Review Article Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight · 2019. 7....

Review ArticleChalcone Scaffold in Anticancer ArmamentariumA Molecular Insight

Manik Das and Kuntal Manna

Department of Pharmacy Tripura University (A Central University) Suryamaninagar Tripura 799022 India

Correspondence should be addressed to Kuntal Manna k manna2002yahoocom

Received 5 October 2015 Revised 7 December 2015 Accepted 15 December 2015

Academic Editor Syed Ali

Copyright copy 2016 M Das and K Manna This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Cancer is an inevitable matter of concern in the medicinal chemistry era Chalcone is the well exploited scaffold in the anticancerdomain The molecular mechanism of chalcone at cellular level was explored in past decades This mini review provides the mostrecent updates on anticancer potential of chalcones

1 Introduction

Cancer which is commonly a harbinger of imminent patientdeath is a group of diseases characterized by uncontrolledgrowth and spread of abnormal cells and aberrant cellbehavior which leads to expansive masses that destroysurrounding normal tissue and is able to attack vital organsresulting in disseminated disease It is an inevitable matterof concern in the medicinal chemistry era and an increasingburden to the population According to estimates from theInternational Agency for Research on Cancer (IARC) theglobal burden is expected to grow to 214 million new cancercases and 132 million cancer deaths by 2030 There were 127million new cancer cases in 2008 worldwide of which 56million were in the economically developed countries and 71million were in the economically developing countries Thecorresponding estimates for total cancer deaths in 2008 were76 million (about 21000 cancer deaths a day) 28 million inthe economically developed countries and 48 million in theeconomically developing countries [1 2] Pathophysiology ofall cancers involves the malfunction of genes that control cellgrowth division and death Cancers evolve throughmultiplechanges resulting from a combination of hereditary andenvironmental factors which mutate genes encoding criticalcell-regulatory proteins The new generations of anticancerdrugs affect the signals that promote or regulate the cellcycle growth factors and their receptors signal transductionpathways and pathways affecting DNA repair and apoptosis

rather than targeting the direct synthesis of DNA Chalconederivatives of diverse chemical architectures are quite signifi-cant in anticancer drug discovery and hence are in the centerof attention of drug hunters Anticancer activity of chalconemight be due to molecular alteration such as induction ofapoptosis DNA and mitochondrial damage inhibition ofangiogenesis tubulin inhibition kinases inhibition and alsodrug effluxprotein activities Chalcones are also implementedin cancer diagnosis too Chalcone is chemically 13-diaryl-2-propen-1-one (Figure 1) in which the two aromatic rings arejoined by a three-carbon 120572120573-unsaturated carbonyl systemrepresenting a class of flavonoids that occur naturally in fruitsand vegetables Chalcones are also metabolic precursors ofsome flavonoids and isoflavonoids The plants containingchalcone are traditionally employed for therapeutical pur-poses [3ndash7]

Chalcones were exploited well for their wide applicationin pharmacological area It is reported that chalcones haveseveral advantages such as poor interaction with DNA andlow risk of mutagenicity [8] Hence some clinically usefulanticancer drugs have reported genotoxicity due to theirinteraction with amino groups in nucleic acids chalconesmay be devoid of these side effects due to their struc-tural flexibility Literature reveals that natural and syntheticchalcones are desirable to elicit cytotoxic and apoptoticactivity (Figure 2) For this reason chalcones have beenwell documented They have been reviewed not only in the

Hindawi Publishing CorporationJournal of ToxicologyVolume 2016 Article ID 7651047 14 pageshttpdxdoiorg10115520167651047

2 Journal of Toxicology

O

AB

Figure 1 Chemical structure of chalcone

S

M

Cell cycle arrest Apoptotic cell death

Activation of caspasesUpregulation of Bax Bak BidDownregulation of Bcl-2 Bcl-xLp53 upregulation

All chromosomesaligned in the M

phase

Chalcone

monitors the DNAreplication andDNA damage

monitors the size ofthe cell and

DNA damage

S phaseDNA synthesis

Trigers mitochondrialapoptotic pathway anddeath receptor pathway

G2M phase arrest

G2

G2M checkpoint

G1

G1S checkpoint

Figure 2 Action of chalcone on cell cycle

articles mentioned in the text but also in more recent articleswhich have eluded the authors [9ndash11] This review (surveyeddatabase 2013ndash2015) is complementary to the researchers foroptimizing the lead chalcone as potential anticancer scaffoldwith increased potency

2 Molecular Mechanism of Apoptosis

Cell death in tumors is a passive degradative reaction knownas necrosismost likely due to inadequate angiogenesis withinthe tumor cell On the other hand apoptotic cell deathincludes a number of gene families and altering proapoptoticpathways specifically in tumors is something of a holy grailfor oncology andmedicinal chemistryWhen cell productionrate exceeds the cell loss rate through mitosis it results innet tumor Apoptosis is often referred to as an altruistic cellsuicide process where damaged DNA in the cell producessignals resulting in both repair and apoptotic pathways andif repair cannot be done then the cell undergoes apoptosis ina manner like ldquobetter dead than wrongrdquoThe cells which har-bour mutant p53 will have a survival advantage over normalcells In response to DNA damage normal cells upregulatep53 which acts as a transcription factor for cell cycle arrestand apoptosis thereafter p53-mutant cells become unable tocarry out this protective arrest or apoptosis andmight survive

with what otherwise would turn to lethal genetic damageperhaps explaining why p53 mutations are so common inhuman cancers The decision of apoptosis is largely playedout on the mitochondrial surface between three major fam-ilies the so-called three horsemen of apoptosis The finalexecutioner proteases called caspases play pivotal role bycleaving critical substrates such as DNA repair enzymes andcytoskeletal proteins but they are stored as zymogens boundto an apoptotic adenosine triphosphate apoptosis-activatingfactor-1 (Apaf-1) which is the mammalian homologue of thenematode Caenorhabditis elegans cell death protein Ced-4Once cytochrome c is released it binds to the cytosolic pro-tein Apaf-1 to facilitate the formation of apoptosome whichin turn activates apoptotic caspases However proapoptoticBcl-2 family proteins such as Bax which is upregulated byp53 can activate apoptosis by releasing cytochrome c (cyt-c) from mitochondria where Apaf-1 activation takes place[2 6 12 13]

3 Molecular Insights of Anticancer Chalcones

Literature on anticancer chalcones highlights the employ-ment of three pronged strategies namely structural manip-ulation of both aryl rings replacement of aryl rings with

Journal of Toxicology 3

OCl

2

O

3

O

O

O

O

OH

7

O

1

O2N

O

O

O

6c

OCH3

H3CO

OR

OCH3

OCH3

OCH3

4 R = 3-OCH3 5 R = 4-CF3

O O

O

O O

O

R1

R3

R2

6b = R1 = OMeR2 = OMe R3 = OMe

R3

R2R1

6a = R1 = OMe R2 = OMe R3 = H

Figure 3 Chalcones against leukemia cell lines (1) CC50of 30 120583M (2) CC

50of 40 120583M and (3) CC

50of 40 120583M increases proapoptotic proteins

Bax Bid and Bak (only chalcone 2) and decreases antiapoptotic Bcl-2 expression Caspase-9 and caspase-12 activation increases CHOPexpression resulting in induction of ER stress (4) IC

50values (4 to 8 120583M) and (5) IC

50values (4 to 8 120583M) induction of apoptosis through

the reduction of the mitochondrial membrane potential reduction in Bcl-2 expression increase in Bax expression and increase in activecaspase-3 ((6a) to (6c)) IC

50s between 12 and 85120583M for HDAC isoenzymes inhibiting total HDAC activity by 20ndash50 at 100 120583M histonedeacetylases (HDACs) inhibitor (7) IC

50of 137 plusmn 08 120583M caspase-3 and caspase-7 activation

heteroaryl scaffolds and molecular hybridization throughconjugation with other pharmacologically interesting scaf-folds for enhancement of anticancer properties Varioussubstitutions on both aryl rings (A and B) of the chalconesdepending upon their positions in the aryl rings appear toinfluence anticancer activity by interfering with various bio-logical targets Similarly heterocyclic rings either as ringAoras ring B in chalcones also influence the anticancer activityshown by this class of compounds Hybrid chalcones for-mulated by chemically linking chalcones to other prominentanticancer scaffolds such as benzodiazepines benzothiazolesand imidazolones have demonstrated synergistic or additivepharmacological activities too [6]

31 Chalcones against Leukemia Cell Lines Anticancer activ-ity of three naphthyl chalcones 1 2 and 3 shown in Figure 3was investigated by Winter et al (2010) [14] In a subsequentstudy these chalcones were found to possess concentration-and time-dependent cytotoxicity on murine lymphoblasticleukemia cell line (L1210) Chalcones 1 2 and 3 inducedapoptosis via an activated caspases-dependent pathway Theactivities of caspase-8 caspase-9 and caspase-12 were foundto increase after the treatment of L1210 cells with the CC

