Nonpungent N-AVAM Capsaicin Analogues and Cancer Therapy

Abstract

Capsaicin displays robust growth-inhibitory activity in multiple human cancers. However, the feasibility of capsaicin as a clinically relevant anticancer drug is hampered by its adverse side effects. This concern has led to extensive research focused on the isolation and synthesis of second-generation nonpungent capsaicin analogues with potent antineoplastic activity. A major class of nonpungent capsaicin-like compounds belongs to the N-acyl-vanillylamide (N-AVAM) derivatives of capsaicin (hereafter referred as N-AVAM capsaicin analogues). This perspective discusses the isolation of N-AVAM capsaicin analogues from natural sources as well as their synthesis by chemical and enzymatic methods. The perspective describes the pharmacokinetic properties and anticancer activity of N-AVAM capsaicin analogues. The signaling pathways underlying the growth-inhibitory effects of N-AVAM capsaicin analogues have also been highlighted. It is hoped that the insights obtained in this perspective will facilitate the synthesis of a second generation of N-AVAM capsaicin analogues with improved stability and growth-suppressive activity in human cancer.

Figure 1.

Structure and pharmacophore of capsaicin.

Figure 2.

N-AVAM capsaicin analogues which have been investigated for their growth-suppressive activity in cell culture or mice models.

Figure 3.

Synthesis of N-AVAM capsaicin analogues by Schemes 4–6.

Figure 4.

Synthesis of N-AVAM capsaicin analogues by Schemes 7–9.

Figure 5.

Schematic diagram showing the synthesis of olvanil by bioimprinting technology.

Figure 6.

Putative sites if metabolism of olvanil.

Figure 7.

Schematic diagram showing the compounds generated by the intestinal metabolism and dermal metabolism of olvanil.

Figure 8.

(A) MTT assays show that the growth-suppressive activity of N-AVAM capsaicin analogues increases with increased unsaturation in the compounds. (B) N-AVAM capsaicin analogues do not impact the viability of HPAEpiCs. (C) N-AVAM capsaicin analogues stimulated the activity of the calpain-1, calpain-2 class of apoptotic proteolytic enzymes. Values represented by the symbol * are statistically significant relative to the control (P ≤ 0.05).

Figure 9.

Structures of iodoolvanil and iodoarvanil.

Scheme 1.

Extraction of N-AVAM Capsaicin Analogues from Capsicum oleoresin

Scheme 2.

Extraction of Capsaicin from Habernero and Takanosume Chili Peppers

Scheme 3.

Synthesis of N-AVAM Capsaicin Analogues from Olive Oil

Scheme 4.

Synthesis of N-AVAM Capsaicin Analogues from Soybean Oil

Scheme 10.

Single Step High-Yielding Synthesis of Arvanil (10)

Scheme 11.

High Yield Synthesis of Arvanil (10) from Methyl-14-hydroxy-(all-cis)-5,8,11-tetradecatrienoate

Scheme 12.

Synthesis of Olvanil (5) Using HATU Coupling Agent Methodology

Scheme 13.

Enzymatic Synthesis of Olvanil Using Lipase B

Scheme 14.

Enzymatic Synthesis of Olvanil Using Recombinant Candida antarctica Lipase B (CALB) Immobilized by Cross-Linked Enzyme Aggregate (CLEA) Techniques