Letters in Drug Design & Discovery

G. Perry
University of Texas
San Antonio, TX
USA
Email: lddd@benthamscience.org

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

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

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.

Keywords: HIV-1, Triterpene, Entry, Maturation

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Article Details

VOLUME: 4
ISSUE: 7
Year: 2007
Page: [471 - 478]
Pages: 8
DOI: 10.2174/157018007781788561
Price: $58