50

of 30 120583M of chalcone 1 and 40 120583M of chalcones 2 and 3It was found that chalcones 1 and 2 induced an increaseof proapoptotic proteins Bax Bid and Bak (only chalcone2) as well as a decrease in antiapoptotic Bcl-2 expressionThese chalcones also induced an increase in death receptorFas and a decrease in p21 and p53 expression Chalcones 1and 2 exert a statistically significant increase in cytochrome

c release from mitochondria to cytoplasm Cytochrome crelease mediates caspase-9 activation while the apoptosisinhibitors from Bcl-2 family prevent the efflux of cytochromec from mitochondria Chalcone 3 seems to act by a differentmechanism to promote cell death as it did not change themitochondrion-related proteins nor did it induce the cyto-chrome c release Chalcones 1 2 and 3 induced an increasein cell calcium concentration and an increase in CHOP (CEBP homologous protein) expression which is the tran-scription factor involved in endoplasmic reticulum stresstogether with an increase in caspase-12 activity suggestingthat chalcones could induce an endoplasmic reticulum (ER)stress They did not result in the arrest of G

0G1 S or

G2M phases of the cell cycle in contrast to paclitaxel which

was used as a positive control in this study and induced astatistically significant enrichment of G

2M fraction They

presented a selectivity index (SI) higher than one indicatingthat chalcones show higher selectivity to leukemic cells whencompared to nontumoral cells (Vero = monkey kidney cellsand NIH3T3 = murine fibroblast) The only exception waschalcone 3 which presented the same toxicity in L1210 andVero cells The selectivity index (SI) corresponds to CC

50

(concentration of the compounds which results in 50 ofcell viability) of chalcones on nontumoral cell lines (Veroand NIH3T3) divided by CC

50determined for cancer cells

(L1210) [15] 210158404101584051015840-trimethoxychalcones4 5 (Figure 3)werefound to reduce the viability of human K562 acute myeloidleukemia cell and human Jurkat acute lymphoid leukemiacell significantly and caused a cytotoxic effect in both celllines in a concentration- and time-dependent manner They


O

9

NH2

HO

O

R1R3

R2

8 R1 = R2 = R3 = OMe

Figure 4 Chalcones against colon cancer cell lines (8) IC50of 145 plusmn 11 120583M increases proapoptotic proteins Bax Bid and Bak (only chalcone

2) and decreases antiapoptotic Bcl-2 expression Caspase 9 and caspase 12 activation increases CHOP expression resulting in induction ofER stress (9) IC

50of 439 120583M increases the death receptors expression (TRAIL-R1 and TRAIL-R2) (Tumor necrosis factor- (TNF-) related

apoptosis-inducing ligand) and proapoptotic markers (p21 Bad Bim Bid Bax Smac caspase-3 and caspase-8) as well as reducing theantiapoptotic markers (livin XIAP and HSP27)

were found to have low IC50

values (4 to 8 120583M) againstboth cell lines and did not have a cytotoxic effect on normalhuman lymphocytes The mechanism of action involves thereduction of cell proliferation which has been shown bya reduction in the expression of cell proliferation markerKi67 Cell death induced by 210158404101584051015840-trimethoxychalconeswas due to induction of apoptosis through the reductionof the mitochondrial membrane potential reduction in Bcl-2 expression increase in Bax expression increase in activecaspase-3 and activating the intrinsic pathway and executionphase of apoptosis [16]

Histone deacetylases (HDACs) are enzymes which cat-alyze removal of acetyl groups from lysine residues HDACstarget nonhistone proteins including 120572-tubulin heat shockprotein 90 or p53 HDACs play a critical role in epigeneticgene regulation and hence control multiple cellular eventsHence HDACs expressions andor activity are deregulatedin various cancer subtypes leading to a target for anticancertherapy Coumarin-containing compounds 6a 6b and 6c(Figure 3) were found to inhibit total HDAC activity by20ndash50 at 100 120583M in chronic myeloid leukemia K562 andhistiocytic lymphoma U937 cell lines The activity of thecompounds was compared to peripheral blood mononuclearcells (PBMCs) of healthy donors which showed no effect onPBMC viability In comparison to 6a compound 6b with amethoxy group at R

3 presented increased levels of inhibition

Activity is due to methoxy group in the architecture Com-pound 6bwas tested against sevenHDAC isoenzymes (1 2 36 8 10 and 11) and acted as a pan-HDACi with IC

50s between12 and 85 120583M 6b inhibited HDAC3 with an IC

50at 12 120583M

and may serve as a lead for targeting this nuclear isoenzyme[17] Chalcone 7 (Figure 3) with monomethoxy group at theortho position showed a significant effect on downregulationof cancer cell proliferation and viability in three differentleukemia cell lines (K562 Jurkat and U937)The executionercaspase cleavage analyses indicated that the cytotoxic effectmediated by chalcone 6 is due to induction of apoptotic celldeath by caspase-3 and caspase-7 activation The cytotoxiceffect was cell type-specific and targeted preferentially cancercells as peripheral blood mononuclear cells (PBMCs) fromhealthy donors were less affected by the treatment comparedto K562 Jurkat andU937 leukemia cells It was observed thatcompound 6 obeyed Lipinskirsquos rule of five which indicatesdrug-likeness property of that molecule [18]

32 Chalcones against Colon Cancer Cell Lines 21015840-Hydroxy-246-trimethoxy-5101584061015840-naphthochalcone 8 (Figure 4) hadmost effectively inhibited the clonogenicity of SW620 coloncancer cellsThe IC

50value for compound 8was 145 plusmn 11 120583M

against SW620 cells Mechanistically compound 8 triggeredcell cycle arrest at G

2M phase followed by an increase in

apoptotic cell death which involves the disruption of micro-tubular networks The mitotic spindle network is essentialfor appropriate segregation of chromosomes between thetwo daughter cells at cell division where disruption leadsto apoptosis Compound 8 was found to destabilize micro-tubule assembly during mitosis associated with failure ofmitotic spindle formation in turn blocking mitosis at theprometaphase ormetaphase-anaphase transitionThemolec-ular mechanism is via both p53-dependent and caspase-2-mediated apoptosis The DNA damage response has beenfound to be associated with 8 induced apoptosis Howeverthe study did not distinguish between the DNA damagecheckpoint and mitotic checkpoint pathways of apoptosisThe microtubule stabilizer paclitaxel and the destabilizercolchicine were used as reference compounds [19] TRAIL(tumor necrosis factor- (TNF-) related apoptosis-inducingligand) is a member of the TNF superfamily of cytokinesTNF family members contain highly conserved carboxyl-terminal domains and induce receptor trimerization for thetransduction of intracellular signal TRAIL is able to induceapoptotic cell death through caspase-dependent mecha-nisms TRAIL binds to four different receptors two of whichare death receptors 4 and 5 (DR4 and DR5 resp) inducesapoptosis and decoys receptors DcR1 and DcR2 which lackthe cytoplasmic death domain for transducing apoptoticdeath signals and protect cells fromTRAIL induced cell deathby interfering with signaling through DR4 and DR5

It is generally believed that transformed tumor cells aremore susceptible to TRAIL-mediated cell death owing to theselective loss of decoy receptors Chalcone 9 (Figure 4)(IC50

= 439 120583M) containing an amino (-NH2) group was

themost potent and selective against TRAIL-resistant humancolon cancer (HT-29) and nontoxic against normal humanembryonic kidney (HEK-293) cells 5-Fluorouracil was usedas reference It was observed that a large portion of HT-29 cells had undergone late apoptosis andor necrosis aftertreatment with 5-fluorouracil (5 120583M) These findings wereconsistent to show that chalcone 33 induces apoptosis rather


O

OO

OO

11

O

O

O

O

R

10a= R = H 10b= R = 2-CH3 10c = R = 2-NO2

Figure 5 Chalcones against cervix adenocarcinoma cell lines ((10a) to (10c)) IC50

values ranging from 236 to 273 120583M increases p18Bax accumulation of cells in S and G

2M phases (11) IC

50of 47 to 76 120583M induction of caspase-dependent intrinsic pathway p53 and

its transcriptional target PUMA upregulation

than necrosis in HT-29 cells It increases the death receptorsexpression (TRAIL-R1 and TRAIL-R2) and proapoptoticmarkers (p21 Bad Bim Bid Bax Smac caspase-3 and cas-pase-8) as well as reducing the antiapoptotic markers (livinXIAP and HSP27) [20]

33 Chalcones against Cervix Adenocarcinoma Cell LinesAnthraquinone based chalcone compounds were synthesizedand evaluated for their anticancer potential where com-pounds 10a 10b and 10c (Figure 5) showed promising activ-ity in inhibition of cervix adenocarcinoma (HeLa) cells withIC50values ranging from 236 to 273 120583Mand low cytotoxicity

against healthy human fetal lung fibroblast cell lines (MRC-5) Cisplatin (IC

50= 210 120583M)was taken as a reference All the

compounds cause the accumulation of cells in S and G2M

phases in a dose-dependent manner and induce caspase-3-dependent apoptosis and noncovalent interaction with theminor groove of the double-helical CT-DNA and the damageof DNA double helix structure Significant increase of p18Bax in treated HeLa cell line yielded consistency with thehigher cytotoxic efficacy of compounds which implies theinvolvement of mitochondria in apoptotic process [21]

Synthesis and antiproliferative activity of a series ofnovel coumarin-chalcone hybrids were done by Singh et al(2014) The most potent molecule of the series was com-pound 11 (Figure 5) Regression of tumors induced by HeLacell xenografts in nod SCID mice was found after oraladministration of this molecule It inhibited proliferation ofcervical cancer cells (HeLa and C33A) by inducing apoptosisand arresting cell cycle at G

