Rational design of novel <i>N</i>‐alkyl amine analogues of noscapine, their chemical synthesis and cellular activity as potent anticancer agents
Rajesh Kumar Meher, Pratyush Pragyandipta, Ravi Kumar Pedapati, Praveen Kumar Reddy Nagireddy, Srinivas Kantevari, Arnab Nayek, Pradeep Kumar Naik
Abstract
The scaffold structure of noscapine (an antitussive plant alkaloid) was modified by inducting N-aryl methyl pharmacophore at C-9 position of the isoquinoline ring to rationally design and screened three novel 9-(N-arylmethylamino) noscapinoids, 15-17 with robust binding affinity with tubulin. The selected 9-(N-arylmethylamino) noscapinoids revealed improved predicted binding energy of -6.694 kcal/mol for 15, -7.118 kcal/mol for 16 and -7.732 kcal/mol for 17, respectively in comparison to the lead molecule (-5.135 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDA-MB-231, as well as with a panel of primary breast tumor cells. These derivatives inhibited cellular proliferation in all the cancer cells that ranged between 3.2 and 32.2 μM, which is 11.9 to 1.8 fold lower than that of noscapine. These novel derivatives effectively arrest the cell cycle in the G2/M phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 9-(N-arylmethyl amino) noscapinoids, 15-17 have a high probability to be a novel therapeutic agent for breast cancers.