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

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, Véronique Mathieu, Snezna Rogelj, Cara B Gonzales, João B. Calixto, Antonio Evidente, Mathieu Gautier, Gnanasekar Munirathinam, Rainer Glass, Patricia BurthStephen C. Pelly, Willem A L Van Otterlo, Robert Kiss, Alexander Kornienko

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2014-2026
Number of pages13
JournalChemMedChem
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2015

Keywords

  • capsaicin
  • capsazepine
  • ion channels
  • resiniferatoxin
  • vanilloid

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry
  • Molecular Medicine

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