2M phase Apoptosis was due

to induction of caspase-dependent intrinsic pathway andalterations in the cellular levels of Bcl-2 family proteinsThe mitochondrial transmembrane potential also got highlydepleted in compound 11 treated cells due to an increase inBaxBcl-2 ratio and intracellular ROS Compound 11 inducedrelease of cytochrome c into the cytosol and activation ofinitiator caspase-9 and executioner caspase-3 and caspase-7 Tumor suppressor protein p53 and its transcriptionaltarget PUMA (p53 upregulated modulator of apoptosis)were upregulated suggesting their role in mediating the celldeath Based on dose response curves the calculated IC

50

(after 48 h treatment) was 47 plusmn 10 120583M for C33A cells and76 plusmn 20 120583M for HeLa cells Similar results were foundin colony formation assay where significant decrease in

cellular colonies was observed in compound treated groupsChalcone 11 was apparently nontoxic to the animals asthey did not show any loss of weight during experimentFluorescence microscopy revealed condensation and frag-mentation of nuclei in the treated cells Cell population withfragmented nuclei increased in a time-dependent mannerwith the addition of chalcone 11 Significant increase in apop-totic cells with fragmented nuclei which is consistentwith thechanges in nuclear morphology and flow cytometry analysisindicated induction of apoptosis by chalcone 11 [22]

34 Chalcones against Lung and Breast Cancer Cell LinesNovel isoxazolyl chalcones were synthesized and evaluatedfor their activities in vitro against human non-small lungcancer cells (H1792H157 A549 andCalu-1) Compounds 12aand 12b (Figure 6) were identified as the most potent anti-cancer agents with IC

50values ranging from 135 to 207120583M

and from 727 to 1107 120583M against H175 A549 and Calu-1 cell lines respectively The structure-activity relationshipstudy showed that compounds bearing electron withdrawinggroups (EWG) at the 2-position of the phenyl ring in arylgroupweremore effective Compounds 12a and 12b increasedthe percentage of cell in sub-G

0phase and decreased the

percentage of cell in G0G1phase These results suggested

that 12a and 12b induced apoptosis in A549 cells in a dose-dependent manner They have upregulated the DR5 in adose-dependent manner which suggests the extrinsic path-ways of apoptosis Cleaved bands of caspase-8 caspase-9 cas-pase-3 and poly (ADP-ribose) polymerase (PARP) alsoindicated the induction of apoptosis [23] Imine derivativesof hybrid chalcone analogues 13a 13b 13c and 13d (Figure 6)containing anthraquinone scaffold were synthesized andevaluated for their in vitro cytotoxic activity against HeLaLS174 and A549 cancer cells Compound 13c with furan ringlinked to imino group showedpotent activity against all targetcells with IC

50values ranging from 176 to 611 120583M which

are comparable to cisplatinThey inhibited tubulogenesis andcompound 13a exhibited strong antiangiogenic effect Gener-ally introduction of electron withdrawing substituents suchas -Cl and -CF

3in metaposition of the phenyl ring was found

to exert good cytotoxicity Compounds did not have tendencyto significantly accumulate the cells in sub-G

1phase except

compound 13a which led to an increase in sub-G1(observed

only in cells undergoing apoptosis) phase inA549 cells as well


NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R

19a = R = 34-dimethoxy19b = R = 345-trimethoxy

Figure 6 Chalcones against lung cancer and breast cancer cell lines (12a) IC50values of 135ndash207 120583Mand (12b) IC

50values of 727ndash1107 120583M

upregulation of the DR5 extrinsic pathway of apoptosis ((13a) to (13d)) IC50values ranging from 176 to 611 120583M inhibited tubulogenesis

caspase-3 and caspase-8 activation and inhibitory potential against matrixmetalloproteinases (MMP-2) secretion (14) IC50values of 141 and

070 120583M cell cycle arrest at G2M phase activation of caspase-3 and cleavage of PARP (15) IC

50value of less than 010 120583M cell cycle arrest

at G2M phase activation of caspase-3 and cleavage of PARP (16) IC

50of 08 120583M enhances tubulin polymerization suggesting the activity as

microtubule stabilizing agents (17) IC50of 016 to 044 120583M and (18) IC

50of 056 to 065 120583M suppress the activation of NF-120581B pathway (19a)

IC50of 225 120583M and (19b) IC

50of 329 120583M induced DNA fragmentation and apoptosis

as changes in G2M arrest of A549 and LS174 cells Com-

pounds induced the activities of caspase-3 and caspase-8in treated HeLa cells and exhibited strong antiangiogenicactivity by showing potent inhibitory potential againstmatrixmetalloproteinases (MMP-2) secretion Strong implicationof MMP-2 is found in angiogenesis and promotes tumormetastatic potential playing crucial role not only in invasionbut also in determination of cancer cell transformationgrowth apoptosis and signal transduction pathways [24] 3-Phenylquinolinylchalcone derivatives 14 and 15 (Figure 6)were synthesized and evaluated for their antiproliferativeactivities Compound 14was active against the growth of non-small cell lung cancer cells H1299 and SKBR-3 breast cancercells with IC

50values of 141 and 070 120583M respectively which

was more active than the positive topotecan (IC50

values of602 and 891 120583M resp) Compound 15 exhibited an IC

50

value of less than 010 120583Magainst the growth of MDA-MB231in a dose- and time-dependentmanner andwas noncytotoxicto the normal mammary epithelial cell (H184B5F5M10)

Mechanism studies indicated that compound 15 inducedcell cycle arrest at G

2M phase The proportion of cells

was decreased in G1and accumulated in G

2M phase after

24 h treatment of compound 15 while the hypodiploid (sub-G0G1phase) cells increased Compound 15 caused activation

of caspase-3 cleavage of PARP and consequently the cell

death Caspase-3 is an executioner caspase whose activationleads to the cleavage of key cellular proteins includingDNA repair enzyme poly (ADP-ribose) polymerase whichis involved in DNA repair predominantly in response toenvironmental stress and is important for the maintenance ofcell viability [25] 120572-Cyano bis(indolyl)chalcone 16 (Figure 6)was found to be the most potent and selective against A549lung cancer cell line (IC

50= 08 120583M) in vitro which is time-

dependentThe activity is due to the presence ofmethoxy andfluoro substituents on indole rings It was found to enhancetubulin polymerization suggesting the activity asmicrotubulestabilizing agents though it was a preliminary study [26] NF-120581B pathway has been shown to be critical to survival of lungcancer cells andmany natural products obtained from plantswere found to inhibit the activation of this pathway Twocardamonin analogs 441015840-dihydroxylchalcone 17 and 441015840-dihydroxy-21015840-methoxychalcone 18 (Figure 6) were found tosuppress the activation of NF-120581B pathway in lung cancercells They were also shown to suppress the growth of A549xenograft mice model Compound 17 inhibited the survivalof primary lung cancer cells with IC

50values of 044 plusmn 005

and 016 plusmn 003 120583M respectively against two lung cancer cellstested Compound 18 inhibited their survival with similarIC50values (056 plusmn 012120583Mand 065 plusmn 136 120583M) Immunoblot

analysis displayed that caspase-3 and PARPwere both cleaved


O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3

Figure 7 Chalcones against hepatocellular carcinoma cell lines (20) IC50of 625 120583Mmitochondria dependent pathway involving inhibition

of Bcl-2 expression leading to disintegration of the outer mitochondrial membrane Caspase-3 and caspase-9 activities (21) IC50of 10120583M

hypoxia inducible factor-1 (HIF-1) inhibitor

in the two lung cancer cell lines treated with compounds17 and 18 indicating the activation of apoptotic pathwaySubsequent estimation of the phosphorylation level of IKK120573NF-120581B pathway stimulating kinase by immunoblotting assaydemonstrated that both decreased IKK120573 phosphorylationin lung cancer cell lines including A549 NCI-H460 andNCI-H1668 and lead to the accumulation of I120581B120572 and I120581B120573and the export of nuclear p65 transcription factor From theimmunofluorescent staining it was shown that transcriptionfactor p65 which is a downstream effect of NF-120581B pathwaywas sequestered in the cytoplasm of A549 cells treated bycompound 17 or compound 18 Incorporation of luciferasereporter system also results in transcription activity of NF-120581Bin lung cancer cells treated with compound 17 or compound18 and demonstrated that relative luciferase expression wassignificantly reduced in compound 17 or compound 18treated lung cancer cells In addition the transcription of tar-get genes of NF-120581B pathway Bcl-2 and survivin was found tobe suppressed in lung cancer cells treated with the two com-pounds Compounds 17 and 18 suppressed the growth of lungcancer xenograft in nude mice model Higher concentrationof the two compounds greatly inhibited the growth of tumorsby 710 and 791 respectively although inhibitory effect wasnot significant at lower concentration Compared with com-pound 17 compound 18 appeared to be slightly more potentto retard the growth of established tumorsMethoxy substitu-tion is found to be effective [27]120573-Carboline based chalconeswere synthesized and evaluated for their cytotoxic activityagainst a panel of human cancer cell lines Compounds 19aand 19b (Figure 6) showed very good antiproliferative activityagainst breast cancer cell line (MCF-7) where IC

50values

were recorded at 225 120583M and 329 120583M respectively Further-more compound 19amarkedly induced DNA fragmentationand apoptosis in breast cancer cells which is an essential stepin the cells undergoing apoptosis [28]

