Discovery of indolizine lactones as anticancer agents and their optimization through late-stage functionalization

Thiago Sabino da Silva; Matheus da Silva Souza; Adriano Defini Andricopulo; Fernando Coelho

doi:10.1039/d3ra03395c

Discovery of indolizine lactones as anticancer agents and their optimization through late-stage functionalization

RSC Adv. 2023 Jul 5;13(29):20264-20270. doi: 10.1039/d3ra03395c. eCollection 2023 Jun 29.

Authors

Thiago Sabino da Silva¹, Matheus da Silva Souza², Adriano Defini Andricopulo², Fernando Coelho¹

Affiliations

¹ Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas Rua Monteiro Lobato, S/N, 13083-970, Campinas São Paulo Brazil facoelho@unicamp.br.
² Laboratory of Medicinal and Computational Chemistry, Institute of Physics of Sao Carlos, University of Sao Paulo - Avenida Joao Dagnone 1100-13563-120 - Sao Carlos SP Brazil.

Abstract

Indolizines fused with a seven-member lactone ring were identified as a promising scaffold in the search for new anticancer agents. Through a modular synthetic sequence, a library of cis and trans indolizines lactones had their antiproliferative activity evaluated against hormone-refractory prostate DU-145 and triple-negative breast MDA-MB-231 cancer cell lines. A methoxylated analogue was identified as an initial hit against MDA-MB-231 and late-stage functionalization of the indolizine core led to analogues within potencies up to twenty times higher than the parent precursor.