Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9‐Epipolygodial against Drug‐Resistant Cancer Cells. Issue 12 (5th October 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: ChemMedChem. Volume 10:Issue 12(2015:Dec.)
• Page Start: 2014
• Page End: 2026
• Publication Date: 2015-10-05
• Subjects: capsaicin -- capsazepine -- ion channels -- resiniferatoxin -- vanilloid; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500360
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: 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. Abstract : Inverting one stereocenter turns the inactive sesquiterpenoid polygodial into a potent anticancer agent with promising activity against drug‐resistant cancer cells. Polygodial and 9‐epipolygodial undergo a Paal–Knorr reaction with electron‐deficient primary amines to form a stable pyrrole derivative, a process of possible biological relevance. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives.