In silico design of novel tubulin binding 9-arylimino derivatives of noscapine, their chemical synthesis and cellular activity as potent anticancer agents against breast cancer

Abstract

We present a series of 9-arylimino derivatives of noscapine (an antitussive plant alkaloid) that binds to tubulin and displaying anticancer activity against a panel of breast cancer cells. These compounds were rationally designed by coupling of Schiff base containing imine groups at position-9 of the isoquinoline ring of noscapine. Based on a combination of Glide docking and free energy of binding (FEB) calculation, we have screened a panel of three 9-compounds, 12–14 with improved binding affinity with tubulin compared to noscapine. The predicted FEB is −6.166 kcal/mol for 12, −6.411 kcal/mol for 13 and −7.512 kcal/mol for 14. In contrast, the predicted FRB of noscapine is −5.135 kcal/mol. These novel derivatives were strategically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast tumor cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.6 and 26.4 µM, which is 11.02–2.03 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrest cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrest the cell cycle in the G2/M-phase and induced apoptosis. Thus, we conclude that 9-arylimino derivatives of noscapine have great potential to be a novel therapeutic agent for breast cancers. Communicated by Ramaswamy H. Sarma