An IMDAF approach to annellated 1,4:5,8-diepoxynaphthalenes and their metathesis reaction leading to novel scaffolds displaying an antiproliferative activity toward cancer cells

Abstract

A series of 1,4:5,8-diepoxynaphthalenes, annellated with six-membered carbo- and heterocycles, was obtained via the intramolecular Diels–Alder furan (IMDAF) cycloaddition approach from bis-furyl dienes and acetylenic dienophiles (dialkyl acetylenedicarboxylates and hexafluoro-2-butyne). To achieve a wide variety of different products for subsequent biotesting, ethylene-promoted ring-opening cross-metathesis (ROCM) reactions, Prilezhaev epoxidation, catalytic hydrogenation, and N- or O-deprotection reactions of pentacycles were performed. The polyfunctional scaffolds of the resulting diverse heterocycles were tested on cancer lines (PC3, DU-145, MDA-MB-231, HT-1080, and HCT116) and normal lung fibroblasts (WI-26 VA4), and it was found that some of the obtained compounds exerted a concentration-dependent antiproliferative action toward MDA-MB-231 human triple-negative breast cancer and especially PC3 human prostate cancer cell lines. It was demonstrated that compound 16f (hydrogenated 7-(tert-butyl)-4,5-dimethyl-2,8a-divinyl-3,5a-epoxyfuro[2,3,4-de]isoquinoline-4,5,7-tricarboxylate) possessed a time-dependent apoptosis induction activity associated with caspase 3/7 activation in prostate cancer cells, which clearly represents a viable lead for the further development of new-generation anticancer agents.