Synthesis and Anti-HIV Activity of Bi-Functional Triterpene Derivatives

Title: Synthesis and Anti-HIV Activity of Bi-Functional Triterpene Derivatives

Volume: 4 Issue: 7

Author(s): Li Huang, Donglei Yu, Phong Ho, Kuo-Hsiung Lee and Chin-Ho Chen

Affiliation:

Keywords: HIV-1, Triterpene, Entry, Maturation

Abstract: We previously reported a bi-functional betulinic acid derivative, A12-2 (4), containing an optimized C-28 side chain that exhibits potent anti-HIV activity by inhibiting both HIV-1 entry and maturation. Compound 4 contains C-3 and C-28 side chains that are pharmacophores for anti-HIV maturation and entry activity, respectively. The betulinic acid core, which serves as a molecular scaffold for compound 4, is also important for anti-HIV activity. The main purposes of the present study were to investigate the structure-activity relationships (SAR) of both the C-3 side chain and scaffold of 4. Further modification of the C-3 side chain of 4 suggested that both bulkier and smaller C-3 substituents negatively impacted the anti-HIV-1 activity. SAR study of the scaffold indicated that the betulinic acid moiety of 4 could be replaced with other scaffolds while still remaining active against HIV-1 replication. Among the synthesized compounds, the most effective molecular scaffold for anti-HIV activity remained to be betulinic acid (0.0026 μM), followed by moronic acid, ursolic acid, and oleanolic acid. On the other hand, substitution of the betulinic acid moiety of 4 with glycyrrhetinic acid or lithocholic acid completely abolished anti-HIV activity. Mechanism of action studies indicated that all active terpenoid analogs of 4 retained both anti-HIV-1 entry and anti-HIV-1 maturation activities.

Cite this article as:

Huang Li, Yu Donglei, Ho Phong, Lee Kuo-Hsiung and Chen Chin-Ho, Synthesis and Anti-HIV Activity of Bi-Functional Triterpene Derivatives, Letters in Drug Design & Discovery 2007; 4 (7) . https://dx.doi.org/10.2174/157018007781788561