| Affiliation: | 1. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX, USA;2. Laboratoire de Cancérologie et de Toxicologie Expérimentale, Faculté de Pharmacie, Université Libre de Bruxelles, Brussels, Belgium;3. Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Picardie Jules Verne, Amiens, France;4. Neurosurgical Research, University Clinics Munich, Munich, Germany;5. Departments of Chemistry and Biology, New Mexico Institute of Mining and Technology, Socorro, NM, USA;6. Center of Innovation and Preclinical Studies, Florianópolis, SC, 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, USA;9. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;10. Department of Biomedical Sciences, College of Medicine, University of Illinois, Rockford, IL, USA;11. Dipartimento di Scienze Chimiche, Università di Napoli Federico II, Complesso Universitario Monte Sant'Angelo, Napoli, Italy;12. Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Centro-Niterói, RJ, Brazil;13. Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, South Africa |
| 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. |
