67a n = 167b n = 2

67c n = 3

69 R = Ph

70 R = OCH371 R = Cl

73a R = H73b R = CH3

OCH3

H3CO

OH

O

OO

( )n

N

N

H

O

OCH3 H

3CO

O

O O

NN

NHO( )

nN

N

H

O

OCH3

OCH3

O

O

O N

R

NH

NH

H3CO

H3CO

HO

H3CO

OO

N

NH

R

OCH3

H3CO

OH

O

O O

O

H( )n

H

N

N

O

OCH3

OCH3

O

O

O N

S

R

NH

H3CO

H3CO

72a k

72a R = H72f R = OCF3

Figure 19. Structures of chalcone-linked PBD conjugates (66 -- 68), chalcone-linked imidazolones (69 -- 71) and chalcone-

linked amidobenzothiazoles (72and 73).

62 BMS 181156 63 Cardamonin

65 Butein64 AGN193198

O

COOH

O

O N COOH

OCH3

OOH

HO

OH

OH

OH

O

HO

Figure 18. Chemical structures of chalcone-based NF-kB inhibitors.



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also well-known compounds and many derivatives of thisfused ring system have been evaluated for potential biologicalactivity particularly for antitumor activity [11,12]. In view ofthe potent bioactivity of imidazothiazoles and chalcones, wedesigned and synthesized new chalcone derivatives incorporat-ing an imidazothiazole skeleton and evaluated their anticanceractivity. The promising activity obtained prompted us toinvestigate their role in the cell proliferation and apoptosisof human breast cancer cell line (MCF7). Further, it was con-sidered of interest to investigate the effect of these compoundson regulatory proteins of cell cycle progression [89].

The imidazothiazole--chalcone derivatives (80a -- p) wereprepared by the Claisen--Schmidt condensation of appropri-ately substituted acetophenones (79a -- f) by treatment withimidazo[2,1-b]thiazole aldehydes (78a -- h) in the presenceof NaOH (10%) as shown in Scheme 1. The imidazo[2,1-b]thiazole aldehydes were obtainedby means of Vilsmeier reactionof the corresponding imidazo[2,1-b]thiazoles (77a-- h), which inturn were prepared from the appropriate 2-aminothiazole (75)and bromoketones (74)as shown in Scheme 1 andTable 1.

All the synthesized compounds showed significant antican-cer activity in the cell panel assay of NCI and the cell viabilityassay with log GI50 values ranging from -7.51 to -4.00.

Detailed biological evaluation of these derivatives toward theMCF-7 cell line was also carried out. The FACS analysisshowed more population in sub-G1 phase indicating thatthese imidazothiazole--chalcones derivatives have apoptosis-inducing ability. These effects were accompanied by changesin expression of key proteins in the G1 phase of the cell cycle.Further modulation of the expression and function of the cellcycle regulatory proteins provide the mechanism for theinhibition of growth and also downregulation of cyclins andupregulation of CDK4, thereby resulting in downregulationof phosphor-Rb (ser780) that suggests cell cycle blocking in

the G1 phase. Further, it was observed that the G1/S checkpoint-associated tumor suppressor proteins, such as p53,p21, p27 and chk2 protein levels, were upregulated that resultsin the induction of cell cycle arrest in G1 phase. These studiesalso support that the upregulation of p53 and concomitantdownregulation of NF-kB in these compounds ultimatelylead to apoptosis. In this study an insight in the cell cycle reg-ulatory role as well as apoptotic-inducing ability of these newchalcones was extensively examined. Thus, this study revealedthat the caspase-mediated apoptotic pathway is responsible forthe apoptosis-inducing ability of the imidazothiazole--chalconeconjugates (Figure 20) and these compounds are potentialcandidates for the detailed biological investigations,particularly for the treatment of breast cancer.

5. Expert opinion

Despite the availability of anticancer agents derived fromnatural products and synthetic derivatives, the developmentof a safe and site-specific anticancer drug still remains a chal-lenge. The major obstacles in this endeavor are the associationof toxicity with drugs which is due to lack of specificity, asthese agents kill healthy cells and the drug resistance which

have arisen in recent years. The combination therapy employ-ing different chemotherapeutic agents has been used to com-bat this problem with some success. However, the possibilityof the development of drug resistance still remains. Keepingpace with these challenges, around the world and from thislaboratory, a good number of diverse molecules with a novelmode of action have been developed based on imidazothia-zoles, chalcones and imidazothiazole--chalcone hybrids.

