Development of 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents for the management of breast cancer.

We developed 1,3-diynyl derivatives of noscapine (an opium alkaloid) through combinatorial approach and screened out a panel of promising derivatives that bind tubulin and display anticancer activity. The selected derivatives such as 9-4-Bu-Ph-Diyne , 9-3,4-Di-Cl-Diyne and 9-3,4-Di-F-Diyne noscapinoids revealed improved predicted binding energy of -6.676 kcal/mol for , -7.294 kcal/mol for and -7.750 kcal/mol for respectively in comparison to noscapine (-5.246 kcal/mol). These 1,3-diynyl derivatives and were strategically synthesized in high yields by regioselective modification of noscapine scaffold and HPLC purified (purity is >96%). The decrease in intrinsic fluorescence of purified tubulin to 8.39%, 17.39% and 25.47% by and respectively, compared to control suggests their binding capability to tubulin. Their cytotoxicity activity was validated based on cellular studies using two human breast adenocarcinoma (MCF-7 and MDA-MB-231), a panel of primary breast tumor cells and one normal human embryonic kidney cell (293 T). The 1,3-diynyl noscapinoids, and inhibited cellular proliferation in all the cancer cells that ranged between 6.2 and 38.9 µM, without affecting the normal healthy cells (cytotoxicity is <5% at 100 µM). Further, these novel derivatives arrest cell cycle in the G2/M-phase, followed by induction of apoptosis to cancer cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.Communicated by Ramaswamy H. Sarma.