title: Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9-Epipolygodial against Drug-Resistant Cancer Cells.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Dasari
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, 1050, Brussels, Belgium.
authors.forename: Annelise
authors.initials: A
authors.lastname: De Carvalho
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Derek C
authors.initials: DC
authors.lastname: Medellin
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA.
authors.forename: Kelsey N
authors.initials: KN
authors.lastname: Middleton
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, 80000, Amiens, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hague
authors.affiliation: Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Marie N M
authors.initials: MN
authors.lastname: Volmar
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, 801 Leroy Place, Socorro, NM, 87801, USA.
authors.forename: Liliya V
authors.initials: LV
authors.lastname: Frolova
authors.affiliation: Center of Innovation and Preclinical Studies, Av. Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil.|Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Mateus F
authors.initials: MF
authors.lastname: Rossato
authors.affiliation: Department of Comprehensive Dentistry, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: De La Chapa
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Dybdal-Hargreaves
authors.affiliation: Department of Biomedical Sciences, College of Medicine, University of Illinois, 1601 Parkview Ave., Rockford, IL, 61107, USA.
authors.forename: Akshita
authors.initials: A
authors.lastname: Pillai
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, 1050, Brussels, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Mathieu
authors.affiliation: Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, 801 Leroy Place, Socorro, NM, 87801, USA.
authors.forename: Snezna
authors.initials: S
authors.lastname: Rogelj
authors.affiliation: Department of Comprehensive Dentistry, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors.forename: Cara B
authors.initials: CB
authors.lastname: Gonzales
authors.affiliation: Center of Innovation and Preclinical Studies, Av. Luiz Boiteux Piazza 1302, Cachoeira do Bom Jesus, Florianópolis, SC, 88056-000, Brazil.|Department of Pharmacology, Federal University of Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
authors.affiliation: Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Via Cintia 4, 80126, Napoli, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Evidente
authors.affiliation: Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, 80000, Amiens, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gautier
authors.affiliation: Department of Biomedical Sciences, College of Medicine, University of Illinois, 1601 Parkview Ave., Rockford, IL, 61107, USA.
authors.forename: Gnanasekar
authors.initials: G
authors.lastname: Munirathinam
authors.affiliation: Neurosurgical Research, University Clinics Munich, Marchioninistr. 15, 81377, Munich, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Burth
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pelly
authors.affiliation: Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Private Bag X1, Matieland, 7602, South Africa.
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.affiliation: Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, 1050, Brussels, Belgium.
authors.forename: Robert
authors.initials: R
authors.lastname: Kiss
authors.affiliation: Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, 78666, USA. a_k76@txstate.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kornienko
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D018408:Patch-Clamp Techniques; D017434:Protein Structure, Tertiary; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D012717:Sesquiterpenes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C034380:polygodial; D004317:Doxorubicin
keywords: capsaicin; capsazepine; ion channels; resiniferatoxin; vanilloid