Open access peer-reviewed chapter

Chalcones: Potential Anticancer Agents

Written By

Adam McCluskey and Cecilia Russell

Submitted: August 22nd, 2019 Reviewed: January 30th, 2020 Published: February 3rd, 2021

DOI: 10.5772/intechopen.91441

Chapter metrics overview

434 Chapter Downloads

View Full Metrics

Abstract

Chalcones in their various guises have been considered either valid and critically important lead compounds in the development of novel anticancer agents or as pan assay interference compounds, PAINS. Medicinal chemistry is replete with exemplars from both “camps” progressing to clinical utility. Chalcones offer a simple starting point for the development of specific compounds with high levels of activity toward key biological targets. Chalcones have been shown to display a wide array of anticancer compounds. This chapter seeks to offer an overview of key examples in an effort to encourage further reading and research in development in this intriguing space.

Keywords

  • chalcones
  • biologically active
  • cancer
  • structure activity relationship data

1. Introduction

Arguably, cancer represents one of the most serious threats to human health. Its incidence is on the rise, and while there have been an increasing number of new drugs and new targets over the past 50 or so years, it is still responsible for multiple deaths across the globe [1]. The advent of targeted therapies arguably commenced with the discovery and clinical use of the protein kinase inhibitor imatinib [2]. Since this first report, there have been multiple novel protein kinase inhibitor-based drugs entering clinical use [3]. More recently, there has been a significant shift in treatment paradigms to the use of mono-clonal antibodies, with this market predicted to be >$US300 billion by 2030 [4]. Despite this, the survival rates for metastatic breast cancer (Stage IV, 5-year survival is <25%), for pancreatic cancer this is a more dire 7% [5]. Treatment of glioblastoma and other neurological cancers has not advanced in the past 3–4 decades [6, 7].

Advertisement

2. Biological activity of chalcones

Chalcones or analogues or derivatives of (E)-1,3-diphenyl-2-propene-1-one represent a very diverse array of molecules. This family of molecules are known to possess a myriad of biological activities spanning (but not limited to) antidiabetic, antimicrobial, antioxidant, anti-inflammatory, anticancer and chemopreventative properties [8]. A number of chalcones are in current clinical use, exemplified by the selected analogues shown in Figure 1 and in other figures throughout this chapter. Note that the breadth of the potential applications of chalcones in cancer is expansive and beyond the scope of this chapter, the intent here is to supply a snapshot of chalcones and their targets to encourage further exploration, by the reader, of this area [8, 9, 10].

Figure 1.

Chemical structures of selected clinically used chalcones: metochalcone (1), sofalcone (2), isoliquiritigenin, xanthohumol (4) and hesperidin methylchalcone (5).

Despite the numerous examples of clinically used chalcones, they are often overlooked for lead development as a function of PAINS filtering [11]. We note the key role here of the medicinal chemist in understanding both the limitations of the lead scaffold, potential promiscuity and the nature of the biological screening conducted. If the scaffold limitations are understood, there is limited rationale in excluding a whole compound class, especially given the current utility of these analogues. However, vigilance is required in SAR examinations. We recommend the removal of PAINS filters from preliminary screening cascades and the introduction of robust orthogonal assay procedures to enable rapid identification of true lead compounds [12, 13]. In so doing, we believe that this will increase the attractiveness of chalcones as leads; potentially matching their use will greatly increase the attractiveness of chalcones as potential starting points for drug discovery [9, 14].

Historically, chalcones, for example 15, have been used in a therapeutic environment for millennia. Typically, through the ingestion of plants and herbs, chalcones have been used in the treatment of a myriad of conditions, spanning but not limited to inflammation, diabetes, and the topic of this chapter, cancer [8, 15, 16, 17, 18]. Metochalcone (1) and sofalcone (2) have been used in the treatment of ulcers and as mucoprotective agents, respectively (Figure 1) [15, 16].

Being able to switch between two chalconoid structures (6aand 6b; Figure 2) in principle establishes two Michael acceptor possibilities for this class of compounds. It is important to recognize at this point that key researchers view these and molecules such as these as PAINS [11]. As such, caution should be used in determining absolute effects and ascribing them to specific compounds’ actions in a biological system. Clearly, Michael acceptors are generally biologically active. Michael acceptor-type compounds are known to be involved in cell signaling cascades and in many cases these compounds are capable of forming covalent attachments to the sulfhydryl of cysteine or other thiols to obtain the Michael adduct 7(Figure 3), which may play an important role in their biological activities [19, 20, 21, 22, 23]. Interestingly, the past reservations about small molecules forming covalent linkages with proteins are subsiding with a wide variety of targeted drugs operating via a covalent interaction mode [24]. This may lead to a resurgence in the examination of chalcones as lead compounds.

Figure 2.

The interplay between the s-cis and s-trans chalconoid structural motifs available to simple chalcones.

Figure 3.

Michael addition of a chalcone (6a) with cysteine to form the Michael adduct7.

Despite the PAINS expectation, there have been a large number of chalcones reported to elicit anticancer activity via specific cell signaling pathways. Of note are those analogues (810) that target the NF-kB pathway. It has been reported that the anticancer activity of 3-hydroxy-4,3′,4′,5′-tetramethoxychalcone (9) correlates with its NF-κB inhibitory activity. The reported mechanism of action requires interaction with the IKKb cysteines (46% inhibition; 10 μM) [23] proceeding via a JNK-mediated autophagy pathway triggering c-IAP (Figure 4) [25].

A key feature of chalcone 9is its ability to synergize with existing clinical treatments. As a combination therapy, 9and the TNF-related apoptosis-inducing ligand (TRAIL) or cisplatin significantly enhanced its cytotoxicity in lung cancer cells. This effect is mediated via the suppression of cellular FLICE (FADD-like IL-1b-converting enzyme)-inhibitory protein large (c-FLIPL) and cellular inhibitor of apoptosis proteins (c-IAPs), which in combination activate autophagy [26, 27].

Within the NF-κB activation pathway the Toll-like receptor 4 (TLR4) and myeloid differentiation 2 (MD2) regulate the downstream signal transduction, such as MAPK phosphorylation. In a LPS-acute lung injury model chalcone 10inhibited the activity of MD2 reducing the inflammatory effects in this model [28].

Figure 4.

Exemplar chalcones known to be NF-κB inhibitors [28].

The removal of purported PAINS is more frustrating with recent examples where promiscuous inhibitors were not removed or the filters demonstrated an oversensitivity toward key compound types. That is, these filters may reject non-promiscuous compounds [12, 29].

The use of bioisosteric replacements with chalcones has high prevalence. Commencing with 2,4,6-trimethoxychalcone (11) a simple H (11) to F (12) isosteric replacement effected a 2-fold potency increase against HeLa (cervical cancer), A498 (renal cancer), and HepG2 (hepatocellular carcinoma) cells, with retention of activity against the A549 (lung adenocarcinoma epithelial) and A375 (skin malignant melanoma) cell lines with IC50 values spanning 0.03–0.120 μM (Table 1) [30].

