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We developed 1,3-diynyl derivatives of noscapine (an opium alkaloid) through  in silico  combinatorial approach and screened out a panel of promising derivatives that bind tubulin and display anticancer activity. The selected derivatives such as 9-4- t Bu-Ph-Diyne  (20p) , 9-3,4-Di-Cl-Diyne  (20k)  and 9-3,4-Di-F-Diyne  (22s)  noscapinoids revealed improved predicted binding energy of −6.676 kcal/mol for  20p , −7.294 kcal/mol for  20k  and −7.750 kcal/mol for  20s  respectively in comparison to noscapine (−5.246 kcal/mol). These 1,3-diynyl derivatives  (20p, 29k  and  20s)  were strategically synthesized in high yields by regioselective modification of noscapine scaffold and HPLC purified (purity is &gt;96%). The decrease in intrinsic fluorescence of purified tubulin to 8.39%, 17.39% and 25.47% by  20p, 20k  and  20s  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,  20p, 20k  and  20s  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 &lt;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

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