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ChemMedChem. 2015 Dec;10(12):2014-26. doi: 10.1002/cmdc.201500360. Epub 2015 Oct 5.

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

Author information

1
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
2
Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, 1050, Brussels, Belgium.
3
Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, 80000, Amiens, France.
4
Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377, Munich, Germany.
5
Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, 801 Leroy Place, Socorro, NM, 87801, USA.
6
Center of Innovation and Preclinical Studies, Av. Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil.
7
Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
8
Department of Comprehensive Dentistry, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
9
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
10
Department of Biomedical Sciences, College of Medicine, University of Illinois, 1601 Parkview Ave., Rockford, IL, 61107, USA.
11
Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Napoli, Italy.
12
Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Outeiro de São João Batista, s/n Campus do Valonguinho, Centro-Niterói, RJ, 24020-140, Brazil.
13
Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
14
Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA. a_k76@txstate.edu.

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.

KEYWORDS:

capsaicin; capsazepine; ion channels; resiniferatoxin; vanilloid

PMID:
26434977
PMCID:
PMC4831215
DOI:
10.1002/cmdc.201500360
[Indexed for MEDLINE]
Free PMC Article

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