A Focused Library of NO‐Donor Compounds with Potent Antiproliferative Activity Based on Green Multicomponent Reactions

Abstract

Cancer is the second leading cause of death worldwide. Herein, a strategy to quickly and efficiently identify novel lead compounds to develop anticancer agents, using green multicomponent reactions followed by antiproliferative activity and structure–activity relationship studies, is described. A second‐generation focused library of nitric oxide‐releasing compounds was prepared by microwave‐assisted Passerini and Ugi reactions. Nearly all compounds displayed potent antiproliferative activities against a panel of human solid tumor cell lines, with 1‐phenyl‐1‐[(tert‐butylamino)carbonyl]methyl 3‐[(3‐phenylsulfonyl‐[1,2,5]oxadiazol‐4‐yl N2‐oxide)oxy]benzoate (4\u2009k) and N‐[1‐(tert‐butylaminocarbonyl)‐1‐phenylmethyl]‐N‐(4‐methylphenyl)‐3‐(3‐phenylsulfonyl‐[1,2,5]oxadiazol‐4‐yl N2‐oxide)oxyphenyl carboxamide (6\u2009d) exhibiting the strongest activity on SW1573 lung cell line (GI50=110 and 21\u2005nm) with selectivity indices of 70 and 470, respectively. Preliminary mechanistic studies suggest a relationship between NO release and antiproliferative activity. Our strategy allowed the rapid identification of at least two molecules as future candidates for the development of potent antitumor drugs.