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

Abstract

We report efficient synthetic methodologies for the preparation of 3-amino and 3-hydroxy 3-pyrrolin-2-ones (unsaturated γ-lactams) through a multicomponent reaction of amines, aldehydes and acetylene or pyruvate derivatives. The densely substituted γ-lactam substrates show in vitro cytotoxicity, inhibiting the growth of the carcinoma human tumor cell lines RKO (human colon epithelial carcinoma), SKOV3 (human ovarian carcinoma) and A549 (carcinomic human alveolar basal epithelial cell). In view of the possibilities for the diversity of the substituents that offer a multicomponent, synthetic methodology, an extensive structure–activity profile is presented. In addition, the bioisosteric replacement of the flat ester group by a tetrahedral phosphonate or phosphine oxide moiety in γ-lactam substrates leads to increased growth inhibition activity. 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.…”

Temperature-Controlled Diastereoselective Doebner/Ugi Tandem Reaction

“…The pyrrolidinone scaffold is present in numerous bioactive agents, such as the endothelin receptor antagonist oteromicyn, 6 antibiotics, 7 antimicrobials, 8 antipyretics, 9 analgesics, 10 novel tyrosinase inhibitors, 11 and molecules for the treatment of Alzheimer’s disease 12 and tumors. 13 14…”

Synthesis of Trifluoromethylated γ-Lactams through Radical Cascades of N-Cyano Alkenes with CF3SO2Na

“…Functionalized γ-lactams have been known as important core structures that appear in various natural alkaloids, pharmaceuticals, and bioactive molecules . Meanwhile, introduction of fluorine-containing groups, such as a fluoride (F) or trifluoromethyl (CF 3 ) group, into organic molecules has a profound impact on the molecules’ physical and biological properties, as those fluorine-containing groups may generally alert the molecules’ hydrophobicities, metabolic stabilities, and bioavailabilities.…”