Isosteric replacements have not been limited to simple Grimm’s isosteres, but they have been explored in nonclassical isostere space with the replacement of the central olefin with a small heterocyclic compound, such as the thiophene analogues shown in Table 2. These modified chalcones, for example, 14developed from 13, displayed good levels of cytotoxicity against a range of cancerous cell lines, with activities noted in the sub-μM to mid-nM range (0.160–0.510 μM) against HeLa, Molt-4 (human T-lymphocyte), CEM (human T-lymphocyte), L1210 (murine leukemia), and FM3A cell lines (murine mammary carcinoma) (Table 2) [31].

2.1 Chalcone hybrids

The biological activity of chalcones, and study thereof is not limited to the parent structure, but has recently expanded to encapsulate hybrid (chimeric) molecules. These chimeras combine the cytotoxicity of the parent chalcone (15) and the biological activity of the second drug. Multiple chimeric partners have been reported including antibiotics (ciprofloxacin, 16) linking through the N-aryl piperazine moiety. This allows access to the known inhibition of human DNA topoisomerase II, itself a known anticancer drug target (Figure 5) [32]. The chalcone-ciprofloxacin hybrid (17) inhibits human DNA topoisomerase II with potent in vitro anticancer activity against myriad of cancer cell lines [33, 34, 35, 36].

Figure 5.

Molecular hybrid obtained from the combination of chalcones (red) and N-aryl piperazine moiety (blue) [32].

Chalcones themselves are known to inhibit several anticancer targets, including thioredoxin reductase [21], and tubulin polymerization [37, 38]. Based on this there was an expectation (upheld) that chimeric molecules possessing a N-aryl piperazine and chalcone moieties would show higher potencies in the cell lines examined. Indeed, with these molecules considerable synergy arising from the combination of both partners was observed. Of the analogues reported, hybrid 17displayed the highest activity against cervical cancer (Hela; IC50 = 190 nM) and gastric cancer (SGC7901; IC50 = 410 nM) cells (Figure 5). These data compare favorably with that reported for cisplatin in the same cell lines with IC50 values of 20 and 12 μM, respectively [32].

The introduction of an active warhead has been accomplished through the synthesis of a α-bromoacryloylamido chalcones (Figure 6). Analogues of this nature are expected to act as covalent modifiers of their target protein [39]. Intriguingly, this combines the once thought of anathema of a covalent inhibitor with a compound classified as a PAINS [11, 24]. Yet, compounds 18and 19exhibit the highest activity against tumor cell growth (IC50 < 1 μM) and 10- to 100-fold increases in potency relative to the corresponding amide derivatives. Preliminary mechanism of action studies support apoptosis induction via mitochondrial engagement and activation of caspase-3. The related amide-linked dithiocarbamate-chalcone (20) also exhibited excellent growth inhibition against SK-N-SH cells, with an IC50 value of 2.03 μM, with negligible toxicity toward the normal GES-1 cell line (IC50 > 50 mM). However, this effect is via G0/G1 arrest and progression through apoptosis. The nature of the linking and pendant moieties affects the compound mode of action [40].

Figure 6.

Chemical structures of selected amide-linked chalcones bearing a covalently active warhead [40].

Chalcones have been hybridized via an ethylene glycol (or related diol linker) linker (often used in medicinal chemistry to enhance solubility) (Figure 7) [41, 42]. Analogues such as the 1,4-dihydropyridyl-chalcones (2124) show growth inhibition via an undetermined mechanism of action [43].

Figure 7.

Chemical structures of example chalcone hybrids linked though a diol linker [43].

Access to chalcones can be via traditional solution phase synthesis approaches, but in some instances there are reports of the use of solid supports. With 22, a supported intramolecular aza-Wittig reductive cyclization is utilized to afford a compound that showed high activity in the NCI-60 cell line panel. Acidity appears to be related to a high level of DNA binding as determined by thermal denaturing analysis [44, 45]. In keeping with the chimeric theme of this section, the inclusion of the dehydroartemisinin scaffold with and ethylene glycol spacer afforded 23,which showed a 6-fold potency enhancement relative to the apparent dehydroartemisinin with an IC50 of 300 nM [46].

While amide linages have been reported in the development of chalcone hybridism, the use of an ester moiety has the added advantage of allowing a cellular esterase cleavage of the hybrid to afford the two parent drugs. In principle, this may allow the presentation of three different biologically active compounds simultaneously: the hybrid, the chalcone, and the co-drug. The ester approach to coupling compound pharmacophores has been elegantly demonstrated with chalcone hybrids leveraging the often-present hydroxyl moiety. This approach, obviously, can also afford the corresponding ether (versus ester) linked analogue, which is significantly more cleavage resistant. Within this coupled pharmacophore environment, chalcone-amidobenzothiazole chimeras 24and 25are 0.185–3.3 μM potent across a panel of cancer cell lines (Figure 8). These analogues induce cell cycle arrest at the G2/M phase boundary [47]. Platinum incorporation into the amidobenzothiazole moiety with 26also gave excellent anticancer activity across 21 cell lines, but no real potency boost relative to the parent chalcone, but the chimera did yield a different long-term treatment and mechanism of apoptosis induction pathway that may be beneficial, especially in the onset of resistance should this occur [48].

Figure 8.

Selected ester and ether-linked chalcones [47,48].

Like a significant number of other chimeric compounds, “click-approaches” have also been applied in the development of a series of chalcone-coumarin chimeras, for example, 27and 28(Figure 9). Gratifyingly, these chimeras displayed higher efficacy against HepG2 cells than etoposide combined with negligible toxicity toward normal cells. Molecular docking studies support, but do not confirm, that these hybrids may act through binding with both tubulin and falcipain [49].

Figure 9.

Selected exemplars of Huisgen “click-linked” chalcone hybrid molecules [50].

Within this subset of click conjugates, 29demonstrated higher efficacy than the archetypal cytotoxic agent 5-fluorouracil against four human cancer cell lines (A459 (lung), Bel-7402 (hepatocellular), HeLa (cervical), and MCF-7 (breast)) and low cytotoxicity to NIH3T3 normal cells. Chalcone 29was synergistic with matrine against the A459 cell line demonstrating a favorable in vivo safety profile. Chalcone 29has been reported as capable of effecting aa ca 90% tumor burden reduction in a A459 mouse xenograft model (10.0 mg/kg/day, 20 days, iv) without any apparent loss of body weight [50].

Continuation of the click-linked chalcone hybrids with β-lactams [51] revealed 30as the most potent analogue within a discrete library. Of particular note was IC50 values < 1 μM against A549 and THP-1 (leukemia) cancer cells [52]. No other noteworthy analogue was reported.

Loch-Neckel et al. reported a further investigation of the mechanism of an analogue (31; Figure 10) [53]. In vitro and in vivo, it could inhibit glioma cell growth and induce mitochondrial apoptosis in U87-MG glioma cells via the inhibition of MDM2.

Figure 10.

Chemical structure of chalcone31, (E)-1-(2,5-dimethoxyphenyl)-3-(quinoxalin-6-yl)prop-2-en-1-one [53].

