Semi-synthesis of C28-modified triterpene acid derivatives from maslinic acid or corosolic acid as potential α-glucosidase inhibitors

Abstract

Combining two bioactive moieties by covalent bond into a novel single hybrid biological entity in view of the principle of active splicing, twenty-two C28-modified derivatives of pentacyclic dihydroxytriterpene carboxylic acids with saturated nitrogen heterocycle segments (i.e. 1-deoxynojirimycin or piperazines) have been synthesized. The inhibitory activities of all final target compounds on α-glucosidase were evaluated in vitro. The results of α-glucosidase inhibition assay indicate that some derivatives (e.g. 4b: IC₅₀ = 1468.4 µM; 12b: IC₅₀ = 499.6 µM 12c: IC₅₀ = 768.5 µM, 13c: IC₅₀ = 819.2 µM) show superior inhibitory activity in α-glucosidase than that of the precursor maslinic acid (IC₅₀ = 2540.6 µM) or corosolic acid (IC₅₀ = 1363.7 µM), in which compound 12b (IC₅₀ = 499.6 µM) possesses stronger inhibitory activity than that of acarbose (IC₅₀ = 606 µM). In addition, the result of enzyme kinetics study reveals that the inhibitory mechanism of the compound 12b is non-competitive inhibition and the inhibition constant K_i is 570 µM. The binding interaction between compounds with α-glucosidase are predicted by molecular docking simulation.

Keywords: 1-Deoxynojirimycin; Corosolic acid; Maslinic acid; Piperazine; α-Glucosidase inhibitory activity.