Microbial Transformation of L-696, 474, a Novel Cytochalasin as an Inhibitor of HIV-1 Protease

• Published in: Journal of natural products (Washington, D.C.) Vol. 56; no. 5; pp. 755 - 761
• Main Authors: Chen, Tom S, Doss, George A, Hsu, Annjia, Hsu, Amy, Lingham, Russell B, White, Raymond F, Monaghan, Richard L
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.05.1993; Amer Chemical Soc; American Society of Pharmacognosy
• Subjects: Actinomycetales - metabolism; AIDS/HIV; Amino Acid Sequence; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Biotransformation; Chemistry, Medicinal; Cytochalasins - metabolism; HIV Protease Inhibitors - metabolism; Hydroxylation; Isoindoles; Life Sciences & Biomedicine; Medical sciences; Molecular Sequence Data; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Plant Sciences; Science & Technology; Hydroxylation; HIV-1 virus; Enzyme; Proteinase; Retroviridae; Enzyme inhibitor; Metabolism; In vitro; Actinomycetales; Virus; Cytochalasin; Biotransformation; Actinoplanes; Bacteria; Lentivirinae; Antiviral; Actinomycetes; Human immunodeficiency virus; Microorganism; Actinoplanaceae
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/np50095a013

The microbiological transformation of L-696,474 [1], a novel cytochalasin that is an inhibitor of HIV- 1 protease, was investigated using Actinoplanes sp. ATCC 5377 1. Six hydroxylated metabolites 2-7 of 1 were isolated and purified using reversed-phase hplc. All six metabolites were found to have undergone hydroxylation at the C- 16 methyl group (C-22) of 1. Three of the compounds, 3, 4, and 5, were further hydroxylated at the para (C-29), the meta (C-28), and both the para and the meta, positions of the phenyl ring, respectively. Metabolites 6 and 7 were shown to result from vicinal dihydroxylation on both C- 16 and its attached Me (C-22). The metabolite 7 was further hydroxylated on the meta position of the phenyl ring. The structures of the metabolites were established using spectroscopic techniques including ms, H-1 nmr, C-13 nmr, and various 2D nmr spectroscopy experiments.