Chalcones (Figure 5.5) are the abundantly present natural products class in nature either in free or in diverse complexed forms. The teim chalcone was coined by Kostanecki and Tambor in the 19th century who first synthesized these chromophoric compounds. The term originated from the word of Greek origin “c/m/cos” which means “bronze,” named after the bronze-like color of the natural chalcones [33]. The prop-2-ene-l-one scaffold comprising of two aromatic rings attached together with a three carbon a, (3 unsaturated carbonyl bridge. It has received attention among the research community owing to a large number of merits such as easy steps for laboratory-oriented synthesis via diverse procedures such as direct crossed-coupling reaction, Julia-Kocienski reaction, carbonylated Heck coupling reaction, Suzuki- Miyaura reaction, Sonogashira isomerization coupling, microwave-assisted reactions, solid acid catalyst mediated reactions, Friedel-Crafts reaction, one-pot reactions, solvent-free reactions, etc.. [34].

The low-molecular-weight feature facilitate swift computational studies, a large number of positions for replaceable hydrogen atoms, multifarious pharmacological activities such as anti-invasive, anti-spasmodic, anti-histaminic, anti-oxidant, anti-retroviral, hypnotic, anti-gout, antibacterial, immunosuppressant, anxiolytic, anti-malarial, anti-nociceptive, anti-hypertensive, osteogenic, anti-angiogenic, anti-filarial, anti-arrhythmic, anti-protozoal, anti-obesity, anti- tubercular, antifungal, anti-ulcer, hypolipidemic, anti-cancer, anti-leishmanial, anti-inflammatory, anti-diabetic, anti-steroidal, anti-platelet, etc., [35, 36].

Structure of chalcone

FIGURE 5.5 Structure of chalcone.

In addition to the above stated pharmacological significance, the pharmacophore expresses potent inhibition of cystic fibrosis transmembrane conductance regulator (CFTR), P-glycoprotein (P-gp), fundamental metabolic enzymes, and antagonism of various factors. Non-pharmacological applications include insecticide, scintillator, polymerization catalyst, artificial sweetener, fluorescent whitening agent, organic brightening agent, fluorescent polymers, and analytical receptor for Fe(III) determination [37].

The scaffold serves as an intermediate for the synthesis of several heterocyclic compounds such as pyrimidine, pyrrole, thiazole, thiophene, indole, isoxazole, oxazole, benzodiazepine, benzoxazepine, benzothiazepine, etc. In the last few years, hybridization has been perceived to be an emerging technique to develop analogs with significantly high biological activity. The fusion of naphthoquinone, chromene, naphthalene, coumarin, sulfonamide, imidazolone, pyrazoline, bifendate, piperazine, etc., has led to several folds enhancement in the activity [38].

Various natural chalcones like liquiritigenin, xanthohumol, flavolcawain B, xanthoangelol, isoliquiritigenin, cardamonin, echinatin, licochalcone, kuwanon, 4-hydroxyderricin, broussochalcone, macdentichalcone, etc., are the eminent candidates with wide pharmacological perspectives in cancer, diabetes, infection, inflammation, and many other activities [39]. The benzylideneacetophenone scaffold is the open chain intermediates in aurones synthesis of flavones and acts as precursors of flavonoids and isoflavonoids. Chalcones and flavonones are isomeric in nature and in the presence of acid or base, they readily undergo interconversion. The edible chalcones have been found to play a pivotal role as Michael acceptor in Michael addition reaction. This small template aids in the structure elucidation of flavanone, flavonoid, chromanochromane, and tannins [40]. Chalcone or chalconoids exist in two forms; cis and trans, where the trans isomeric form is thermodynamically more stable than the cis form. The conjugated double bond system with a delocalized 7r-electron system facilitates several electron transfer reactions and produces a decrease in redox potential which promotes numerous interactions with the biological targets [41].


