Natural-Like Spirocyclic Δα,β-Butenolides Obtained from Diazo Homophthalimides

alpha-Diazo homophotalimides were reacted with various propiolic acids on Rh-2(esp)(2) catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Delta(alpha,beta)-spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural-like Delta(alpha,beta)-spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities. The Delta(alpha,beta)-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 mu M), 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.

Automated summary

Alpha-diazo homophotalimides reacted with propiolic acids on Rh-2(esp)(2) catalysis to produce novel Delta(alpha,beta)-spirobutenolides, which showed potential as anticancer agents by selectively binding selenocysteine.