Several hybrids besides those discussed above have also been reported to exhibit potent anticancer activities (Figure 11). For example, β-carboline−chalcone (32) exhibits significant DNA binding interaction and DNA stabilization [54]. Imidazothiazole-chalcone (33) exhibits promising cytotoxicity with a microtubule destabilizing mechanism and could compete with colchicine [55, 56]. Anthraquinone-chalcone (34) shows high cytotoxicity in HeLa cells [57, 58]. The compound induces the activity of caspase-3 and caspase-8 in HeLa cells and has shown potent inhibition of MMP-2 secretion.

Figure 11.

Representatives of fused chalcone analogues [54].

2.2 Inhibition of tubulin

Clinically, targeting microtubules—the multifunctional cytoskeletal proteins comprising α- and β-tubulin heterodimers—has provided considerable success in the treatment of multiple cancers. Archetypal microtubule-targeting compounds include the taxanes used in the treatment of metastatic pancreatic cancer [59], and vinca alkaloids in the treatment of hematological and lymphatic neoplasms [60]. However, the continued use of these agents, like a significant number of anticancer drugs, is limited by toxicity (here neurotoxicity) and drug resistance [61, 62]. In this target space, multiple natural and synthetic chalcones (35-42) have been reported with microtubule activity (Figure 12).

Figure 12.

Examples of natural and synthetic chalcones with reported biological activity against microtubules [60].

Given the current toxicity and resistance issues with the taxanes and vinca alkaloids, in combination with the decorated microtubule activity of chalcones, it is not surprising that the hybridization of these compound classes has been explored. Some groups have attempted to develop these combination drugs using rational drug design approaches. Niu approached this via molecular docking and high-correlation quantitative pharmacophore models (40 compounds with experimental data and 800 decoys to discriminate active versus inactive molecules) were generated using the SAR of known tubulin inhibitors [63]. Model validation followed by virtual screening identified ca. 1000 drug-like molecules that were pharmacophore matched. Ultimately, five differentially substituted (4347) chalcones with diverse substituents and strong molecular interactions with the key amino acids in the tubulin-binding site were identified (Figure 13). Two compounds were of particular note, with 48and 49(Figure 14) demonstrating potent inhibitory activity against MCF-7 cells with IC50 values of 28 and 54 nM respectively [63].

Figure 13.

Selected chalcones arising as hits from QSAR-based drug design strategy [63].

Figure 14.

Chalcones with anticancer activity identified by integration of ligand-based pharmacophore screening and molecular docking studies [63]. Active against the breast cancer cell line, MCF-7 with IC50 = 28 and 54 nM, respectively (48,49).

Isolated from Combretum caffrum, Combretastatin A-4 is a microtubule-targeting natural product that has been further developed through imidazolone incorporation (51) (Figure 15) [64]. Evaluation in a broad-spectrum panel containing 53 human tumor cell lines spanning leukemia, non-small cell lung, colon, CNS, renal, prostate, ovarian, breast, and melanoma determined 51showed good anticancer activity, with GI50 values ranging from 1.26 to 10.5 μM and arresting cells at G2/M phase [65].

Figure 15.

Variety of linked chalcones including examples that induce apoptosis via the PI3K/Akt/mTOR pathway [64,65,66,67].

Other hybrids, for example, anthraquinone-chalcone (54), have high cytotoxicity toward HeLa cells but low toxicity to normal cells [66], as does the quinazolinone chalcone derivative (56), which induces mitochondria-dependent apoptosis and inhibits the PI3K/Akt/mTOR signaling pathway [67].

Chalcone modification afforded the amino-substituted 58with subsequent examination of these analogues for their tubulin-binding, vascular-targeting, antitumor and antimetastatic activities revealing it to be the best compound in the series developed by Canela et al [68]. Chalcone 58inhibited the proliferation of endothelial (HMEC-1, microvascular endothelial cell line-1; and BAEC, bovine aortic endothelial cells) and tumor (B16-F10.luc2, melanoma cells expressing firefly luciferase 2; Cem; and HeLa) cell lines with IC50 values of 1 and 4 nM [68]. The low solubility of 58(0.016 mg/mL) was ameliorated through the incorporation of an amino acid-based pro-moiety with the L-Lysine-L-Proline derivative 59approximately 2000x more soluble than 58(Figure 16). Pro-drug 59was effective in inhibiting tumor and endothelial cell proliferation, parent 58was successfully released by the liver, and 59demonstrated excellent in vivo anticancer activity in melanoma (10 mg/kg) and breast cancer models (15 mg/kg) by causing rapid intertumoral vascular shutdown and massive tumor necrosis [68].

Figure 16.

Latentiation represented by the replacing the amine of58with an L-Lysine-L-Proline (red) [68].

Isolated from Millettia pachycarpa, millepachine (60) induces cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo [69]. The development of amino-substituted-millepachines was explored in an effort to enhance the antiproliferative activity of the natural product lead (Figure 17). Millepachine derivative (61) exhibited excellent anticancer activity against a panel of drug-sensitive cancer cell lines and multidrug-resistant cancer cells. Studies support the inhibition of tubulin polymerization as the mechanism of action, by binding at the colchicine site [70, 71, 72]. More conformationally restrained analogues 6265and 68in this amino-substituted series retained high levels of activity, again acting as anti-microtubule agents.

Figure 17.

Family of novel chalcones hypothesised to inhibit tubulin by binding at the colchicine site [70,71,72].

Novel o-aryl chalcone (66) showed potent cytotoxicity against several multidrug-resistant cancer cell lines (paclitaxel-resistant human ovarian carcinoma cells, vincristine-resistant human ileocecum carcinoma cells, and doxorubicin-resistant human breast carcinoma cells) in an extremely low nanomolar range. This has been shown to be G2/M phase cell cycle arrest effect, mediated by 66binding to the colchicine site of tubulin as was observed with 6265and 68[73], which is a key feature of anti-microtubule agents [74]. Acting via the colchicine-binding site [75], 67was effective in mouse A549 xenograft models with no dose-limiting weight loss observed [37, 73]. An indole-chalcone (68), namely, IPP51, induced prometaphase arrest and the subsequent apoptosis of bladder cancer cells and showed a significant inhibition of tumor growth without a great loss in body weight [75].

Confirmation of the tubulin-binding target has been obtained with TUB091 (58), TUB092 (69), and TUB099 (59) series of compounds [68]. TUB092 (70) was soaked in the crystals of a protein complex comprising αβ-tubulin (T2) dimers, a stathmin-like protein RB3 (R), and tubulin tyrosine ligase (TTL) (Figure 18). The subsequent high-resolution cocrystal structure (2.4 Å) showed the chalcone bound with tubulin at the colchicine-binding site. The chalcone is organized such that the 1,3-benzodioxole ring of 69is located in the β-tubulin residue-derived hydrophobic pocket, with a water-mediated hydrogen bond to the backbone carbonyl and amide of Gly237 and Cys241. The α,β-unsaturated ketone hydrogen bonds with Asp251 and two additional water-mediated hydrogen bonds are evident from the backbone carbonyls of Thr179 and Asn349 with the hydroxyl and methoxy groups. Optimization of lead solubility via L-Lys-L-Pro dipeptide incorporation yielded pro-drug 59with a ca. 2000x solubility enhancement (31 mg/mL in PBS versus 0.016 mg/mL in PBS). 59also inhibited primary tumor growth and spontaneous metastasis in mice (iv injection, 10 mg/kg, 5 days) with 90% or higher inhibition.