In a computational study, the anti-breast cancer potential of a novel 3-phenyl- quinolinylchalcone derivative, (£)-3-(3-(4-methoxyphenyl) quinolin-2-yl)- l-phenylprop-2-en-l-one (Figure 5.6A) was studied by establishing the possible interaction with the Hsp90 (PDB ID: 1UYE) through molecular docking approach. The study presented significant inhibition of the molecular target (Gscore-10.0 kcal/mol) via interaction with the amino acid Phel38 residue through hydrogen bonding [42].

A novel chalcone molecule (Figure 5.6B) finds future application in treating triple-negative breast cancer, one of the most belligerent form of neoplasm by selectively impairing the growth of MDA-MB-231 breast cancer cells through ubiquitin-proteasome pathway where degradation of Hsp90 client proteins such as EGFR, Met, Her2, c-Raf, Akt, and Cdk4 remained the hallmark characteristic of Hsp90 inhibition. However, the rnRNA levels after expression of Met and Akt were not associated with the transcriptional regulation, suggesting an alternative pathway, known as “ubiquitin-proteasome pathway.” The treatment of ligand in escalating concentration presented cleavage of PARP, caspase 3/8 and downregulation of anti-apoptotic protein Bcl-2. The study opened avenues for treating this complex form of cancer by preventing metastasis to bone, brain, lung, and liver and enhancing the five-year survival rate [43].

In an effort towards drug discovery, the dose-dependent concentration of 2,’4’-dimethoxychalcone (Figure 5.6C) has been found to considerably inhibit the growth of iressa-resistant non-small cell lung cancer (NSCLC, H1975) by the disruption of Hsp90 chaperoning function. This exemplified a pioneering step for overcoming the possible drug resistance induced by Met amplification and EGFR mutation [44].

The anti-prostate cancer role of methoxylated chalcone (Figure 5.6D) has been explored by Kim and co-workers where the low-molecular-weight- ligands (LMWLs) prevent the translocation of Hsp90-androgen receptor complex in the cytoplasm under the androgen-non-responsive state. The compound paved the pathway towards anti-androgen therapy with its unique mechanism of action and finds application in incurable castrate-resistant prostate cancer conditions [45].

Based on the principles of rational drug design, a novel series of chalcone molecules were rationally designed by linking the resorcinol and the trime- thoxyphenyl ring. The prop-2-ene-l-one molecule (Figure 5.6E), designed thr ough SBDD way expressed inhibition of Hsp90 which results in complete suppression of several oncogenic molecules such as EGFR, Her2, Met, and Akt proteins, prevents HI975 cell proliferation (GI.0 of 48 pM), and overcoming gefitinib-resistance. The molecular docking expressed a noteworthy interaction with Hsp90 target along with several interesting results which clearly supported the disruption of Hsp90 chaperone machinery. The resorcinol ring binds with the hydrophilic portion whereas the trimethoxyphenyl ring dominates in the hydrophobic part (-7.91 kcal/rnol) while interacting with the Tlrrl84, Asp93, Leu48, and Vail86 residues through hydrogenbonding and Van der Waals contact [46].

Similar to the above context, licochalcone A (Figure 5.6F), and a natural product targeting Hsp90 has been seen to effectively overcome gefitinib- resistant in NSCLC. Screening against in vitro model H1975 cancer cells at 70 pM showed the profound concentration-dependent cytotoxic effect by downregulating the expression levels of EGFR, Her2, Hsp70, Met, Akt, and Hsp90. The results have been found to be analogous to the positive control, geldanamycin, where protein folding machinery was disrupted, with the consequent degradation of Hsp90 in the cytoplasm, and transcriptional upregulation of cochaperone Hsp70. Further evidence from in silico studies confirmed inhibition of Hsp90 by effectual binding (-8.84 kcal/mol) with the amino acid residues of the hydrophilic region (Asp93, Asp54, Thrl84) as well as hydrophobic region (Phel38, Trpl62, Leul07, Vall50, Tyrl39) thr ough both hydrogen-bonding and Van der Waals contact [47].