Cytotoxicity assayson a panel of human cancer cell lines as wellas preclinical and clinical studies of imidazothiazole--chalconederivatives exhibited that these compounds could be developed

74 75

79a f 78a h

80a p

77a h

acetone

reflux, 6 8 h

10% aq. NaOH,12 h, rt, 75 85%

POCl3, DMF

reflux, 1 h, 70 80%

O

BrR2

R

S

N

N

O

R2

R1

N

NS

CHO

R2R+

+

CH3

O

R1

NH2

N

SR reflux, 1 h,

85 95%

2N HCl

R2RN

NS

76

R2

NH

N O .HBr

SR

Scheme 1. Synthesis of imidazothiazole--

chalcone conjugates.

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as promising chemotherapeutics for the use of cancer. Interest-ingly, some of the new-generation imidazothiazole, chalconeand imidazothiazole--chalcone derivatives possess enhancedpotency in comparison with most of the standard anticanceragents. Based on the impressive efficacy and potency data in ani-mal models, many molecules of this type are being evaluated inthe clinic and are at different stages. A number of structurallyrelatedimidazothiazoles,chalconesand imidazothiazole--chalconederivatives have been reported to exert antitumor effects;however, their mechanism of action is not yet fully evaluated fortheir lead optimization and clinical development. These studies

assume importance in the context of the recent interest in drugdesign based on pharmacophore conjugation approach. Thisapproach may possibly enhance the potency of previously uncon-

jugated agents that display little or no antitumor activity on theirown. Importantly, the hybrid molecule strategy is notrecommended for the entities when their targets are too different.Drug development for cancer treatment remains as challenging as

ever, despite the identification of numerous potential drugcandidates, due to toxicity issues and the many obstacles inpharmacokinetics. Based on the biological importance ofimidazothiazole--chalcone conjugates, it is of considerable interestin the design and synthesis of new conjugates as anticancer agents.Combination chemotherapy with drugs of different mechanismsof action is one of the methods that is adopted to treat cancer.

Alternatively, a single drug which incorporates two pharmaco-phores with different modes of action may be employed for treat-ment. It is anticipated that the search for novel chemotherapeuticagentsbasedon imidazothiazole--chalcone conjugates may providemore efficient and safer anticancer drugs in the years to come.Now efforts are being focused toward the intervention of conju-

gate molecules as anticancer agents eventually to develop effectivechemotherapeutics for the treatment of human malignancies.

Declaration of interest

MK Reddy and A Viswanath are Senior Research Fellows forthe Division of Organic Chemistry of the Indian Institute ofChemical Technology (CSIR-IICT). A Kamal is an ActingDirector (Outstanding Scientist) of the CSIR-IICT, Hydera-bad. The authors have no competing interests to declare andhave received no payment in support of this manuscript.

Apoptosis

p53Chk2

G1 phase

Cdk4Cyclin D1 Cyclin E

S-phase

NF-B

Cell cycle

Apoptosis

Cdk2

Caspase activation

Figure 20. Schematic diagram representing the action of

imidazothiazole--chalcone conjugates on modulate cell cycle

and apoptosis: Conjugates arrest cells at G1 phase of cell cycle

affecting the cyclin E/Cdk2 and cyclin D1/Cdk4. The tumor

suppressor protein p53 was induced in compound-treated cells

by suppressing NF-kB protein. The balance between p53 and

NF-kB controls the apoptoticevent by inducing caspase proteins.

Table 1. Representative chemical structures of imidazothiazole--chalcone conjugates (80a-- p).

80a p

R

S

N

N

O

R2

R1

Entry Compound R R1 R2

1 80a H Trimethoxyphenyl 4-Methoxyphenyl2 80b H Trimethoxyphenyl 4-Fluorophenyl3 80c H Trimethoxyphenyl 2-Thienyl4 80d H Trimethoxyphenyl Trifluoromethyl5 80e H Trimethoxyphenyl 3,4-Dimethoxyphenyl6 80f H 3,4-Dimethoxyphenyl Trifluoromethyl7 80g CH3 Trimethoxyphenyl 4-Methoxyphenyl8 80h CH3 Trimethoxyphenyl 4-Fluorophenyl9 80i CH3 Trimethoxyphenyl 2-Thienyl10 80j H 2-Pyrrolyl 4-Methoxyphenyl11 80k H 2-Thienyl 4-Methoxyphenyl12 80l H 3,5-Difluorophenyl 4-Methoxyphenyl13 80m H 3,4-Benzodioxolyl 4-Methoxyphenyl14 80n H 3,4-Benzodioxolyl 4-Fluorophenyl15 80o H 3,4-Dimethoxyphenyl 4-Methoxyphenyl16 80p H 3,4-Dimethoxyphenyl 4-Fluorophenyl



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AffiliationAhmed Kamal, Methuku Kashi Reddy &

Arutla ViswanathAuthor for correspondence

CSIR--Indian Institute of Chemical Technology,

Division of Organic Chemistry,

Tarnaka, Hyderabad 500607, India

Tel: +91 40 27193157; Fax: +91 40 27193189;

E-mail: [email protected]

A. Kamal et al.


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