Chemical and enzymatic modifications of integric acid and HIV-1 integrase inhibitory activity.
Integric acid (1), an acyl eremophilane sesquiterpenoid, was identified as an inhibitor of HIV-1 integrase, the enzyme responsible for provirus entry into the host cell nucleus and integration in to the host genome. Chemical and enzymatic modification of integric acid led to the preparation of several selective chemical derivatives of integric acid. Preparation, HIV-1 inhibitory activity, and the structure-activity relationship against coupled and strand transfer assays are described. It appears that most of the groups present in the natural product are required for inhibition of HIV-1 integrase strand transfer activity. In contrast, inhibition of 3' processing activity is less stringent suggesting distinct SAR for the two integrase reactions.
Singh
S B
SB
Natural Products Drug Discovery, Merck Research Laboratories, Rahway, NJ 07065, USA. sheo_singh@merck.com
Felock
P
P
Hazuda
D J
DJ
D000577:Amides / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry* / Q000494:pharmacology*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology*; D006868:Hydrolysis; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000577:Amides; D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D009281:Naphthalenes; C120097:integric acid