The chalcone bioisosterics (Figure 5.6G) developed from resorcinol-based N-benzyl benzamide derivatives displayed tremendous growth inhibition (GIJ0 of 0.42 pM) against NSCLC (H1975) by apoptotic pathway (PARP and Caspase cleavage). The chalcone-like compound inhibited the Hsp90 (IC.0

5.3 nM), the ubiquitous molecular chaperone along with its protein clients Her2, EGFR, Met, Akt, and c-Raf as confirmed by the immunostaining and western immunoblot analysis. Inhibition of this imperative molecular target will lead to stabilization and maturation of many oncogenic proteins. Furthermore, the novel inhibitor showed weak inhibition of P450 isoforms (1A2,2C9, 2C19, 2D6, and ЗА) with IC50 values of <5 pM. Moreover, the compound inhibited the tumor growth in a mouse xenograft model bearing subcutaneous H1975 [48].

The secondaiy metabolites (flavokawains A, B. and C) obtained from the kava plant (Piper methysticum) have been found to circumvent the gefitinib- resistant in NSCLC in a similar context. The metabolite В (Figure 5.6H) and synthetic flavokawain derivative (Figure 5.61) gained attention among the scientific community owing to its trait in disordering Hsp90 chaperoning utility along with impairing the growth of H1975 cancer cells (ICJ0 value of 33.5 pM). In addition to it, the natural product drastically reduces the expression levels of EGFR, Met, Her2, Akt, Cdk4, Hsp70, and Hsp90 in a concentration-dependent manner. The studies indicated towards potential suppression of multiple oncogenic signaling pathways (PI3K-Akt-mTOR and Ras-Raf-Mek-Erk) simultaneously, thereby lessening the prospects of molecular feedback loops and mutations, which lead to the plausible overcoming of tumor resistance in NSCLC [49, 50].

Flavokawain В (Figure 5.6H) has also been reported to demonstrate antiproliferative activity against human oral carcinoma HSC-3 cells and hepa- totoxicity against HepG2 cells by inducing cell-cycle arrest, transcriptional responses, and apoptosis through disruption of Hsp90 chaperone machinery [51,52].

The role of chalcones was perceived to be universal and not restricted to anticancer applications. Seo et al. identified the anti-infective perspective Hsp90 inhibitory potential of 2,’4’-dihydroxychalcone (2,’4’-DHC) (Figure 5.6J) in Aspergillus fumigatus. The chalcone analog significantly decreased the growth of fungus by selectively suppressing the Hsp90 in the Hsp90-calcinurin pathway by binding with the ATPase domain (Figure 5.6) [53].

Chalcone based Hsp90 inhibitors

FIGURE 5.6 Chalcone based Hsp90 inhibitors.


The chapter emphasized on the displayed promises laid by the chalcone scaffold bearing molecules originated from the nature and laboratory in the complete inhibition of the critical anti-cancer molecular target Hsp90 as well as downregulating the client proteins such as EGFR, Her2, Met, Akt, and c-Raf. As the first journey started 25 years ago with discovery programs headed by academia, it has now gained attention among the scientists of all fields. About 20 small molecules developed in academia-industry collaborations as competitive Hsp90 inhibitors have reached the clinical trial stage either alone or with another anti-cancer drug combination, which certainly indicated towards the future avenues of pharmacotherapeutics for cancer of multiple origins. In the present scenario, these clinically active candidates are still miles away from the regulatory approval, although, it is quite motivating for the medicinal chemists and researchers for further studies. The encouraging results of these small molecules at preclinical stages in modulating the biological target in multiple oncogenic pathways have certainly attracted pharmaceutical exerts for better optimization, establishment of an accurate structure-activity-relationships, development towards utility in multiple diseases (inflammation, AIDS, different kinds of infections, metabolic diseases, and many more) and superior chemotherapeutic applications.


  • cystic fibrosis transmembrane conductance regulator
  • heat shock protein 90
  • low-molecular-weight-ligands
  • p-glycoprotein
  • structure-based drug design
  • tetratroicopeptide repeat


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