lithospermic-acid and HIV-Infections

The HIV-1 nucleocapsid protein (NC) is a desirable target in antiretroviral therapy due to its high conservation among HIV-1 strains, and to its multiple and crucial roles in the HIV-1 replication cycle. Natural products represent a valuable source of NC inhibitors, with the catechol group being a privileged scaffold in NC inhibition. By coupling molecular modeling with NMR spectroscopy and fluorescence-based assays, we disclosed lithospermic acid, a catechol derivative extracted from

Topics: Anti-HIV Agents; Benzofurans; Biological Products; Depsides; Dose-Response Relationship, Drug; Drug Stability; HIV Infections; HIV-1; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Nucleocapsid Proteins; Protein Binding; Structure-Activity Relationship

Two "privileged fragments", caffeic acid and piperazine, were integrated into bevirimat producing new derivatives with improved activity against HIV-1/NL4-3 and NL4-3/V370A carrying the most prevalent bevirimat-resistant polymorphism. The activity of one of these, 18c, was increased by 3-fold against NL4-3 and 51-fold against NL4-3/V370A. Moreover, 18c is a maturation inhibitor with improved metabolic stability. Our study suggested that integration of privileged motifs into promising natural product skeletons is an effective strategy for discovering potent derivatives.

Topics: Animals; Anti-HIV Agents; Caffeic Acids; Cell Line; Chlorocebus aethiops; COS Cells; Drug Resistance, Viral; HIV Infections; HIV-1; Humans; Piperazine; Piperazines; Succinates; Triterpenes; Virus Replication

An efficient and convergent route for the synthesis of the natural product (+)-lithospermic acid, which possesses anti-HIV activity, was accomplished. The (±)-trans-dihydrobenzo[b]furan core therein was prepared by two different strategies. The first strategy involved the use of a palladium-catalyzed annulation to generate an appropriately substituted benzo[b]furan ester followed by a stereoselective reduction of a carbon-carbon double bond with Mg-HgCl(2)-MeOH. The second strategy relied on an aldol condensation between a suitably substituted methyl arylacetate and 3,4-dimethoxybenzaldehyde, followed by cyclization. Finally, a total synthesis of (+)-lithospermic acid was completed via coupling of a trans-dihydrobenzo[b]furan cinnamic acid with an enantiomerically pure methyl lactate.

Topics: Anti-HIV Agents; Benzaldehydes; Benzofurans; Biological Products; Catalysis; Cyclization; Depsides; HIV Infections; Humans; Palladium; Stereoisomerism