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.