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Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells

par Dasari, Ramesh;Dybdal-Hargreaves, Nicholas Francis;Pillai, Akshita;Mathieu, Véronique ;Rogelj, Snezna;Gonzales, Cara Brigham;Calixto, João Batista;Evidente, Antonio;Gautier, Mathieu;Munirathinam, Gnanasekar;Glass, Rainer;De Carvalho, Annelise;Burth, Patricia;Pelly, Stephen C;van Otterlo, Willem A L;Kiss, Robert ;Kornienko, Alexander;Medellin, Derek D.C.;Middleton, Kelsey K.N.;Hague, Frédéric;Volmar, Marie N M;Frolova, Liliya V;Rossato, Mateus M.F.;De La Chapa, Jorge J.J.
Référence ChemMedChem, 10, 12, page (2014-2026)
Publication Publié, 2015-12

Article révisé par les pairs

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Résumé :

Polygodial, a terpenoid dialdehyde isolated from Polygonum hydropiper L., is a known agonist of the transient receptor potential vanilloid 1 (TRPV1). In this investigation a series of polygodial analogues were prepared and investigated for TRPV1-agonist and anticancer activities. These experiments led to the identification of 9-epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9-Epipolygodial was found to maintain potency against apoptosis-resistant cancer cells as well as those displaying the multidrug-resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal-Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.