Polygodial and Ophiobolin A Analogues for Covalent Crosslinking of Anticancer Targets
Vladimir A. Maslivetc, Breana Laguera, Sunena Chandra, Ramesh Dasari, Wesley J. Olivier, Jason A. Smith, Alex C. Bissember, Marco Masi, Antonio Evidente, Véronique Mathieu, Alexander Kornienko
Abstract
In a search of small molecules active against apoptosis-resistant cancer cells, including glioma, melanoma, and non-small cell lung cancer, we previously prepared α,β- and γ,δ-unsaturated ester analogues of polygodial and ophiobolin A, compounds capable of pyrrolylation of primary amines and demonstrating double-digit micromolar antiproliferative potencies in cancer cells. In the current work, we synthesized dimeric and trimeric variants of such compounds in an effort to discover compounds that could crosslink biological primary amine containing targets. We showed that such compounds retain the pyrrolylation ability and possess enhanced single-digit micromolar potencies toward apoptosis-resistant cancer cells. Target identification studies of these interesting compounds are underway.