35 Chalcones against Hepatocellular Carcinoma Cell LinesThemolecular mechanism to induce apoptosis in human he-patoma SMMC-7721 cells was investigated by using 2101584041015840-di-hydroxy-61015840-methoxy-3101584051015840-dimethylchalcone 20 (Figure 7)isolated from the buds of Cleistocalyx operculatus It inhibitsproliferation of SMMC-7721 cells by inducing apoptosisCompound 20 induced apoptosis via a mitochondria depen-dent pathway involving inhibition of Bcl-2 expression leadingto disintegration of the outer mitochondrial membraneFurther downstream of the apoptosis cascade compound 20increases caspase-3 and caspase-9 activities [29]

Angiogenesis and invasion are two highly interconnectedevents in cancerous cells where involvement of multiplemolecules and pathways takes place Hypoxia induciblefactor-1 (HIF-1) has been identified as an important pro-tein involved in those events Activated HIF-1 controls theexpression of genes involved in tumor cell immortalizationstem cell maintenance metabolic reprogramming autocrinegrowth and treatment failure therebymaking it an importanttarget for the development of new antitumor therapy A novelseries of chalcone derivatives were synthesized and theirbiological activities against HIF-1 were evaluated by Wanget al (2015) It has been found that compound 21 (Figure 7)exhibited inhibitory effects on HIF-1 at 10 120583M concentrationby downregulating the expression of HIF-1120572 and HIF-1120573under hypoxic conditions The HIF inhibition rate has beenfound to be 830 plusmn 169 while topotecan HIF-1120572 inhibitorwas used as control and for comparison it has the inhibitionrate of 828 plusmn 29 In addition compound 21 displayedinhibitive effect against the migration and the invasion ofHep3B (human liver cancer cell line) and human umbilicalvein endothelial cells (HUVEC) and tube formation ofHUVECs and significant antiangiogenic and anti-invasiveactivities From the in vivo study it has been found that21 could retard tumor growth of Hep3B xenograft modelsand reduced CD31 and MMP-2 expression in tumor tissuesCD31 (cluster of differentiation 31) is platelet endothelial celladhesion molecule (PECAM-1) which is a protein foundto be expressed in certain tumors Compound 27 was welltolerated and was found to be nontoxic up to 200mgkg inSwiss mice in acute intravenous toxicity [30]

36 Chalcones against Bladder and Prostate Cancer Cell LinesThe molecular mechanisms of growth inhibition in humanbladder cancer cell lines T24 and HT-1376 by chalcone 22(Figure 8) are due to the induction of apoptosis cell cycleprogression inhibition by regulating cell cycle related factorlike significant reduction in the expression of cyclin A andcyclin B1 decreases in the expression of Cdc2 and alsoincreases in the expression of p21 and p27

So chalcone may cause cell cycle arrest by reducing thecomplex of Cdc2cyclin B due to downregulation of mul-tiple G2M regulating proteins It triggers the mitochon-drial apoptotic pathway by releasing cytochrome c fromthe cytoplasm with an increase in caspase-9 and activatingcaspase-3 It is also increases the expression of proapoptoticproteins Bax and Bak which are responsible for the ini-tiation of mitochondrial apoptotic pathway and decreases


O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+

Figure 8 Chalcones against bladder and prostate cancer cell lines (22) Concentration of 6120583gmL reduction in the expression of cyclin Aand cyclin B1 decrease in the expression of Cdc2 and an increase in the expression of p21 and p27 increase in the expression of proapoptoticproteins Bax and Bak and decrease in the expression of antiapoptotic proteins Bcl-2 Bcl-xL proteins NF-120581B activation by increasing theexpression of I120581B120572 in cytoplasm leads to apoptosis (23) IC

50value of 595 120583M copper ions might act as penetration enhancers of chalcones

into cancer cells and might act as inhibitors of drug efflux proteins

the expression of antiapoptotic proteins Bcl-2 and Bcl-xLwhile overexpression of Bcl-2 and Bcl-xL is associated withenhanced oncogenic potential Chalcone inhibits the NF-120581Bactivation by increasing the expression of I120581B120572 in cytoplasmleading to apoptosis [31] The copper chelate complex 23(Figure 8) showed promising activity with IC

50value of

595 120583M against PC3 cancer cell line in vitro The estimatedIC50

value for doxorubicin was 87 120583M which was used aspositive control It was found that cancer cells have highaffinity to copper ions thus upon chelation of chalcones withcopper they are thought to bemore liable to target cancer cellsin microdendron architecture It was assumed that copperions might act as penetration enhancers of chalcones intocancer cells Even if copper ions are noncytotoxic to cancercells they might act as inhibitors of drug efflux proteinscharacteristic to cancer cells Drug efflux proteins such as P-glycoproteins (Pgp) breast cancer resistance protein (BCRP)and multidrug resistance-associated protein 1 (MRP1) areresponsible for drug resistance of cancer cells The highcytotoxic activity is attributed to the presence of the p-methylphenyl moiety of ring B and the copper ion [32]

37 Chalcones against Multiple Cancer Cell Lines Hybridsof N-4-piperazinyl-ciprofloxacin-chalcone were prepared byAbdel-Aziz et al (2013) National Cancer Institute (NCI)selected 5 compounds namely 24a 24b 24c 24d and24e (Figure 9) to carry out in vitro one-dose anticancerassay against full NCI 60 cell lines derived from leukemialungs colon renal melanoma CNS prostate ovarian andbreast cancer cell lines Of the selected compounds 24a and24d exhibited the highest ability to inhibit the proliferationof different cancer cell lines while undergoing one-doseanticancer test Among the nine tumor subpanels tested forcompound 24awas found to have broad-spectrum antitumoractivity with selectivity ratios ranging between 042 and187 at the GI

50level without producing selectivity while

compound 24d showed high selectivity towards the leukemiasubpanel with selectivity ratio of 671 at GI

50level More-

over compound 24d showed remarkable anticancer activityagainst most of the tested cell lines with GI

50ranging from

021 to 576120583M Furthermore compounds 24c and 24e haveshown remarkable topo-II inhibitory activity compared toetoposide at 100 120583M and 20120583M concentrations Compounds24c and 24e were found to be potent topo-I inhibitors at20120583M concentration when compared to camptothecin Theresults that were obtained indicated that introduction ofN-4-piperazinyl moiety of ciprofloxacin into the chalconesderivatives dramatically increases the anticancer activity ofthe tested compounds severalfold higher than that of theactivity shown by weak anticancer ciprofloxacin Increase inantiproliferative activity of the tested compounds might bethe result of either synergistic effect of the chalcone deriva-tives andor alteration of the physicochemical properties ofciprofloxacin To determine the DNA unwinding propertiesof 24c and 24e amsacrine (m-AMSA) a well-known DNAintercalator was chosen as a standard where a supercoiledpHOT1 DNA was used as a substrate since unwinding of thedouble strand of DNA helix is a practical characteristic ofintercalating drugs Amsacrine blocked unwinding of pHOT1DNA in the presence of excess topo-I in dose-dependentmanner while compounds 24c and 24e did not block DNAunwinding at high concentration up to 1000120583M treatmentThe assay indicated that 24c and 24e do not interact withDNA but interact with topoisomerases for their inhibitoryactivity [33] Compound 25 (Figure 9) with a propionyloxygroup at the 4-position of the left phenyl ring showed themost potent inhibition activity which inhibited the growthof HepG2 A549 A375 SMMC-7221 and K562 cancer celllines with IC

50values of 015 036 062 061 and 052 120583M

respectively Compound 25 was also shown to arrest cellsin the G

2M phase of the cell cycle and inhibit the poly-

merization of tubulin Molecular docking study suggestedthat compound 25 binds into the colchicine binding site oftubulin In summary these findings suggest that compound23 is a promising new antimitotic compound for the potentialtreatment of cancer [34] A new series of pyrano chalconederivatives containing indole moiety synthesized by Wanget al (2014) were evaluated for antiproliferative activitiesAmong those compound 26 (Figure 9) with a propionyloxy


OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O

24a = Ar = -C6H5 24b = Ar = 4-chlorophenyl

24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar

31a = Ar = 3-fluorophenyl31b = Ar = 4-fluorophenyl

24c = Ar = 4-methoxyphenyl 24d = Ar = 345-trimethoxyphenyl

Figure 9 Chalcones against multiple cancer cell lines ((24a) to (24c)) GI50

of 021 to 576 120583M topoisomerase-I and topoisomerase-IIinhibition (25) IC

50of 015 to 052 120583M arrest cells in the G

2M phase of the cell cycle and inhibit the polymerization of tubulin Binds

into the colchicine binding site of tubulin (molecular docking study) (26) IC50values of 022 to 180 120583M induced cell cycle arrest in G

2M

phase and inhibited the polymerization of tubulin binds at the colchicine binding site of tubulin (frommolecular docking analysis) (27) IC50

value of 089 120583molL cell division cycle 25 (CDC25) inhibitor (28) IC50values of 176 120583molL cell division cycle 25 (CDC25) inhibitor (29)

IC50value of 001 120583gmL and 004 120583gmL molecular mechanism not studied (30) IC

50values of 64 120583M and 85 120583M cytotoxic molecular

mechanism not studied (31a) IC50value of 102 120583M and 079 120583M and (31b) IC

50value of 081 120583M and 1 120583M cytotoxic

group at the 4-position of the phenyl ring A and N-methyl-5-indolyl on the B ring displayed the most potent cytotoxicactivity against all tested cancer cell lines includingmultidrugresistant phenotype which inhibits cancer cell growth withIC50

values ranging from 022 to 180 120583M The tested celllines were SMMC-7221 HepG2 (liver) PC-3 (prostate) A549(lung) K562 (leukemia) HCT116 (colon) SKOV3 (ovarian)MCF-7 (breast) vincristine resistant HCT-8 (HCT-8V) andtaxol resistant HCT-8 (HCT-8T) Compound 26 was themost potent towards HepG2 cells with IC

