Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer agents

Abstract

A series of novel chalcone analogues were designed, synthesized and evaluated as antitcancer agents. The results of antiproliferative activity test showed most of most analogues exhibited moderated to very good antiproliferative activities with GI50 values in micromol to sub-micromol range. Especially, compounds 10a, gave 0.026 μM to 0.035 μM of GI50 value for five cancer cell line. The mechanism studies including tubulin polymerization inhibition, disruption of microtubule dynamics and cell cycle arrest assay demonstrated that compound 10a could effectively inhibit in vitro cellular tubulin polymerization, interfere with the mitosis, resulting in a prolonged G2/M cell cycle arrest and ultimately lead to cell apoptosis of cancer cells. Taken together, these results suggested that 10a may became a promising lead compound for development of new anticancer drugs.both indoles and indanones exhibited varied pharmacological activities, herein, we designed and evaluated and chalcone analogues derived from indole aldehydes and indanones as inhibitors of tubulin polymerization.

Arylidene indanone scaffold: medicinal chemistry and structure–activity relationship view

“…46,48 Tubulin depolymerization agents require the trimethoxy substitution on the indanone ring to mimic the colchicine type activity. 74,80,81,91,95 Tunability of the a,b-unsaturated ketone system as a Michael acceptor is paramount to the type of biological activity, 132 since these systems are present in many natural products like chalcones as well as AI, where the molecule is more planar comparatively and the transmission of electronic effects of the aryl substituents are directed towards the carbonyl group. 13 The importance of the double bond at the 2-position in arylidene indanone has been veried by SAR studies, indicating no DUSP inhibition activity if removed 28 or improved tubulin activity compared to unsubstituted compounds 79,81 or diminished AChE activity if removed or hydrogenated.…”

“…11) gave promising results in several cancer cell lines and inhibited tubulin with no inuence of the position of contact with the indole moiety. 95 Similarly, millepachine-indolyl chalcone 22c with substitution at the 5-position of N-methyl indole was the most potent among others and showed cytotoxicity against all tested cancer cells. 96 The bioavailability of millepachine derivative 22d was improved by 47% aer forming its hydrochloride salt.…”

Novel Natural Product- and Privileged Scaffold-Based Tubulin Inhibitors Targeting the Colchicine Binding Site

“…An N -methyl-5-indolyl group on the right ring and a propionyloxy group at the 4 position of the left phenyl ring had beneficial effects on the cytotoxic activity. Chen et al designed and synthesized a series of novel chalcone analogues through the aldol condensation of indanones and indole carbaldehydes [84]. Compounds obtained from 4,5,6-trimethoxy indanone with different indole carbaldehydes usually exhibited more potent antiproliferative activities.…”

Concise Synthesis and Biological Evaluation of Chalcone Derivatives Bearing N-Heterocyclic Moieties

“…10 Due to their flexible character bearing α, β-unsaturated ketone unit, chalcones are playing the vital role in drug research through structural modification. [11][12][13][14] Nitrogen heterocycles are important class of compounds having versatile biological activities, which are used in drug design and synthesis generally as active units. The combination of the chalcone and imidazole in one frame, has been reported in previous literature and is likely to lead to hybrid compounds with potential activity.…”

“…16 On the basis of these results, we wanted to design and synthesize molecules towards the recombination of chalcone and active nitrogen heterocycle moieties in the same structure through medicinal chemistry hybridization. Here, we (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) following the literature procedure, and no aza-Michael addition product was observed. 18,19 Initially, K2CO3 was used in synthesis of title compounds.…”