ChemMedChem · 2015
Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАПоддержка правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Dasari Ramesh, De Carvalho Annelise, Medellin Derek C, Middleton Kelsey N, Hague Frédéric, Volmar Marie N M, Frolova Liliya V, Rossato Mateus F, De La Chapa Jorge J, Dybdal-Hargreaves Nicholas F, Pillai Akshita, Mathieu Véronique, Rogelj Snezna, Gonzales Cara B, Calixto João B, Evidente Antonio, Gautier Mathieu, Munirathinam Gnanasekar, Glass Rainer, Burth Patricia, Pelly Stephen C, van Otterlo Willem A L, Kiss Robert, Kornienko Alexander
Аннотация
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.