50value of 022120583M

Colchicine (25 120583M) and paclitaxel (25 120583M) were used asa reference Compound 26 produced cytotoxic activity innormal human liver cell line (LO2) above the concentrationof 10 120583M It significantly induced cell cycle arrest in G

2M

phase and inhibited the polymerization of tubulin It was alsoshown from molecular docking analysis that compound 26binds at the colchicine binding site of tubulin Chalcone 26also exerted potent anticancer activity in HepG2 xenograftsin BALBc nude mice where the growth of tumors in micetreated with chalcone 26 (30mgkg) was reduced by 5658compared with that in control mice treated with vehicle only

at day 35 Positive control reduced the growth of tumors by2593 [35]

Cell division cycle 25 (CDC25) which includes CDC25AB and C homologues a subfamily of dual-specificity proteintyrosine phosphatases plays a role in the regulation of the cellcycleTheCDC25A and CDC25B isoforms are overexpressedin primary tissue samples from various human cancerswhich is strongly associated with tumor aggressiveness andpoor prognosis CDC25B controls cell cycle progression bycatalyzing removal of covalently attached contiguous phos-phates and the subsequent activation of cyclin-dependentkinase 1 (Cdk1) CDC25B has been proposed to regulate reen-try into mitosis after DNA damage CDC25B overexpressionhas been documented in a variety of human cancers includ-ing head and neck and colon and non-small cell lung cancervalidates its oncogenic potential A series of 21015840-hydroxy-41015840-isoprenyloxychalcone derivatives were evaluated for theinhibition of CDC25B activity by Zhang et al (2014) Amongthose two compounds 27 and 28 (Figure 9) have been foundto have the potent inhibition activity and significantly inhib-ited CDC25B with inhibition rates of 9995 and 9975


O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO

Figure 10 Chalcones against multiple cancer cell lines (32) IC50

= 053 120583M and (33) IC50

value of 818 120583M could snugly occupy thecolchicine binding site of 120573-tubulin (molecular docking study) (34) Concentration of 02 120583M cell cycle arrest in G

2M phase promoted

tubulin polymerization into microtubules and caused microtubule stabilization similar to paclitaxel (35) IC50

values of 160 120583M and (36)IC50values of 282 120583M inhibition of clonogenicity

respectively at a dose of 20 120583gmL which is similar to theknown tyrosine phosphatase inhibitor sodium orthovana-date In vitro cytotoxic activity assays showed that compounds27 and 28 were potent against HCT116 HeLa and A549cells They were particularly cytotoxic against colon HCT116cancer cell line with IC

50values of 089 and 176 120583molL

respectively for compounds 27 and 28 Irinotecan (IC50

=214 120583molL) a clinically relevant camptothecin was chosenas a reference drug In colo205 xenograft BALBc nude malemice compound 27 produced a tumor volume inhibitionof about 50 [36] A new series of pyrazole chalconeswere screened for the in vitro anticancer activities againstMCF-7 (human breast adenocarcinoma) and HeLa (humancervical tumor cells) cell lines Compound 29 (Figure 9)showed the highest inhibition in human MCF-7 and HeLacell lines with an IC

50value of 0018120583gmL and 0047 120583gmL

respectively The IC50for standard doxorubicin in HeLa and

MCF-7 cells was 115 120583gmL and 184 120583gmL respectivelyThe activity is due to the presence of 4-fluorophenyl and5-fluoropyridin moieties [37] New prenylated chalcone 30(Figure 9) named as renifolin C was isolated from wholeDesmodium renifolium plants and cytotoxicity was evaluatedagainst five human tumor cell lines (NB4 A549 SHSY5YPC3 and MCF7) using the MTT method using paclitaxel asa positive control The IC

50values were 64 120583M and 85 120583M

against NB4 and PC3 cell lines and above 10 120583M for the othercell line tested [38] Various benzylidene pregnenolones weresynthesized and in vitro cytotoxicity studies were performedby Banday et al (2014) Compounds 31a and 31b (Figure 9)

were found to be active against theHCT-15 (colon) andMCF-7 (breast) cell lines Chalcone 31a has IC

50value of 102 120583M

and 079120583M respectively against HCT-15 and MCF-7 while31b has 081 120583Mand 1 120583M respectively Electron withdrawinggroups have an effect over the activity [39] Chalcone-coumarin hybrid 33 (Figure 10) (IC

50= 053 120583M) displayed

cytotoxicity against human lymphoblastic leukemia cell line(MOLT-3) where etoposide (IC

50= 005 120583M) was taken

as a standard Compounds 32 and 33 shown in Figure 10displayed higher cytotoxic potency against HepG2 cells thanthe control drug etoposide The hybrid 33 (IC

50= 426 120583M)

was potent but was found to be toxic toward noncancerousAfrican greenmonkey kidney cell line (Vero)Though analog32 displayed cytotoxic activity against HepG2 with IC

50

value of 818 120583M it was found to be nontoxic against Verocells It has been shown from molecular docking study thatcompounds could snugly occupy the colchicine binding siteof 120573-tubulin [40]

A series of millepachine derivatives were synthesized byCao et al (2013) Among them potent chalcone 34 (Figure 10)induced apoptotic cell death of a wide variety of tumor celllines including multidrug resistant human tumor cell lines inthe nanomolar range by attacking microtubules Flow cyto-metric study showed that chalcone 34 significantly inducedcell cycle arrest in G

2M phase at 02 120583M concentration

In vitro immunofluorescence staining and tubulin polymer-ization assay displayed that chalcone 34 promoted tubulinpolymerization into microtubules and caused microtubulestabilization similar to paclitaxel which is suggesting that


O OH

OH

37

Figure 11 Chalcone obtained by using a fission yeast bioassay (37)Concentration of 8120583Mto 20 120583MinducesDNAdamagewhich blockscell cycle progression at the G

2M transition in a Rad3-dependent

and Chk1-dependent manner

chalcone 34 is a microtubule stabilizer via enhancing the rateof tubulin polymerizationThen in in vivo study 34 exhibitedpotent inhibitory activities in humanHepG2 xenograft tumormodels [41] Chalcone derivatives named parasiticins C 35and 36 (Figure 10) were isolated from the leaves ofCyclosorusparasiticus The in vitro cytotoxic activities were evaluatedagainst lung cancer A549 hepatocellular carcinoma HepG2breast cancer MCF-7 and MDA-MB-231 leukemia ALL-SIL and pancreatic cancer SW1990 Compounds 35 and 36exhibited substantial cytotoxicity against all six cell linesespecially toward HepG2 with the IC

50values of 160 and

282 120583M respectively which is comparable to the doxorubicinpositive control (119 120583M) They induced apoptosis in theHepG2 cell line In the clonogenicity assay onHepG2 cell linecapacity of single cancer cells to generate colonies was almostcompletely blocked by compound 35 at a concentration of24 120583M Compound 35 showedmore potent cytotoxicity than36 suggesting that the presence of an additional lactone ringfused enhances the cytotoxic activity [42]

38 Chalcone obtained by Using a Fission Yeast BioassayA fission yeast Schizosaccharomyces pombe was utilized inbioassay guided screening on several plant extracts to searchfor anticancer agents by Sanchez-Pico et al (2014)

It was found that an extract from leaves of Corema albumbelonging to family Ericaceae had antiproliferative activity2101584041015840-Dihydroxychalcone 37 (Figure 11) the promising cyto-toxic compound was found in this extract and cytotoxicactivity is likely due to its ability to induce DNA damagewhich blocks cell cycle progression at theG

2M transition in a

concentration of 8120583M to 20120583M Compound 37 could induceDNA damage or interfere with DNA replication whichwould eventually result in the activation of the cell cyclecheckpoints thus blocking cell cycle in G

2 In subsequent

study deletions of Rad3 Chk1 and Cds1 three key kinasesrequired for DNA checkpoints operating at G

2M were done

Rad3 is required in order to signal downstream of eitherDNA replication problems or DNA damage whereas Chk1transmits DNA damage-induced signals and Cds1 signals inresponse to defective DNA replication It was found thatboth Rad3 and Chk1 deletions suppressed the cell cycle blockproduced by compound 37 while Cds1 deletion showedpartial suppression suggesting that the G

2M block observed

in compound 37 is mostly caused by the activation ofDNAdamage checkpoint responseMethylmethanesulfonate(MMS) an alkylating compound that induces DNA damagewas used as control Thus compound 37 (8ndash20120583M) directly

O

O

OH

38

N+minusO

Figure 12 Chalcone against cathepsin B and cathepsin H obtainedfrom goat liver (38) 119870

119894values of 618 times 10minus8M for cathepsin B 119870

119894

values of 28 times 10minus7M for cathepsin H cathepsin B and cathepsin Hinhibitor

O

N

N

NNR

39a = Ph 39b =

F3C

Figure 13 Chalcones against brain cancer cell line ((39a) and(39b)) cotreatment of 10120583M with TRAIL (25 ngmL) TRAIL sen-sitizers

or indirectly causes damage to the DNA which results in aRad3-dependent and Chk1-dependent cell cycle block at theG2M transition [43]

