Natural-Like Spirocyclic Δα,ß -Butenolides Obtained from Diazo Homophthalimides.

ABSTRACT

α-Diazo homophotalimides were reacted with various propiolic acids on Rh2 (esp)2 catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Δα,ß -spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural-like Δα,ß -spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities. The Δα,ß -spirobutenolides thus obtained were shown to inhibit thioredoxin reductase, a selenocysteine enzyme target for cancer. Moreover, for the best compound in the series (TrxR IC50 1.49±0.08 µM), by using MALDI-TOF mass-spectrometry it was shown that it selectively binds selenocysteine in the presence of a 10-fold excess of cysteine. This validates the new compound as a promising lead for anticancer therapy development.