Synthesis and Biological Evaluation of Indole-2-Carboxamides with Potent Apoptotic Antiproliferative Activity as EGFR/CDK2 Dual Inhibitors

Abstract

The apoptotic antiproliferative actions of our previously reported CB1 allosteric modulators 5-chlorobenzofuran-2-carboxamide derivatives VIIa–j prompted us to develop and synthesise a novel series of indole-2-carboxamide derivatives 5a–k, 6a–c, and 7. Different spectroscopic methods of analysis were used to validate the novel compounds. Using the MTT assay method, the novel compounds were examined for antiproliferative activity against four distinct cancer cell lines. Compounds 5a–k, 6a–c, and 7 demonstrated greater antiproliferative activity against the breast cancer cell line (MCF-7) than other tested cancer cell lines, and 5a–k (which contain the phenethyl moiety in their backbone structure) demonstrated greater potency than 6a–c and 7, indicating the importance of the phenethyl moiety for antiproliferative action. Compared to reference doxorubicin (GI50 = 1.10 µM), compounds 5d, 5e, 5h, 5i, 5j, and 5k were the most effective of the synthesised derivatives, with GI50 ranging from 0.95 µM to 1.50 µM. Compounds 5d, 5e, 5h, 5i, 5j, and 5k were tested for their inhibitory impact on EGFR and CDK2, and the results indicated that the compounds tested had strong antiproliferative activity and are effective at suppressing both CDK2 and EGFR. Moreover, the studied compounds induced apoptosis with high potency, as evidenced by their effects on apoptotic markers such as Caspases 3, 8, 9, Cytochrome C, Bax, Bcl2, and p53.

Discovery of new 5-substituted-indole-2-carboxamides as dual epidermal growth factor receptor (EGFR)/cyclin dependent kinase-2 (CDK2) inhibitors with potent antiproliferative action

“…The 4-phenylpiperazine derivatives 6a–c had mild antiproliferative activity against the four cancer cell lines examined, with GI 50 values ranging from 125 nM to 193 nM, demonstrating the relevance of the phenethyl ring moiety for the antiproliferative impact. 23,24…”

“…3-Ethylindole-2-carboxylates 3a–c , 25 carboxylic acids 4a–c , 26 and carboxamides 5a–k and 6a–c 24 were synthesized according to previously reported procedures. See Appendix A (ESI†).…”

“…In another study, 24 a new series of 3-methyl-indole-2-carboxamide derivatives IVa–k (Fig. 1) were synthesised in which the methyl group was kept as a substituent at C3 and the para positions of the phenethyl tails were left unsubstituted or substituted with 4-dimethylamino, morpholin-4-yl, piperidin-1-yl, or 2-methylpyrrolidine-1-yl.…”

“…The compounds induced apoptosis in MCF-7 cells, with significant increases in caspase 3, 8, and 9, cytochrome C levels, and Bax levels, and a decrease in anti-apoptotic Bcl-2 protein levels. 23 In another study, 24 a new series of 3-methyl-indole-2carboxamide derivatives IVa-k (Fig. 1) were synthesised in…”

Integrating network pharmacology and pharmacological evaluation to investigate the anticancer effects of Duranta erecta Linn. Verbenaceae in breast cancer

“…A few evidence are found in the literature 48 . For instance, Al-Wahaibi and colleagues synthesized indole-2-carboxamides and prove its antiproliferative and apoptotic activities through EGFR/CDK2 inhibition 49 . The inhibition of EGFR was also associated with tumor microenvironment modulation in non-small cell lung cancer 50 .…”