Figure 18.

Chemical structure of TUB092 (69), which binds to tubulin at the colchicine site; this analogue is directly related to chalcones58and59(seeFigure 16) [68].

2.3 Miscellaneous chalcones

Chalcone-benzoxaborole (70), prepared from the intermediates 6-formylbenzoxaborole and the corresponding ketone, has recently been found to inhibit Trypanosoma bruceigrowth and possess antitrypanosomal activity (Figure 19) [76]. Boronic-chalcone (71) was described early in 2002 as a fluorescent probe for the detection of fluorides [77]. Boronic-chalcone hybrid (71) exhibits not only fluorescent properties but also other biological activity. Compound 71has been reported as an antitumor agent targeting MDM2 oncoprotein [78]. Compound 72can induce antitumor activity against malignant glioma cell lines both in vitro and in vivo [79]. Compound 73exhibits potent anticancer activity (HCT116 cells, IC50 = 3.9 μM) together with proteasome inhibitory activity [80].

Figure 19.

Chemical structures of boron-containing chalcones [76,77,78,79,80].

2.4 Selected mechanism of action studies

Ducki et al. predicted tubulin to be the target of chalcone due to the similarity between chalcone and the β-tubulin inhibitor combretastatin A4 [81]. A 5D-QSAR model was used to conclude that the methyl group at the α-position made a sizable difference in the preferred conformation from s-cis (74) to s-trans (75) for tubulin binding. This theory explains the high potency of α-methyl chalcone (K562, IC50 = 0.21 nM; tubulin, IC50 = 0.46 μM) [81, 82]. In 1992, MDL-27048 (76) was the first chalcone found to have antimitotic activity [83]. This compound was bound to tubulin at the colchicine-binding site and inhibited tubulin polymerization. Based on a proposed binding model for MDL-27048 [83, 84], a virtual screening of 9720 natural compounds was carried out. Compound 77has been found to show good inhibitory activity of tubulin polymerization [85]. Compounds 7885(Figure 20) have been designed and synthesized in later medicinal chemistry work. These compounds were originally predicted to bind to tubulin at the colchicine-binding site, which has been confirmed via in vitro competition binding assays [47, 75, 86, 87, 88, 89, 90]. Very recently, a series of novel indole-chalcone derivatives were synthesized and evaluated for their antiproliferative activity. Among these indole-chalcones, compound 81has exhibited IC50 values of 3−9 nM against six cancer cell lines, with similar activities against resistant cancer cells, and low toxicity toward normal human cells. Molecular docking and mechanistic studies have demonstrated that this compound could bind to the colchicine-binding site, inhibit tubulin polymerization with an IC50 of 2.68 μM, arrest the cell cycle at the G2/M phase, induce apoptosis, and decrease the mitochondrial membrane potential (MMP). Moreover, this compound and its phosphate salt 82with better water solubility have been shown to exhibit 66 and 70% in vivo antitumor inhibitory rates (ip, 30 mg/kg), respectively, without any apparent loss of body weight.

Figure 20.

Chalcones computationally predicted to target tubulin [81,82].

2.5 Targeting topoisomerase

Critically, the correct assembly of DNA is essential for cellular function. This assembly is in part governed by a series of topoisomerases (TOPOs), including TOPO-I and TOPO-II, which are responsible for the winding and unwinding of DNA. TOPO function is a critical process for DNA transcription and replication, and has been targeted as an anticancer strategy [91]. Several chalcones have shown TOPO inhibitory activity [92]. Chalcone 86in addition to being a nonspecific inhibitor of TOPO-I/II also inhibits cathepsin. The observed cytotoxicity was comparable with camptothecin and etoposide. The correlations between TOPO inhibition and cytotoxicity was not reported [93]. Natural product-derived (isolated from Angelica keiskei) chalcone-based inhibitors of TOPO-II have also been reported by the Akihisa group with the most potent in the series, 87, a more potent TOPO-II inhibitor than etoposide (a clinically used TOPO inhibitor) [93]. Other chalcone-based selective TOPO-II (versus TOPO-I) inhibitors such as 88have been reported with high anticancer activity (Figure 21) [93, 94].

Figure 21.

Chemical structures of chalcones known to inhibit topoisomerases (TOPO) [93,94].

2.6 Estrogen receptor

In many cancers, the hormone receptor status is a governing factor in determining the treatment protocols. For example, in breast cancer key treatment drivers relate to the presence (or absence) of the estrogen, progesterone, and HER receptor subtypes. The first two receptors are sex-linked and act as transcription factors guiding the interplay between endogenous ligands such as 17β-estradiol. There are multiple clinical drugs that target aberrant ER activity to alleviate the symptoms of menopause, inflammation, and cancer [95].

Chalcone isoliquiritigen in (89) was isolated from liquorish root and displayed a concentration-dependent differential activity against ER-positive breast cancer cells (T-47D) (Figure 22). At low concentrations, 89stimulates cell growth, at high dose it displays inhibitory activity; intriguingly, the activity at high concentration was noted as being ER concentration independent. In agreement with other studies, 89was found to directly bind to the ER with low micromolar affinity. The related candidachalcone (90) is also an ER-responsive chalcone; and while not exact data were presented, it is suggested to be a mid-micromolar ER ligand [96, 97].

Figure 22.

Chalcone isokiquiriten (89) and an analogue (90) with activity against the ER-positive breast cancer cell line (T-47D) [96,97].

Gan et al. reported that chalcones 91and 92showed cellular TrxR inhibitory activity in a panel of Michael acceptor-type pharmacophores (Figure 23). MS analysis demonstrated that the most potent chalcone derivative (92) covalently modified TrxR at the selenocysteine residue U498 [21]. In 2015, Zhang et al. reported a series of chalcone analogues based on xanthohumol (4). Among them, compound 93displayed good cytotoxicity against HeLa cells (IC50 = 1.4 μM), selective inhibition of TrxR, and induction of cell apoptosis. Mechanistically, the U498C mutation of TrxR was performed to support the covalent mechanism. As a result, this compound could significantly decrease the cellular thiol level and induce the expression of reactive oxygen species (ROS) [98].

Figure 23.

Chemical structures of selected chalcones known as TrxR inhibitors [21].

2.7 Targeting CYPs

The parent analogue, ANF (94), has long been recognized as displaying a broad range of pharmacological activities. Of particular note is its effects on CYP1. It has been shown that ANF (94) is capable of reversing CYP1B1-mediated drug resistance, increasing the efficacy of cytotoxic drugs. Simple ring opening of the flavone moiety releases a hydroxynaphthyl chalcone (95). Modification of the pendant phenyl ring was shown to impart modest CYP inhibition relative to ANF (Table 3). The parent phenyl (96) displays a CYP1B1 IC50 of 157.7 nM (c.f. ANF IC50 5.9 nM). Introduction of ring substituents enhances activity with the 4-F (97; 48 nM), 2-OCH3 (98; 37.7 nM), and 3-pyridyl (99; 16.7 nM), also with improved CYP1A2/B1 selectivity. Increasing the hydrophobicity of the phenyl moiety was detrimental to potency, but the introduction of a tetrasubstituted naphthyl moiety proved to be highly efficacious [99] (Figure 24).

