Synthesis and anti-HIV activity of Bif-functional triterpene derivatives
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. © 2007 Bentham Science Publishers Ltd.
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Related Subject Headings
- Medicinal & Biomolecular Chemistry
- 3404 Medicinal and biomolecular chemistry
- 3214 Pharmacology and pharmaceutical sciences
- 1115 Pharmacology and Pharmaceutical Sciences
- 1101 Medical Biochemistry and Metabolomics
- 0601 Biochemistry and Cell Biology
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Medicinal & Biomolecular Chemistry
- 3404 Medicinal and biomolecular chemistry
- 3214 Pharmacology and pharmaceutical sciences
- 1115 Pharmacology and Pharmaceutical Sciences
- 1101 Medical Biochemistry and Metabolomics
- 0601 Biochemistry and Cell Biology