39 Chalcone against Cathepsin B and Cathepsin H Obtainedfrom Goat Liver Cathepsins have emerged as a potentialtarget for chemoprevention and anticancer therapy Increasedlevels of cathepsin B and cathepsin H in a variety of tumorshave shown their contribution towards invasion and metas-tasis

Molecule 38 (Figure 12) has been found to be potentamong the synthesized inhibitors which inhibits cathepsinB and HThe119870

119894(inhibition constant) value against cathepsin

B was 618 times 10minus8M and 28 times 10minus7M for cathepsin H Theinhibition was of competitive type 21015840-Hydroxychalconeshave been evaluated as potential inhibitors to these cysteineproteases probably due to presence of 120572120573-unsaturated car-bonyl moiety in the molecule -CH

2SH moiety present at the

active site of enzymes can interact with the electron deficientcenter present in the chalcones inhibiting the enzymesactivity Nitrosubstitution is useful for an effective interactionwith cathepsins B and H Its inhibition to cathepsin B ascompared with cathepsinH indicates that cathepsin Brsquos activesite is more susceptible to these compounds as compared tocathepsin H The results were also found to be consistentwhen compared with in silico docking studies [44]

310 Chalcones against Brain Cancer Cell Lines Cotreatmentwith a chemosensitizer such as compounds 39a and 39b(Figure 13) and TRAIL was found to be more efficient to treatGBM(GlioblastomaMultiforme) than treatmentwithTRAILalone

GBM is one of themost aggressive forms of humanmalig-nant brain tumors characterized by rapid growth extensive


O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2

Figure 14 Chalcone against multidrug resistant cancer cell lines (40) IC50value of 254 120583M arresting the cell cycle between G

0G1phases

which is via the strong induction of apoptosis by disrupting mitochondrial membrane potential (MMP) and an increased production ofreactive oxygen species (ROS) (41) Combined effects of 36 and Tipifarnib reduce the IC

50value of Tipifarnib from 90 120583M (applied alone)

to 38 120583M increased the expression of HIF-1120572 (42) GI50of 387 120583M and (43) GI

50of 395 120583M trigger cell cycle arrest at the G

2M phase and

apoptotic cell death aurora A kinase inhibitor

invasiveness and robust neoangiogenesis Against humanCRT-MG astroglioma cells by using the lactate dehydroge-nase (LDH) release assay it was found that compounds 39aand 39b with TRAIL (25 ngmL) showed good cytotoxicity2-Ethylamino and substituted triazole groups are promisingtemplates in the backbone of chalcone to develop TRAILsensitizers as anticancer agents [45]

311 Chalcone against Multidrug Resistant Cancer Cell LinesChemoresistance is a clinical problem that severely lim-its treatment success MDR (multidrug resistance) can bedefined as the ability of cancer cells to survive exposure to dif-ferent chemotherapeutic agents and is a major cause of treat-ment failure in human cancers 41015840-Hydroxy-261015840-dimethox-ychalcone 40 (Figure 14) was isolated from Polygonumlimbatum with IC

50values of 254 120583M against multidrug

resistant CEMADR5000 leukemia cells P-glycoprotein-expressing andmultidrug resistantCEMADR5000 cells weremuchmore sensitive toward compound 40 than doxorubicin(IC50= 19512 120583M) which is a reference drug Compound 40

(Figure 14) has been found to arrest the cell cycle betweenG0G1phases which is via the strong induction of apoptosis

by disrupting mitochondrial membrane potential (MMP)and an increased production of reactive oxygen species (ROS)in the studied leukemia cell line It was found that caspaseswere not involved in the apoptotic pathway induced bycompound 40The presence of hydroxyl (-OH) andmethoxy

(-OCH3) substituents influences the activity of compound 40

[46]The membrane transporter P-glycoprotein (P-gp) en-

coded by mdr1 gene is the main mechanism responsiblefor resulting in decreased intracellular drug accumulationin human MDR cancers Mitogen activated protein (MAP)kinase pathway is involved in P-gp-mediatedMDR Dimer ofchalcone named as tomoroside B 41 (Figure 14) was isolatedfrom the aerial parts of Helichrysum zivojinii The combinedeffects of chalcone dimer 41 and Tipifarnib (the inhibitorof MAP kinase signaling cascade a farnesyltransferaseinhibitor) inMDR cancer cell line NCI-H460R were foundThese results point to the ability of compound 41 to enhanceTipifarnib efficacy in MDR cancer cells as it reduced the IC

50

for Tipifarnib from 90 120583M(applied alone) to 38 120583MActivitywas compared to Tipifarnib employing human sensitive non-small cell carcinoma cell line NCI-H460 (IC

50= 198 120583M for

compound 41 alone) its multidrug resistant (MDR) counter-part NCI-H460R (IC

50= 172 120583M for compound 41 alone)

and spontaneously immortalized normal human keratino-cyte cell line HaCaT The concentration around 100 120583M ofcompound 41 significantly inhibited the growth of normalHaCaT cells considering that HaCaT are normal but trans-formed cells with immortalized phenotype these resultspoint to the potential of compound 41 to exert the cancerpreventive effects Compound 41 increased the expression ofHIF-1120572 probably by exerting antioxidant and redox status


modulator effect Compound 41 increased the expression ofHIF-1120572 and acted synergistically with Tipifarnib probablyby inhibiting the MAP kinase prosurvival signaling [47]To identify potent anticancer agents against the cisplatin-resistant human ovarian cancer cell line A2780Cis a seriesof compounds were synthesized by Shin et al (2014) Amongthem the two most active compounds were 42 (GI

50=

387 120583M) and 43 (GI50

= 395 120583M) (Figure 14) It was foundthat compounds42 and43 trigger cell cycle arrest at theG

2M

phase and apoptotic cell death in A2780Cis cancer cellsThe compounds act through caspase-7 activation Aurora Akinase is known to be involved in cell cycle arrest at the G

2M

phase In vitro aurora A kinase assay of compound 42 showedthe half-maximal inhibitory concentration (IC

50) of 664 120583M

Because aurora A kinase may not be a real molecular targetof compound 42 GI

50value of compound 42 is higher than

the IC50value of 42 [48]

4 Conclusion

Chalcone architecture linked with various substitutions suchasmethoxy amino and hydroxyl and alteration of both ringshas been found to be effective in making it a potential can-didate in the anticancer armamentarium The related studiesshowed excellent cytotoxic activities of chalcones in thedifferent cell death pathways not just acting in blocking theprocess of cell division Inhibitory concentrations in nanom-olar range were impressive to show its ability to arrest celldivision Furthermore besides preclinical study clinicalstudy of chalcone may yield the development of researchin this field It is expected that this review may give themedicinal chemists a basis to get in touch with the recentupdates and will be helpful for enrichment in this field

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are grateful to Department of Pharmacy TripuraUniversity (a Central University) and also to UniversityGrant Commission (UGC) Govt of India for providingStartupGrant for newly recruited faculty as financial support

References

[1] AmericanCancer SocietyGlobal Cancer Factsamp Figures Amer-ican Cancer Society Atlanta Ga USA 2nd edition 2011

[2] M R Alison ldquoCancerrdquo Encyclopedia of life sciences NaturePublishing Group 2011 httpwwwelsnet

[3] DNDharTheChemistry of Chalcones andRelatedCompoundsJohn Wiley amp Sons New York NY USA 1981

[4] N K Sahu S S Balbhadra J Choudhary and D V KohlildquoExploring pharmacological significance of chalcone scaffold areviewrdquoCurrentMedicinal Chemistry vol 19 no 2 pp 209ndash2252012

[5] BV BabuNKKonduruWNakanishi SHayashi NAhmedand PMMitrasinovic ldquoExperimental and theoretical advancesin functional understanding of flavonoids as anti-tumor agentsrdquoAnti-Cancer Agents in Medicinal Chemistry vol 13 no 2 pp307ndash332 2013

[6] A Boumendjel X Ronot and J Boutonnat ldquoChalcones deriva-tives acting as cell cycle blockers potential anti-cancer drugsrdquoCurrent Drug Targets vol 10 no 4 pp 363ndash371 2009

[7] D I Batovska and I T Todorova ldquoTrends in utilization ofthe pharmacological potential of chalconesrdquo Current ClinicalPharmacology vol 5 no 1 pp 1ndash29 2010

[8] J R Dimmock D W Elias M A Beazely and N M KandepuldquoBioactivities of chalconesrdquo Current Medicinal Chemistry vol6 no 12 pp 1125ndash1149 1999

[9] Z Rozmer and P Perjesi ldquoNaturally occurring chalcones andtheir biological activitiesrdquo Phytochemistry Reviews 2014

[10] N Abu W Y Ho S K Yeap et al ldquoThe flavokawains uprisingmedicinal chalconesrdquo Cancer Cell International vol 13 no 1article 102 pp 2ndash7 2013

[11] E-H Zhang R-F Wang S-Z Guo and B Liu ldquoAn update onantitumor activity of naturally occurring chalconesrdquo Evidence-Based Complementary and Alternative Medicine vol 2013Article ID 815621 22 pages 2013

[12] H Lodish A Berk S L Zipursky P Matsudaira D Baltimoreand J Darnell Molecular Cell Biology W H Freeman NewYork NY USA 4th edition 2000

[13] K H Vousden and D P Lane ldquop53 in health and diseaserdquoNature ReviewsMolecular Cell Biology vol 8 no 4 pp 275ndash2832007