Table 1.

Effect of H to F bioisosteric modification on the cytotoxicity of a 2,4,6-trimethoxychalcone (11). IC50 values are expressed in μM.

Table 2.

Bioisosterism represented by the replacing the double bond of the enone (blue) with a thiophene (red) [31]. IC50 values are expressed in μM.

Table 3.

Inhibitor potency of modified chalcones against CYP1 enzymes.

Figure 24.

Structural modification of ANF leading to a family of CYP1B1 inhibitors displaying high levels of cytotoxicity, seeTable 3for details of “R” [99].

Of the modified ANF analogues reported, 100and 101displayed CYP1B1 inhibition level equivalent to ANF but with significantly enhanced selectivities of 150- and >200-fold (ANF, CYP1A2/B1 = 3.1) (Table 3).

Examination of these analogues against MCF-7, MDA-MB-231, LCC6/P-gp, and MCF-7/1B1 revealed the 2-pyridyl chalcone analogue to be broad-spectrum active in both the wild type (MCF-7 and MDA-MB-231 cells) and also in the drug-resistant cells (LCC6/P-gp and MCF-7/1B1) (Table 3). Replacement of the phenyl moiety with a tetramethoxynaphthalene resulted in a drop in CYP1B1 activity (IC50 > 1000 nM), but the MCF-7 and LCC6/P-gp cytotoxicity increased. This presumably is a consequence of increased cellular uptake [99] (Table 4).

IC50 values (μM)
CompoundMCF-7MDA-MB-231LCC6/P-gpMCF-7/1B1
ANF (94)80.7 ± 7.6>10082.3 ± 8.5>100
9525.9 ± 3.246.2 ± 5.3>10032.3 ± 4.5
9648.1 ± 3.779.6 ± 4.948.6 ± 2.9>100
9743.4 ± 1.675.3 ± 6.843.9 ± 4.4>100
987.6 ± 0.719.8 ± 2.88.0 ± 2.312.7 ± 1.7
996.3 ± 1.415.8 ± 2.29.6 ± 1.315.1 ± 1.8
10046.8 ± 4.748.9 ± 4.1>10020.4 ± 3.3

Table 4.

Cytotoxic activities of benzochalcones against MCF-7, MDA-MB-231, LCC6/P-GP, and MCF-7 cell lines.

Advertisement

3. Conclusions

The medicinal chemistry landscape is a mobile one. Approaches that were viewed as unviable mere 5- to 10-years ago are now gaining traction. The introduction of PAINS filters has stymied some areas of medicinal chemistry development, correctly; but in other areas, the changing paradigms may necessitate a reexamination of the type of screening filters applied. This is especially relevant to the potential development of chalcones in the anticancer drug space. It has been consistently shown that not only do these agents possess high levels of antiproliferative activity as single agents, they synergise well across a significant number of clinically used anticancer drugs.

As this field progresses, careful reevaluation of off-target effects, compound specificity, and promiscuity will remain key, but there is significant potential for transformation of chalcones into true clinical compounds. It is worth noting that it is the role of the medicinal chemist to modulate the unfavorable effects of lead compounds in the development of clinical candidates. This, perhaps though is best left in an academic environment until “compound cleaning” to a true development candidate can be achieved.

Advertisement

Acknowledgments

AM is the recipient of NH&MRC project funding targeting the development of novel anticancer agents. CCR and AM are recipients of funding from the University of Newcastle Priority Research Centre for Drug Development.

Advertisement

Conflicts of interest

The authors declare no conflicts of interest.

