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

Abstract

An efficient synthetic methodology for the preparation of 3-amino 1,5-dihydro-2H-pyrrol-2-ones through a multicomponent reaction of amines, aldehydes, and pyruvate derivatives is reported. In addition, the densely substituted lactam substrates show in vitro cytotoxicity, inhibiting the growth of carcinoma human tumor cell lines HEK293 (human embryonic kidney), MCF7 (human breast adenocarcinoma), HTB81 (human prostate carcinoma), HeLa (human epithelioid cervix carcinoma), RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma), and A549 (carcinomic human alveolar basal epithelial cell). Given the possibilities in the diversity of the substituents that offer the multicomponent synthetic methodology, an extensive structure-activity profile is presented. In addition, both enantiomers of phosphonate-derived γ-lactam have been synthesized and isolated and a study of the cytotoxic activity of the racemic substrate vs. its two enantiomers is also presented. Cell morphology analysis and flow cytometry assays indicate that the main pathway by which our compounds induce cytotoxicity is based on the activation of the intracellular apoptotic mechanism.

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

“…As has been addressed above, some 3-pyrrolin-2-one derivatives have been demonstrated to induce apoptosis in several cancer cell lines [ 10 , 11 ]. For this reason and in order to underscore the usefulness of our functionalized γ-lactam substrates, next, the in vitro cytotoxicity of some of the heterocycles was evaluated by testing their antiproliferative activities against several human cancer cell lines.…”

“…Thus, tremendous efforts have been devoted during the last decades towards the efficient synthesis of functionalized γ-lactam derivatives [ 3 , 4 , 5 , 6 , 7 ]. In particular, 3-pyrrolin-2-ones (also named as 1,5-dihydropyrrol-2-ones), closely related to γ-lactams, are not only useful building blocks in chemical synthesis [ 8 , 9 ], but also core structures of bioactive natural products and pharmaceuticals [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…More recently, we have extended this strategy to the preparation of the corresponding phosphorus and fluorine-containing analogs, using in this case fluorine and/or phosphonate-substituted aldehydes and pyruvates [ 25 ]. Remarkably, many of those molecules have shown strong antiproliferative activity, inhibiting the growth of several carcinoma human tumor cell lines through the activation of the apoptotic mechanism [ 10 , 11 ]. Key features of the structure of those substrates are the very reactive cyclic enamine moiety and the presence of a chiral stereocenter at the 5-membered ring.…”

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 ].…”

“…In this context, very recently, we conducted a study on the antiproliferative activity of 3-amino 3-pyrrolin-2-ones, showing evidence of the ability of these substrates to activate the intracellular apoptotic mechanism [ 29 ]. Taking into consideration the potential of five-membered heterocycles containing the 3-pyrrolin-2-one skeleton to act as anticancer agents, we believe that this report on the synthesis of unsaturated 3-hydroxy and 3-amino γ-lactam derivatives obtained by multicomponent methodologies and study of their applications as antiproliferative agents will be of great value to this field.…”