[14] EWinter L D Chiaradia C A S deCordova R J Nunes R AYunes and T B Creczynski-Pasa ldquoNaphthylchalcones induceapoptosis and caspase activation in a leukemia cell line therelationship between mitochondrial damage oxidative stressand cell deathrdquo Bioorganic and Medicinal Chemistry vol 18 no22 pp 8026ndash8034 2010

[15] E Winter L D Chiaradia A H Silva R J Nunes R AYunes and T B Creczynski-Pasa ldquoInvolvement of extrinsicand intrinsic apoptotic pathways together with endoplasmicreticulum stress in cell death induced by naphthylchalcones in aleukemic cell line advantages ofmulti-target actionrdquoToxicologyin Vitro vol 28 no 5 pp 769ndash777 2014

[16] A Costa L D Chiaradia-Delatorre L dos Santos Bubniak etal ldquoApoptotic effect of synthetic 210158404101584051015840-trimethoxychalconesin human K562 and Jurkat leukemia cellsrdquoMedicinal ChemistryResearch vol 23 no 10 pp 4301ndash4319 2014

[17] C Seidel M Schnekenburger C Zwergel et al ldquoNovel inhib-itors of human histone deacetylases design synthesis andbioactivity of 3-alkenoylcoumarinesrdquo Bioorganic amp MedicinalChemistry Letters vol 24 no 16 pp 3797ndash3801 2014

[18] B Orlikova J C J M D S Menezes S Ji S P Kamat J AS Cavaleiro and M Diederich ldquoMethylenedioxy flavonoidsassessment of cytotoxic and anti-cancer potential in humanleukemia cellsrdquo European Journal of Medicinal Chemistry vol84 pp 173ndash180 2014

[19] J M Lee M S Lee D Koh Y H Lee Y Lim and S Y ShinldquoA new synthetic 21015840-hydroxy-246-trimethoxy-5101584061015840-naphtho-chalcone induces G2M cell cycle arrest and apoptosis by dis-rupting themicrotubular network of human colon cancer cellsrdquoCancer Letters vol 354 no 2 pp 348ndash354 2014

[20] C W Mai M Yaeghoobi N Abd-Rahman Y B Kang andM R Pichika ldquoChalcones with electron-withdrawing and elec-tron-donating substituents anticancer activity against TRAIL


resistant cancer cells structure-activity relationship analysisand regulation of apoptotic proteinsrdquo European Journal ofMedicinal Chemistry vol 77 pp 378ndash387 2014

[21] VMarkovic NDebeljak T Stanojkovic et al ldquoAnthraquinonendashchalcone hybrids synthesis preliminary antiproliferative evalu-ation andDNA-interaction studiesrdquo European Journal ofMedic-inal Chemistry vol 89 pp 401ndash410 2015

[22] N Singh J Sarkar K V Sashidhara S Ali and S Sinha ldquoAnti-tumour activity of a novel coumarin-chalcone hybrid is medi-ated through intrinsic apoptotic pathway by inducing PUMAand altering BaxBcl-2 ratiordquo Apoptosis vol 19 no 6 pp 1017ndash1028 2014

[23] M Wan L Xu L Hua et al ldquoSynthesis and evaluation of novelisoxazolyl chalcones as potential anticancer agentsrdquo BioorganicChemistry vol 54 pp 38ndash43 2014

[24] B Kolundzija V Markovic T Stanojkovic et al ldquoNovel anthra-quinone based chalcone analogues containing an imine frag-ment synthesis cytotoxicity and anti-angiogenic activityrdquo Bio-organic amp Medicinal Chemistry Letters vol 24 no 1 pp 65ndash712014

[25] C-H Tseng Y-L ChenC-YHsu et al ldquoSynthesis and antipro-liferative evaluation of 3-phenylquinolinylchalcone derivativesagainst non-small cell lung cancers and breast cancersrdquo Euro-pean Journal of Medicinal Chemistry vol 59 pp 274ndash282 2013

[26] D Kumar N Maruthi Kumar M P Tantak M Ogura EKusaka and T Ito ldquoSynthesis and identification of 120572-cyanobis(indolyl)chalcones as novel anticancer agentsrdquo Bioorganic ampMedicinal Chemistry Letters vol 24 no 22 pp 5170ndash5174 2014

[27] W He Y Jiang X Zhang Y Zhang H Ji and N Zhang ldquoAnti-cancer cardamonin analogs suppress the activation of NF-kappaB pathway in lung cancer cellsrdquo Molecular and CellularBiochemistry vol 389 no 1-2 pp 25ndash33 2014

[28] S S Chauhan A K Singh S Meena et al ldquoSynthesis of novel120573-carboline based chalcones with high cytotoxic activity againstbreast cancer cellsrdquo Bioorganic amp Medicinal Chemistry Lettersvol 24 no 13 pp 2820ndash2824 2014

[29] C L Ye X G Liu Q Huang and X L Zhao ldquoInduction ofapoptosis in human hepatoma SMMC-7721 cells using 2101584041015840-dihydroxy-61015840-methoxy-3101584051015840-dimethylchalcone a chalconefrom buds of Cleistocalyx operculatusrdquo Food Science and Bio-technology vol 22 no 5 pp 1421ndash1427 2013

[30] L Wang G Chen X Lu et al ldquoNovel chalcone derivatives ashypoxia-inducible factor (HIF)-1 inhibitor synthesis anti-inva-sive and anti-angiogenic propertiesrdquoEuropean Journal ofMedic-inal Chemistry vol 89 pp 88ndash97 2015

[31] K-H Shen J-K Chang Y-L Hsu and P-L Kuo ldquoChalconearrests cell cycle progression and induces apoptosis throughinduction of mitochondrial pathway and inhibition of nuclearfactor kappa B signalling in human bladder cancer cellsrdquo Basicamp Clinical Pharmacology amp Toxicology vol 101 no 4 pp 254ndash261 2007

[32] M R El Sayed Aly H H Abd El Razek Fodah and S Y SalehldquoAntiobesity antioxidant and cytotoxicity activities of newlysynthesized chalcone derivatives and their metal complexesrdquoEuropean Journal of Medicinal Chemistry vol 76 pp 517ndash5302014

[33] M Abdel-Aziz S-E Park G E-D A A Abuo-Rahma MA Sayed and Y Kwon ldquoNovel N-4-piperazinyl-ciprofloxacin-chalcone hybrids synthesis physicochemical properties anti-cancer and topoisomerase I and II inhibitory activityrdquo EuropeanJournal of Medicinal Chemistry vol 69 pp 427ndash438 2013

[34] GWang F PengD Cao et al ldquoDesign synthesis and biologicalevaluation of millepachine derivatives as a new class of tubulinpolymerization inhibitorsrdquo Bioorganic amp Medicinal Chemistryvol 21 no 21 pp 6844ndash6854 2013

[35] G Wang C Li L He et al ldquoDesign synthesis and biologicalevaluation of a series of pyrano chalcone derivatives containingindole moiety as novel anti-tubulin agentsrdquo Bioorganic ampMedicinal Chemistry vol 22 no 7 pp 2060ndash2079 2014

[36] J Zhang F-J Ji Y Gu X-Y Zhang and S-X Qiao ldquoChal-cones derivatives as potent Cell division cycle 25B phosphataseinhibitorsrdquo Pharmacological Reports vol 66 no 3 pp 515ndash5192014

[37] U Sankappa Rai A M Isloor P Shetty K S R Pai and HK Fun ldquoSynthesis and in vitro biological evaluation of newpyrazole chalcones and heterocyclic diamides as potential anti-cancer agentsrdquo Arabian Journal of Chemistry vol 8 no 3 pp317ndash321 2015

[38] Y-P Li Y-C Yang Y-K Li et al ldquoPrenylated chalcones fromDesmodium renifoliumrdquo Phytochemistry Letters vol 9 no 1 pp41ndash45 2014

[39] A H Banday S M M Akram and S A Shameem ldquoBenzy-lidine pregnenolones and their oximes as potential anticanceragents synthesis and biological evaluationrdquo Steroids vol 84 pp64ndash69 2014

[40] R Pingaew A Saekee P Mandi et al ldquoSynthesis biologicalevaluation and molecular docking of novel chalcone-coumarinhybrids as anticancer and antimalarial agentsrdquo European Jour-nal of Medicinal Chemistry vol 85 pp 65ndash76 2014

[41] D Cao X Han G Wang et al ldquoSynthesis and biologicalevaluation of novel pyranochalcone derivatives as a new class ofmicrotubule stabilizing agentsrdquo European Journal of MedicinalChemistry vol 62 pp 579ndash589 2013

[42] H Wei X Zhang G Wu et al ldquoChalcone derivatives from thefern Cyclosorus parasiticus and their anti-proliferative activityrdquoFood and Chemical Toxicology vol 60 pp 147ndash152 2013

[43] A Sanchez-Pico A J Leon-Gonzalez C Martın-Cordero andR R Daga ldquoScreening for natural anticancer agents using afission yeast bioassayrdquo Phytochemistry Letters vol 8 pp 184ndash189 2014

[44] N Raghav and S Garg ldquoSAR studies of o-hydroxychalconesand their cyclized analogs and study them as novel inhibitorsof cathepsin B and cathepsin Hrdquo European Journal of Pharma-ceutical Sciences vol 60 pp 55ndash63 2014