References

  1. 1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International Journal of Cancer. 2019;144:1941-1953
  2. 2. Reichardt P. The story of imatinib in GIST—A journey through the development of a targeted therapy. Oncology Research and Treatment. 2018;41:472-477
  3. 3. Kannaiyan R, Mahadevan D. A comprehensive review of protein kinase inhibitors for cancer therapy. Expert Review of Anticancer Therapy. 2018;18:1249-1270
  4. 4. Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al. Development of therapeutic antibodies for the treatment of diseases. Journal of Biomedical Science. 2020;27:1. DOI: 10.1186/s12929-019-0592-z
  5. 5. Sun J, Russell C, Scarlett CJ, McCluskey A. Small molecule inhibitors in the treatment of pancreatic cancer. RSC Medicinal Chemistry. 2020;11:164-183. DOI: 10.1039/c9md00447e
  6. 6. Alphandéry E. Glioblastoma Treatments: An account of recent industrial developments. Frontiers in Pharmacology. 2018;9:1-31. DOI: 10.3389/fphar.2018.00879
  7. 7. GBD 2016 Brain and Other CNS Cancer Collaborators. Global, regional, and national burden of brain and other CNS cancer, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology. 2019;18:376-393
  8. 8. Zhou B, Xing C. Diverse molecular targets for chalcones with varied bioactivities. Medicinal Chemistry. 2015;5:388-404
  9. 9. Zhuang C, Zhang W, Sheng C, Zhang W, Chengguo Xing C, Miao Z. Chalcone: A privileged structure in medicinal chemistry. Chemical Reviews. 2017;117:7762-7810
  10. 10. Gomes MN, Muratov EN, Pereira M, Peixoto JC, Rosseto LP, Cravo PVL, et al. Chalcone derivatives: Promising starting points for drug design. Molecules. 2017;22:1210
  11. 11. Baell JB, Holloway GA. New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays. Journal of Medicinal Chemistry. 2010;53:2719-2740
  12. 12. Capuzzi SJ, Muratov EN, Tropsha A. Phantom PAINS: Problems with the utility of alerts for pan—Assay interference compounds. Journal of Chemical Information and Modeling. 2017;57:417-427
  13. 13. Lagorce D, Oliveira N, Miteva MA, Villoutreix BO. Pan-assay interference compounds (PAINS) that may not be too painful for chemical biology projects. Drug Discovery Today. 2017;22:1131-1133. DOI: j.drudis.2017.05.017
  14. 14. Newman DJ. Natural products as leads to potential drugs: An old process or the new hope for drug discovery? Journal of Medicinal Chemistry. 2008;51:2589-2599
  15. 15. Batovska DI, Todorova IT. Trends in utilization of the pharmacological potential of chalcones. Current Clinical Pharmacology. 2010;5:1-29
  16. 16. Sahu NK, Balbhadra SS, Choudhary J, Kohli DV. Exploring pharmacological significance of chalcone scaffold: A review. Current Medicinal Chemistry. 2012;19:209-225
  17. 17. Singh P, Anand A, Kumar V. Recent developments in biological activities of chalcones: A mini review. European Journal of Medicinal Chemistry. 2014;85:758-777
  18. 18. Karthikeyan C, Moorthy NS, Ramasamy S, Vanam U, Manivannan E, Karunagaran D, et al. Advances in chalcones with anticancer activities. Recent Patents on Anti-Cancer Drug Discovery. 2015;10:97-115
  19. 19. Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P. Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proceedings of the National Academy of Sciences of the United States of America. 2001;98:3404-3409
  20. 20. Dinkova-Kostova AT, Cheah J, Samouilov A, Zweier JL, Bozak RE, Hicks RJ, et al. Phenolic Michael reaction acceptors: Combined direct and indirect antioxidant defenses against electrophiles and oxidants. Medicinal Chemistry. 2007;3:261-268
  21. 21. Gan FF, Kaminska KK, Yang H, Liew CY, Leow PC, So CL, et al. Identification of Michael acceptor-centric pharmacophores with substituents that yield strong thioredoxin reductase inhibitory character correlated to antiproliferative activity. Antioxidants & Redox Signaling. 2013;19:1149-1165
  22. 22. Dinkova-Kostova AT, Abeygunawardana C, Talalay P. Chemoprotective properties of phenylpropenoids, bis(benzylidene)-cycloalkanones, and related Michael reaction acceptors: Correlation of potencies as phase 2 enzyme inducers and radical scavengers. Journal of Medicinal Chemistry. 1998;41:5287-5296
  23. 23. Srinivasan B, Johnson TE, Lad R, Xing C. Structure activity relationship studies of chalcone leading to 3-hydroxy-4,3′,4′,5′-tetramethoxychalcone and its analogues as potent nuclear factor kappaB inhibitors and their anticancer activities. Journal of Medicinal Chemistry. 2009;52:7228-7235
  24. 24. Jackson PA, Widen JC, Harki DA, Brummond KM. Covalent modifiers: A chemical perspective on the reactivity of α,β-unsaturated carbonyls with thiols via hetero-Michael addition reactions. Journal of Medicinal Chemistry. 2016;60:839-885
  25. 25. He W, Wang Q, Srinivasan B, Xu J, Padilla MT, Li Z, et al. A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy. Oncogene. 2014;33:3004-3013
  26. 26. Xu J, Xu X, Shi S, Wang Q, Saxton B, He W, et al. Autophagy-mediated degradation of IAPs and c-FLIP potentiates apoptosis induced by combination of TRAIL and Chal-24. Journal of Cellular Biochemistry. 2016;117:1136-1144
  27. 27. Shi S, Wang Q, Xu J, Jang JH, Padilla MT, Nyunoya T, et al. Synergistic anticancer effect of cisplatin and Chal-24 combination through IAP and c-FLIPL degradation, Ripoptosome formation and autophagy-mediated apoptosis. Oncotarget. 2015;6:1640-1651
  28. 28. Zhang Y, Wu J, Ying S, Chen G, Wu B, Xu T, et al. Discovery of new MD2 inhibitor from chalcone derivatives with anti-inflammatory effects in LPS induced acute lung injury. Scientific Reports. 2016;6:25130
  29. 29. Senger MR, Fraga CAM, Dantas RF, Silva-Júnior FP. Filtering promiscuous compounds in early drug discovery: Is it a good idea? Drug Discovery Today. 2016;21:868-872
  30. 30. Burmaoglu S, Algul O, Aktas D, Gobek A, Gulbol G. Synthesis and anti-proliferative activity of fluoro-substituted chalcones. Bioorganic & Medicinal Chemistry Letters. 2016;26:3172-3176
  31. 31. Romagnoli R, Baraldi PG, Carrion MD, Cara CL, Cruz-Lopez O, Preti D, et al. Design, synthesis, and biological evaluation of thiophene analogues of chalcones. Bioorganic & Medicinal Chemistry. 2008;16:5367-5376
  32. 32. Mao Z, Zheng X, Qi Y, Zhang M, Huang Y, Wan C, et al. Synthesis and biological evaluation of novel hybrid compounds between chalcone and piperazine as potential antitumor agents. RSC Advances. 2016;6:7723-7727
  33. 33. Koziel R, Szczepanowska J, Magalska A, Piwocka K, Duszynski J, Zablocki K. Ciprofloxacin inhibits proliferation and promotes generation of aneuploidy in Jurkat cells. Journal of Physiology and Pharmacology. 2010;61:233-239
  34. 34. Aranha O, Grignon R, Fernandes N, McDonnell TJ, Wood DP, Sarkar FH. Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis. International Journal of Oncology. 2003;22:787-794
  35. 35. Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE. Effect of ciprofloxacin on the proliferation of osteoblast-like MG-63 human osteosarcoma cells in vitro. Journal of Orthopaedic Research. 1998;16:509-512
