PubMed 26360047

Referenced in Channelpedia wiki pages of: none

Automatically associated channels: ClvC4

Title: Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines.

Authors: Ramesh Dasari, Annelise De Carvalho, Derek C Medellin, Kelsey N Middleton, Frédéric Hague, Marie N M Volmar, Liliya V Frolova, Mateus F Rossato, Jorge J De La Chapa, Nicholas F Dybdal-Hargreaves, Akshita Pillai, Roland E Kälin, Véronique Mathieu, Snezna Rogelj, Cara B Gonzales, João B Calixto, Antonio Evidente, Mathieu Gautier, Gnanasekar Munirathinam, Rainer Glass, Patricia Burth, Stephen C Pelly, Willem A L van Otterlo, Robert Kiss, Alexander Kornienko

Journal, date & volume: Eur J Med Chem, 2015 Oct 20 , 103, 226-37

PubMed link:

Many types of cancer, including glioma, melanoma, non-small cell lung cancer (NSCLC), among others, are resistant to proapoptotic stimuli and thus poorly responsive to current therapies based on the induction of apoptosis in cancer cells. The current investigation describes the synthesis and anticancer evaluation of unique C12-Wittig derivatives of polygodial, a sesquiterpenoid dialdehyde isolated from Persicaria hydropiper (L.) Delabre. These compounds were found to undergo an unprecedented pyrrole formation with primary amines in a chemical model system, a reaction that could be relevant in the biological environment and lead to the pyrrolation of lysine residues in the target proteins. The anticancer evaluation of these compounds revealed their promising activity against cancer cells displaying various forms of drug resistance, including resistance to proapoptotic agents. Mechanistic studies indicated that compared to the parent polygodial, which displays fixative general cytotoxic action against human cells, the C12-Wittig derivatives exerted their antiproliferative action mainly through cytostatic effects explaining their activity against apoptosis-resistant cancer cells. The possibility for an intriguing covalent modification of proteins through a novel pyrrole formation reaction, as well as useful activities against drug resistant cancer cells, make the described polygodial-derived chemical scaffold an interesting new chemotype warranting thorough investigation.