Synthesis, in vitro cytotoxicity, and molecular docking study of novel 3,4‐dihydroisoquinolin‐1(2H)‐one based piperlongumine analogues

Abstract

With the aim of expanding the scope of SAR on piperlongumine (PL), a naturally occurring anticancer molecule, we have designed a novel hybrid molecule bearing 3,4‐dihydroisoquinolin‐1(2H)‐one and trans‐cinnamic acids. The structure, based on hybridization strategy, is used for hybridization of naturally occurring scaffolds. We have synthesized 14 hybrid molecules by coupling 3,4‐dihydroisoquinolin‐1(2H)‐one core with cinnamic acids using the mix anhydride approach. The newly synthesized inhibitors were evaluated for cell viability against breast cancer MCF‐7 and cervical cancer HeLa cell lines. Furthermore, the active compounds were screened for their potential in breast cancer MDA‐MB‐231, cervical cancer C33A cell lines, prostate cancer DU‐145, PC‐3, and normal VERO cells. From the series, compound 10g was seen to inhibit MCF‐7 cell growth significantly with GI50 < 0.1 μM along with growth inhibition in MDA‐MB‐231 (GI50 = 20 μM) and C33A (GI50 = 3.2 μM). While the inhibitor 10i inhibits MCF‐7 breast cancer cell growth GI50 = 3.42 μM along with inhibition of cell growth in MDA‐MB‐231 (GI50 = 30 μM), HeLa (GI50 = 7.67 μM), C33A (GI50 = 13 μM), DU‐145 (GI50 = 6.45 μM), PC‐3 (GI50 = 8.68 μM), and VERO (GI50 = 2.93 μM), respectively. Furthermore, molecular docking study demonstrated these compounds could bind tightly to the colchicine domain of tubulin through a network of favorable steric and electrostatic interactions and thus act as a tubulin polymerization inhibitor.