  36. 36. Somekh E, Douer D, Shaked N, Rubinstein E. In vitro effects of ciprofloxacin and pefloxacin on growth of normal human hematopoietic progenitor cells and on leukemic cell lines. The Journal of Pharmacology and Experimental Therapeutics. 1989;248:415-418
  37. 37. Lawrence NJ, McGown AT, Ducki S, Hadfield JA. The interaction of chalcones with tubulin. Anti-Cancer Drug Design. 2000;15:135-141
  38. 38. Ducki S. Antimitotic chalcones and related compounds as inhibitors of tubulin assembly. Anti-Cancer Agents in Medicinal Chemistry. 2009;9:336-347
  39. 39. Romagnoli R, Baraldi PG, Carrion MD, Cruz-Lopez O, Cara CL, Balzarini J, et al. Hybrid alpha-bromoacryloylamido chalcones. Design, synthesis and biological evaluation. Bioorganic & Medicinal Chemistry Letters. 2009;19:2022-2028
  40. 40. Fu DJ, Zhang SY, Liu YC, Zhang L, Liu JJ, Song J, et al. Design, synthesis and antiproliferative activity studies of novel dithiocarbamate-chalcone derivates. Bioorganic & Medicinal Chemistry Letters. 2016;26:3918-3922
  41. 41. Yang Y, Hahne H, Kuster B, Verhelst SH. A simple and effective cleavable linker for chemical proteomics applications. Molecular & Cellular Proteomics. 2013;12:237-244
  42. 42. Austin MB, Noel JP. The chalcone synthase superfamily of type III polyketide synthases. Natural Product Reports. 2003;20:79-110
  43. 43. Dong X, Du L, Pan Z, Liu T, Yang B, Hu Y. Synthesis and biological evaluation of novel hybrid chalcone derivatives as vasorelaxant agents. European Journal of Medicinal Chemistry. 2010;45:3986-3992
  44. 44. Kamal A, Shankaraiah N, Prabhakar S, Reddy CR, Markandeya N, Reddy KL, et al. Solid-phase synthesis of new pyrrolobenzodiazepine-chalcone conjugates: DNA-binding affinity and anticancer activity. Bioorganic & Medicinal Chemistry Letters. 2008;18:2434-2439
  45. 45. Kamal A, Prabhakar S, Janaki Ramaiah M, Venkat Reddy P, Ratna Reddy C, Mallareddy A, et al. Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1,2,3-triazole ring side-armed with alkane spacers. European Journal of Medicinal Chemistry. 2011;46:3820-3831
  46. 46. Gaur R, Pathania AS, Malik FA, Bhakuni RS, Verma RK. Synthesis of a series of novel dihydroartemisinin monomers and dimers containing chalcone as a linker and their anticancer activity. European Journal of Medicinal Chemistry. 2016;122:232-246
  47. 47. Kamal A, Mallareddy A, Suresh P, Shaik TB, Lakshma Nayak V, Kishor C, et al. Synthesis of chalcone-amidobenzothiazole conjugates as antimitotic and apoptotic inducing agents. Bioorganic & Medicinal Chemistry. 2012;20:3480-3492
  48. 48. Schobert R, Biersack B, Dietrich A, Knauer S, Zoldakova M, Fruehauf A, et al. Pt(II) complexes of a combretastatin A-4 analogous chalcone: Effects of conjugation on cytotoxicity, tumor specificity, and long-term tumor growth suppression. Journal of Medicinal Chemistry. 2009;52:241-246
  49. 49. Pingaew R, Saekee A, Mandi P, Nantasenamat C, Prachayasittikul S, Ruchirawat S, et al. Synthesis, biological evaluation and molecular docking of novel chalcone coumarin hybrids as anticancer and antimalarial agents. European Journal of Medicinal Chemistry. 2014;85:65-76
  50. 50. Zhao L, Mao L, Hong G, Yang X, Liu T. Design, synthesis and anticancer activity of matrine-1H-1,2,3-triazole-chalcone conjugates. Bioorganic & Medicinal Chemistry Letters. 2015;25:2540-2544
  51. 51. O’Boyle NM, Carr M, Greene LM, Bergin O, Nathwani SM, McCabe T, et al. Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents. Journal of Medicinal Chemistry. 2010;53:8569-8584
  52. 52. Singh P, Raj R, Kumar V, Mahajan MP, Bedi PM, Kaur T, et al. 1,2,3-Triazole tethered beta-lactam-chalcone bifunctional hybrids: Synthesis and anticancer evaluation. European Journal of Medicinal Chemistry. 2012;47:594-600
  53. 53. Loch-Neckel G, Bicca MA, Leal PC, Mascarello A, Siqueira JM, Calixto JB. In vitro and in vivo anti-glioma activity of a chalcone-quinoxaline hybrid. European Journal of Medicinal Chemistry. 2015;90:93-100
  54. 54. Shankaraiah N, Siraj KP, Nekkanti S, Srinivasulu V, Sharma P, Senwar KR, et al. DNA-binding affinity and anticancer activity of beta-carboline-chalcone conjugates as potential DNA intercalators: Molecular modelling and synthesis. Bioorganic Chemistry. 2015;59:130-139
  55. 55. Kamal A, Balakrishna M, Nayak VL, Shaik TB, Faazil S, Nimbarte VD. Design and synthesis of imidazo[2,1-b]thiazolechalcone conjugates: Microtubule-destabilizing agents. ChemMedChem. 2014;9:2766-2780
  56. 56. Kamal A, Kashi Reddy M, Viswanath A. The design and development of imidazothiazole-chalcone derivatives as potential anticancer drugs. Expert Opinion on Drug Discovery. 2013;8:289-304
  57. 57. Kamal A, Dastagiri D, Ramaiah MJ, Reddy JS, Bharathi EV, Srinivas C, et al. Synthesis of imidazothiazole-chalcone derivatives as anticancer and apoptosis inducing agents. ChemMedChem. 2010;5:1937-1947
  58. 58. Kolundzija B, Markovic V, Stanojkovic T, Joksovic L, Matic I, Todorovic N, et al. Novel anthraquinone based chalcone analogues containing an imine fragment: Synthesis, cytotoxicity and anti-angiogenic activity. Bioorganic & Medicinal Chemistry Letters. 2014;24:65-71
  59. 59. Lemstrova R, Melichar B, Mohelnikova-Duchonova B. Therapeutic potential of taxanes in the treatment of metastatic pancreatic cancer. Cancer Chemotherapy and Pharmacology. 2016;78:1101-1111
  60. 60. Martino E, Casamassima G, Castiglione S, Cellupica E, Pantalone S, Papagni F, et al. Vinca alkaloids and analogues as anti-cancer agents: Looking back, peering ahead. Bioorganic & Medicinal Chemistry Letters. 2018;28:2816-2826
  61. 61. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nature Reviews. Cancer. 2004;4:253-265
  62. 62. Dumontet C. Mechanisms of action and resistance to tubulin-binding agents. Expert Opinion on Investigational Drugs. 2000;9:779-788
  63. 63. Niu M, Qin J, Tian C, Yan X, Dong F, Cheng Z, et al. Tubulin inhibitors: Pharmacophore modeling, virtual screening and molecular docking. Acta Pharmacologica Sinica. 2014;35:967-979
  64. 64. Pettit GR, Cragg GM, Herald DL, Schmidt JM, Lohavanijaya P. Antineoplastic agents. Part 84. Isolation and structure of combretastatin. Canadian Journal of Chemistry. 1982;60:1374-1376
  65. 65. Kamal A, Ramakrishna G, Raju P, Viswanath A, Ramaiah MJ, Balakishan G, et al. Synthesis and anti-cancer activity of chalcone linked imidazolones. Bioorganic & Medicinal Chemistry Letters. 2010;20:4865-4869
  66. 66. Markovic V, Debeljak N, Stanojkovic T, Kolundzija B, Sladic D, Vujcic M, et al. Anthraquinone-chalcone hybrids: Synthesis, preliminary antiproliferative evaluation and DNA-interaction studies. European Journal of Medicinal Chemistry. 2015;89:401-410
  67. 67. Wani ZA, Guru SK, Rao AV, Sharma S, Mahajan G, Behl A, et al. A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells. Food and Chemical Toxicology. 2016;87:1-11
  68. 68. Canela M-D, Noppen S, Bueno O, Prota AE, Bargsten K, Sáez-Calvo G, et al. Antivascular and antitumor properties of the tubulin-binding chalcone TUB091. Oncotarget. 2017;8:14325-14342