[45] Y Ahn S Oh S J Lee et al ldquoSynthesis of diethylamino-curcumin mimics with substituted triazolyl groups and theirsensitization effect of TRAIL against brain cancer cellsrdquo Bioor-ganic and Medicinal Chemistry Letters vol 24 no 15 pp 3346ndash3350 2014

[46] VKuete AH LNkuete A TMbaveng et al ldquoCytotoxicity andmodes of action of 41015840-hydroxy-2101584061015840-dimethoxychalcone andother flavonoids toward drug-sensitive and multidrug-resistantcancer cell linesrdquo Phytomedicine vol 21 no 12 pp 1651ndash16572014

[47] I S Aljancic I Vuckovic M Jadranin et al ldquoTwo structurallydistinct chalcone dimers from Helichrysum zivojinii and theiractivities in cancer cell linesrdquo Phytochemistry vol 98 pp 190ndash196 2014

[48] S Y Shin H Jung S Ahn et al ldquoPolyphenols bearing cinna-maldehyde scaffold showing cell growth inhibitory effects onthe cisplatin-resistant A2780Cis ovarian cancer cellsrdquo Bioor-ganic ampMedicinal Chemistry vol 22 no 6 pp 1809ndash1820 2014

Submit your manuscripts athttpwwwhindawicom

PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom

Volume 2014

ToxinsJournal of

VaccinesJournal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

AntibioticsInternational Journal of

ToxicologyJournal of


StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Drug DeliveryJournal of



Advances in Pharmacological Sciences

Tropical MedicineJournal of


Medicinal ChemistryInternational Journal of


AddictionJournal of



BioMed Research International

Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Autoimmune Diseases


Anesthesiology Research and Practice

ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of


Pharmaceutics


MEDIATORSINFLAMMATION

of


O

AB

Figure 1 Chemical structure of chalcone

S

M

Cell cycle arrest Apoptotic cell death

Activation of caspasesUpregulation of Bax Bak BidDownregulation of Bcl-2 Bcl-xLp53 upregulation

All chromosomesaligned in the M

phase

Chalcone

monitors the DNAreplication andDNA damage

monitors the size ofthe cell and

DNA damage

S phaseDNA synthesis

Trigers mitochondrialapoptotic pathway anddeath receptor pathway

G2M phase arrest

G2

G2M checkpoint

G1

G1S checkpoint

Figure 2 Action of chalcone on cell cycle

articles mentioned in the text but also in more recent articleswhich have eluded the authors [9ndash11] This review (surveyeddatabase 2013ndash2015) is complementary to the researchers foroptimizing the lead chalcone as potential anticancer scaffoldwith increased potency

2 Molecular Mechanism of Apoptosis

Cell death in tumors is a passive degradative reaction knownas necrosismost likely due to inadequate angiogenesis withinthe tumor cell On the other hand apoptotic cell deathincludes a number of gene families and altering proapoptoticpathways specifically in tumors is something of a holy grailfor oncology andmedicinal chemistryWhen cell productionrate exceeds the cell loss rate through mitosis it results innet tumor Apoptosis is often referred to as an altruistic cellsuicide process where damaged DNA in the cell producessignals resulting in both repair and apoptotic pathways andif repair cannot be done then the cell undergoes apoptosis ina manner like ldquobetter dead than wrongrdquoThe cells which har-bour mutant p53 will have a survival advantage over normalcells In response to DNA damage normal cells upregulatep53 which acts as a transcription factor for cell cycle arrestand apoptosis thereafter p53-mutant cells become unable tocarry out this protective arrest or apoptosis andmight survive

with what otherwise would turn to lethal genetic damageperhaps explaining why p53 mutations are so common inhuman cancers The decision of apoptosis is largely playedout on the mitochondrial surface between three major fam-ilies the so-called three horsemen of apoptosis The finalexecutioner proteases called caspases play pivotal role bycleaving critical substrates such as DNA repair enzymes andcytoskeletal proteins but they are stored as zymogens boundto an apoptotic adenosine triphosphate apoptosis-activatingfactor-1 (Apaf-1) which is the mammalian homologue of thenematode Caenorhabditis elegans cell death protein Ced-4Once cytochrome c is released it binds to the cytosolic pro-tein Apaf-1 to facilitate the formation of apoptosome whichin turn activates apoptotic caspases However proapoptoticBcl-2 family proteins such as Bax which is upregulated byp53 can activate apoptosis by releasing cytochrome c (cyt-c) from mitochondria where Apaf-1 activation takes place[2 6 12 13]

3 Molecular Insights of Anticancer Chalcones

Literature on anticancer chalcones highlights the employ-ment of three pronged strategies namely structural manip-ulation of both aryl rings replacement of aryl rings with


OCl

2

O

3

O

O

O

O

OH

7

O

1

O2N

O

O

O

6c

OCH3

H3CO

OR

OCH3

OCH3

OCH3

4 R = 3-OCH3 5 R = 4-CF3

O O

O

O O

O

R1

R3

R2


R3

R2R1

6a = R1 = OMe R2 = OMe R3 = H


50of 40 120583M and (3) CC



50values (4 to 8 120583M) and (5) IC







50



0G1 S or



2M fraction They


50





O

9

NH2

HO

O

R1R3

R2

8 R1 = R2 = R3 = OMe











50at 12 120583M











O

OO

OO

11

O

O

O

O

R

10a= R = H 10b= R = 2-CH3 10c = R = 2-NO2



2M phases (11) IC












50













1phase except




NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R












IC50of 225 120583M and (19b) IC







50





2M phase after










O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


OCl

2

O

3

O

O

O

O

OH

7

O

1

O2N

O

O

O

6c

OCH3

H3CO

OR

OCH3

OCH3

OCH3

4 R = 3-OCH3 5 R = 4-CF3

O O

O

O O

O

R1

R3

R2


R3

R2R1

6a = R1 = OMe R2 = OMe R3 = H


50of 40 120583M and (3) CC



50values (4 to 8 120583M) and (5) IC







50



0G1 S or



2M fraction They


50





O

9

NH2

HO

O

R1R3

R2

8 R1 = R2 = R3 = OMe











50at 12 120583M











O

OO

OO

11

O

O

O

O

R

10a= R = H 10b= R = 2-CH3 10c = R = 2-NO2



2M phases (11) IC












50













1phase except




NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R












IC50of 225 120583M and (19b) IC







50





2M phase after










O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O

9

NH2

HO

O

R1R3

R2

8 R1 = R2 = R3 = OMe











50at 12 120583M











O

OO

OO

11

O

O

O

O

R

10a= R = H 10b= R = 2-CH3 10c = R = 2-NO2



2M phases (11) IC












50













1phase except




NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R












IC50of 225 120583M and (19b) IC







50





2M phase after










O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O

OO

OO

11

O

O

O

O

R

10a= R = H 10b= R = 2-CH3 10c = R = 2-NO2



2M phases (11) IC












50













1phase except




NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R












IC50of 225 120583M and (19b) IC







50





2M phase after










O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


NO

14MeO

O

OH

HO

17

OH

O

HO

O18

ON

O Cl

Br

Ar

H3C

NO2

12a = Ar =

12b= Ar =

O

O

O

RN

Cl

O

C

13b R =

13d R =13c R =

13a R =

CF3

H2CH2

NH

CNO

NH

F

16

H3CO

NO

MeO

S

15

H2N

N

N

HO

R












IC50of 225 120583M and (19b) IC







50





2M phase after










O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O OH

O

HO

O

21

O

HO OH

20

CH3

CH3

OCH3





50values







O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O

22

O

R

NMO

ONO

R23 = R = Me M = Cu2+





50value of






50level More-


50ranging from


50values of 015 036 062 061 and 052 120583M





OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


OO

O N

O

25

O

N

F

HNN

F

29

O

30

OHHOHO

MeO

NH

N

NO N

O

COOHF

Ar

O


24e = Ar = 34-OCH2O-C6H3

O

OO

N R

26 R = propionyl

O OH

O

R

27 = R = 4-Cl28 = R = 4-CH2CH5C(CH3)2

HOO

Ar








2M









50value of 022120583M


2M





O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O

O

O

NNN

O

O

O

32

OO

O

NNN

O

O

O

33

OO

O O

O

O

34

O

O

OH

OH

O

35

CH3O OH

OH

36

CH3

CH3

H3CO


= 053 120583M and (33) IC50


2M phase promoted













50value of 102 120583M


50= 053 120583M) displayed


50= 005 120583M) was taken


50= 426 120583M)


50






O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O OH

OH

37





50values of 160 and




2M transition in a


2 In subsequent


2M were done


2M block observed


O

O

OH

38

N+minusO



119894


O

N

N

NNR

39a = Ph 39b =

F3C












O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of


O

O

HO

HO

HO

HO HO

O OH

OHOH

O

O

OH

OH

OH

OH

OH

O41

OH

O

43

H3CO

H3COH3CO

OCH3

O

40

OH

OCH3

H3CO

OHO

R1

R2

R3R4

42 R1 = R2 = R3 = R4 = OMe

CH2


0G1phases





2M phase and











50


50= 198 120583M for






50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



50=

387 120583M) and 43 (GI50


2M


2M


50) of 664 120583M




4 Conclusion




Acknowledgments


References























































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of



































Volume 2014

ToxinsJournal of

VaccinesJournal of















AddictionJournal of






Autoimmune Diseases




Journal of


Pharmaceutics



of

Review Article Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight · 2019. 7....

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Transcript of Review Article Chalcone Scaffold in Anticancer Armamentarium: A Molecular Insight · 2019. 7....