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

Xabier Del Corte,Edorta Martínez De Marigorta,Aitor Maestro,Ilia Villate-Beitia,Francisco Palacios,Myriam Sainz-Ramos,José Luis Pedraz,Javier Vicario,Adrián López-Francés

doi:10.3390/ph14080782

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.

Highlights

Introduction published maps and institutional affilPopulation aging is one of humanity’s greatest achievements, and one of its biggest challenges
The stoichiometry of the reaction is 2:1:1 implies the reaction of aromatic amines 1 with aldehydes 2 and pyruvate derivatives 3 in, equivalents of pyruvate derivative the presence of a catalytic amountthree of BINOL
Very good selectivity was obtained towards MRC5 non-malignant cell line (Figure 2). With these results in hand, we extended our study of the cell proliferation inhibitory activities of our family of γ-lactams using RKO, SKOV3, and A549 cell lines

Summary

Introduction

Introduction published maps and institutional affilPopulation aging is one of humanity’s greatest achievements, and one of its biggest challenges. From a health point of view, one of the main side effects of the growth in life expectancy is the increasing occurrence of disorders associated with aging In this regard, cancer diseases are currently one of the biggest health problems worldwide [1] and, malignant neoplasms have become nowadays one of the primary targets in medicinal sciences. One of the major goals of cancer therapy has been the specific and effective elimination of tumor cells by apoptosis, a programmed and highly regulated cellular death mechanism triggered by multiple factors that induce cellular stress In this regard, there are already available some FDA-approved anticancer agents designed to target intracellular apoptotic pathways, and iations

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Conclusion