  69. 69. Wu W, Ye H, Wan L, Han X, Wang G, Hu J, et al. Millepachine, a novel chalcone, induces G2/M arrest by inhibiting CDK1 activity and causing apoptosis via ROS-mitochondrial apoptotic pathway in human hepatocarcinoma cells in vitro and in vivo. Carcinogenesis. 2013;34:1636-1643
  70. 70. Yang Z, Wu W, Wang J, Liu L, Li L, Yang J, et al. Synthesis and biological evaluation of novel millepachine derivatives as a new class of tubulin polymerization inhibitors. Journal of Medicinal Chemistry. 2014;57:7977-7989
  71. 71. Wang G, Peng F, Cao D, Yang Z, Han X, Liu J, et al. Design, synthesis and biological evaluation of millepachine derivatives as a new class of tubulin polymerization inhibitors. Bioorganic & Medicinal Chemistry. 2013;21:6844-6854
  72. 72. Wang G, Li C, He L, Lei K, Wang F, Pu Y, et al. Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents. Bioorganic & Medicinal Chemistry. 2014;22:2060-2079
  73. 73. Zhu C, Zuo Y, Wang R, Liang B, Yue X, Wen G, et al. Discovery of potent cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis with affinity-based fluorescence. Journal of Medicinal Chemistry. 2014;57:6364-6382
  74. 74. Shen KH, Chang JK, Hsu YL, Kuo PL. Chalcone arrests cell cycle progression and induces apoptosis through induction of mitochondrial pathway and inhibition of nuclear factor kappa B signalling in human bladder cancer cells. Basic & Clinical Pharmacology & Toxicology. 2007;101:254-261
  75. 75. Martel-Frachet V, Keramidas M, Nurisso A, DeBonis S, Rome C, Coll JL, et al. IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma. Oncotarget. 2015;6:14669-14686
  76. 76. Qiao Z, Wang Q, Zhang F, Wang Z, Bowling T, Nare B, et al. Chalconebenzoxaborole hybrid molecules as potent antitrypanosomal agents. Journal of Medicinal Chemistry. 2012;55:3553-3557
  77. 77. DiCesare N, Lakowicz JR. Chalcone-analogue fluorescent probes for saccharides signaling using the boronic acid group. Tetrahedron Letters. 2002;43:2615-2618
  78. 78. Kumar SK, Hager E, Pettit C, Gurulingappa H, Davidson NE, Khan SR. Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents. Journal of Medicinal Chemistry. 2003;46:2813-2815
  79. 79. Sasayama T, Tanaka K, Mizukawa K, Kawamura A, Kondoh T, Hosoda K, et al. Trans-4-lodo,4′-boranylchalcone induces antitumor activity against malignant glioma cell lines in vitro and in vivo. Journal of Neuro-Oncology. 2007;85:123-132
  80. 80. Achanta G, Modzelewska A, Feng L, Khan SR, Huang P. A boronic-chalcone derivative exhibits potent anticancer activity through inhibition of the proteasome. Molecular Pharmacology. 2006;70:426-433
  81. 81. Ducki S, Mackenzie G, Lawrence NJ, Snyder JP. Quantitative structure-activity relationship (5D-QSAR) study of combretastatin-like analogues as inhibitors of tubulin assembly. Journal of Medicinal Chemistry. 2005;48:457-465
  82. 82. Ducki S, Rennison D, Woo M, Kendall A, Chabert JF, McGown AT, et al. Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and biological evaluation of antivascular activity. Bioorganic & Medicinal Chemistry. 2009;17:7698-7710
  83. 83. Edwards ML, Stemerick DM, Sunkara PS. Chalcones: A new class of antimitotic agents. Journal of Medicinal Chemistry. 1990;33:1948-1954
  84. 84. Peyrot V, Leynadier D, Sarrazin M, Briand C, Menendez M, Laynez J, et al. Mechanism of binding of the new antimitotic drug MDL 27048 to the colchicine site of tubulin: Equilibrium studies. Biochemistry. 1992;31:11125-11132
  85. 85. Kim DY, Kim KH, Kim ND, Lee KY, Han CK, Yoon JH, et al. Design and biological evaluation of novel tubulin inhibitors as antimitotic agents using a pharmacophore binding model with tubulin. Journal of Medicinal Chemistry. 2006;49:5664-5670
  86. 86. Zhang H, Liu JJ, Sun J, Yang XH, Zhao TT, Lu X, et al. Design, synthesis and biological evaluation of novel chalcone derivatives as antitubulin agents. Bioorganic & Medicinal Chemistry. 2012;20:3212-3218
  87. 87. Ruan BF, Lu X, Tang JF, Wei Y, Wang XL, Zhang YB, et al. Synthesis, biological evaluation, and molecular docking studies of resveratrol derivatives possessing chalcone moiety as potential antitubulin agents. Bioorganic & Medicinal Chemistry. 2011;19:2688-2695
  88. 88. Kamal A, Kumar GB, Vishnuvardhan MV, Shaik AB, Reddy VS, Mahesh R, et al. Synthesis of phenstatin/isocombretastatin-chalcone conjugates as potent tubulin polymerization inhibitors and mitochondrial apoptotic inducers. Organic & Biomolecular Chemistry. 2015;13:3963-3981
  89. 89. Konieczny MT, Bulakowska A, Pirska D, Konieczny W, Skladanowski A, Sabisz M, et al. Structural factors affecting affinity of cytotoxic oxathiole-fused chalcones toward tubulin. European Journal of Medicinal Chemistry. 2015;89:733-742
  90. 90. Konieczny MT, Bulakowska A, Polak J, Pirska D, Konieczny W, Gryn P, et al. Structural factors affecting cytotoxic activity of (E)-1-(Benzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one derivatives. Chemical Biology & Drug Design. 2014;84:86-91
  91. 91. Pommier Y, Leo E, Zhang H, Marchand C. DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. Chemistry & Biology. 2010;17:421-433
  92. 92. Kim SH, Lee E, Baek KH, Kwon HB, Woo H, et al. Chalcones, inhibitors for topoisomerase I and cathepsin B and L, as potential anti-cancer agents. Bioorganic & Medicinal Chemistry Letters. 2013;23:3320-3324
  93. 93. Akihisa T, Kikuchi T, Nagai H, Ishii K, Tabata K, et al. 4-Hydroxyderricin from Angelica keiskei roots induces caspase-dependent apoptotic cell death in HL60 human leukemia cells. Journal of Oleo Science. 2011;60:71-77
  94. 94. Na Y, Nam JM. Synthesis and topoisomerase II inhibitory and cytotoxic activity of oxiranylmethoxy- and thiiranylmethoxy-chalcone derivatives. Bioorganic & Medicinal Chemistry Letters. 2011;21:211-214
  95. 95. Paterni I, Bertini S, Granchi C, Macchia M, Minutolo F. Estrogen receptor ligands: A patent review update. Expert Opinion on Therapeutic Patents. 2013;23:1247-1271
  96. 96. Hajirahimkhan A, Simmler C, Yuan Y, Anderson JR, Chen SN, et al. Evaluation of estrogenic activity of licorice species in comparison with hops used in botanicals for menopausal symptoms. PLoS ONE. 2013;8:e67947
  97. 97. Hegazy ME, El-Hamd H, Mohamed A, El-Halawany AM, Djemgou PC, Shahat AA, et al. Estrogenic activity of chemical constituents fromTephrosia candida. Journal of Natural Products. 2011;74:937-942
  98. 98. Zhang B, Duan D, Ge C, Yao J, Liu Y, Li X, et al. Synthesis of xanthohumol analogues and discovery of potent thioredoxin reductase inhibitor as potential anticancer agent. Journal of Medicinal Chemistry. 2015;58:1795-1805
  99. 99. Dong J, Huang G, Zhang Q, Wang Z, Cui J, Wu Y, et al. Development of benzochalcone derivatives as selective CYP1B1 inhibitors and anticancer agents. MedChemComm. 2019;10:1606-1614

Written By

Adam McCluskey and Cecilia Russell

Submitted: August 22nd, 2019 Reviewed: January 30th, 2020 Published: February 3rd, 2021