Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Abstract

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.

Pyrrolo[2′,3′:3,4]cyclohepta[1,2-d][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types

“…Microtubules are intracellular polymers involved in the regulation of a large number of cellular processes, including proliferation, division, determination and maintenance of cellular shape, motility, and intracellular transport. 1 They are highly dynamic structures composed of multiple heterodimers of α- and β-tubulin, and they undergo alternating polymerization and depolymerization phases. 2 Disrupting this dynamic equilibrium interferes with cell division and leads to cell death.…”

Exploring the Gallic and Cinnamic Acids Chimeric Derivatives as Anticancer Agents over HeLa Cell Line: An in silico and in vitro Study

“…A search for molecules that present the aromatic ring motif in their structure with their cytotoxic activity in the HeLa cell line, reported through the IC 50 obtained by the MTT colorimetric assay, [49][50][51][52][53][54][55][56][57][58][59][60][61] was carried out. From this search a total of 170 molecules were identified that met our proposed criteria.…”

A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors

“…A class of novel chalcone derivatives containing 3′,4′,5′- trimethylyl and indole fragments 29 ( Figure 20 ) have been obtained, and their antiproliferative activity against a panel of HeLa, human colon carcinoma (HT29), MCF-7, and human lymphoma (HL-60) cells (3–5 × 10 4 cells) lines also tested 68 . The majority of the synthesised compounds showed superior activities to the reference drug.…”