Discovery of Dihydropyrrol-2-ones as Novel G0/G1-Phase Arresting Agents Inducing Apoptosis

Abstract

A series of dihydropyrrol-2-ones (DHPs) were designed and synthesized via an efficient multicomponent reaction at room temperature for evaluation of their bioactivities against four human cancer lines (MCF-7, RKO, HeLa, and A549) in vitro. Preliminary structure–activity relationship studies showed that R4 = 3-MeO-4-OH-Ph is a crucial group for increasing cytotoxicities against RKO cells and the influences of R1–R3 depend on their combination. It was found that DHPs 5a, 5q, and 5s showed the best antiproliferative activities against A549, RKO, and all four studied cell lines, respectively (IC50 = 1.9, 0.8, and 0.9–2.4 μM). They can be used as new lead compounds for developing potentially selective or broad spectrum anticancer agents. 5q proves as a potent G0/G1-phase arresting agent inducing cell apoptosis by increasing/decreasing the levels of p53 and p21/cyclin D1.

Multicomponent Synthesis of Unsaturated γ-Lactam Derivatives. Applications as Antiproliferative Agents through the Bioisosterism Approach: Carbonyl vs. Phosphoryl Group

“…Interestingly, some unsaturated γ-lactam substrates have been identified as p53−MDM2 [ 20 ] and STAT3 [ 21 ] inhibitors that have strong antiproliferative activity. In addition, several 2-pyrrolidone derivatives have been described as antitumor agents [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”

Exploring the Synthetic Potential of γ-Lactam Derivatives Obtained from a Multicomponent Reaction—Applications as Antiproliferative Agents

“…In addition, from a synthetic point of view, 3-amino 3-pyrrolin-2-ones are cyclic enamine substrates and, therefore, they are outstanding tools in chemical synthesis [ 41 ]. Interestingly, some pyrrolone-based systems have been identified as p53−MDM2 [ 42 ] and STAT3 [ 43 ] inhibitors, which result in strong antiproliferative activity, and, in addition, many other molecules containing the pyrrolone scaffold have been described as efficient antitumoral agents [ 44 , 45 , 46 , 47 , 48 ].…”

A Multicomponent Protocol for the Synthesis of Highly Functionalized γ-Lactam Derivatives and Their Applications as Antiproliferative Agents

“…Interestingly, some 2-pyrrolone substrates have been recently identified as p53−MDM2 [ 16 ] and STAT3 [ 17 ] inhibitors, which results in a strong antiproliferative activity and, besides, many other 2-pyrrolone derivatives have been described as antitumoral agents [ 18 , 19 , 20 , 21 , 22 , 23 ].…”