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

Abstract

Polygodial, a terpenenoid dialdehyde isolated from Polygonum hydropiper L., is a known TRPV1 agonist. In this investigation a series of polygodial analogues were prepared and investigated for TRPV1 agonistic and anticancer activities. These experiments led to the identification of 9-epipolygodial, possessing antiproliferative potency significantly exceeding that of polygodial. Epipolygodial maintained potency against apoptosis-resistant cancer cells as well as those displaying the MDR phenotype. In addition, a chemical feasibility for the previously proposed mechanism of action of polygodial, involving the Paal-Knorr pyrrole formation with a lysine residue on the target protein, was demonstrated through the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. They should inspire further work in this area aimed at the development of new pharmacological agents or exploration of novel mechanisms of covalent modification of biological molecules with natural products.

Covalent modification of biological targets with natural products through Paal–Knorr pyrrole formation

“…Unfortunately, the manner in which polygodial inhibits TRPV1 and whether covalent pyrrole adducts are involved remains to be elucidated. 32 …”

“…32,33 To obtain firm evidence of Paal–Knorr reactivity in these compounds, we attempted to isolate such pyrrole adducts (Scheme 9). Our proposed explanation for the lack of stability of the produced pyrroles was their electron-rich character and, thus, high propensity toward oxidation.…”

“…Finally, 24c , in which the nitrogen substituent was a highly electron-withdrawing p -nitrophenyl, was a stable isolable pyrrole-containing compound that was fully characterized. 32 …”

Wittig derivatization of sesquiterpenoid polygodial leads to cytostatic agents with activity against drug resistant cancer cells and capable of pyrrolylation of primary amines

“…In our own attempts [55] to demonstrate the feasibility of what could be referred to as the modified Paal-Knorr [56] pyrrolylation of proteins by 1 , it was found that although N -alkyl pyrrole 2 (R = Bn, Figure 2A) formed, it was extremely unstable and readily oxidized in air. This stability problem was solved by the preparation and successful isolation of electron-deficient N -aryl pyrroles 2 (R = Ph and p -NO 2 -C 6 H 4 ); however, these adducts are obviously not relevant biologically as the resultant covalent complex with a lysine residue would be an alkyl pyrrole and thus also readily oxidizable.…”

“…Encouraged by several earlier reports of cytotoxic activity associated with 1 [49–54], we prepared a series of its chemical derivatives and studied their TRPV1 agonistic and anticancer activities in detail. A related publication resulting from this study describes the discovery of useful anticancer activities associated with 9-epipolygodial [55]. Herein, we present a series of C12-Wittig derivatives of 1 that exert their antiproliferative action mainly through cytostatic effects and possess promising activities against cancer cells resistant to apoptosis as well as those with an MDR phenotype.…”