Recyclization of morpholinochromonylidene–thiazolidinone using nucleophiles: facile synthesis, cytotoxic evaluation, apoptosis, cell cycle and molecular docking studies of a novel series of azole, azine, azepine and pyran derivatives

Abstract

A convenient synthetic approach for construction of a novel series of substituted azoles, azines, azepines and pyrans clubbed with a morpholinothiazolidinone hybrid was achieved. The methodology depended on ring-opening and ring-closure (RORC) of chromone ring in 2-(morpholinoimino)-5-[(4-oxo-4H-chromen-3-yl)methylene]-3-phenylthiazolidin-4-one (3) through its reaction with a series of nitrogen and carbon nucleophiles under mild reaction conditions. The cytotoxic effects of all products were evaluated against three cancerous cell lines (MCF-7, HepG-2 and SKOV-3) by the standard SRB method. Fortunately, the products 7, 11, 12, 15, 19, 22, 26 and 28 were found to be the most active against all cancer cell lines, comparable to doxorubicin. Apoptosis was determined using flow cytometry along with cell cycle analysis and supported by molecular docking. The products 7, 11, 12, 15, 19, 22, 26 and 28 induced a significant early-and late-apoptotic effect against all tumor cells. In addition, these products preferred to arrest all cancer cells in the G1 and G2 phases. Finally, molecular docking was attempted to investigate the binding mode of products 12 and 22 with p53-MDM2 protein receptor.