valtrate and HIV-Infections

Rational design by the MO calculation disclosed 5,6-dihydrovaltrate (2) as the bioisostere of valtrate (1), the Rev-export inhibitor with anti-HIV activity. The synthesis of 2 was accomplished by ingenious use of asymmetric Diels-Alder reaction and stereoselective epoxidation associated with the adjacent hydroxyl group. Because of similar biological potency to 1, the analog 2 should be recognized as a promising scaffold for new anti-HIV agents with an unprecedented mechanism of action, inhibition for nuclear export of Rev protein, in the conventional remedy.

Topics: Active Transport, Cell Nucleus; Anti-HIV Agents; Gene Products, rev; HeLa Cells; HIV Infections; Humans; Iridoids; Molecular Conformation

The concise synthesis of 5,6-dihydrovaltrate (2), the bioisostere of valtrate (1) showing anti-HIV activity by inhibition for nuclear export of Rev, has been achieved from the commercially available iridoid genipin (3). Analysis of steric influence of the substituents linked to the three hydroxyl groups was conducted by the synthesized three analogs (2a-2c). Consequently, attenuation of steric hindrance around the epoxy portion was revealed to enhance inhibitory potency for Rev-export. In addition to this finding, 1-acetoxy analog 2b was disclosed as the promising Rev-export inhibitor superior to 1.

Topics: Anti-HIV Agents; Cell Nucleus; HeLa Cells; HIV Infections; HIV-1; Humans; Iridoid Glycosides; Iridoids; Protein Transport; rev Gene Products, Human Immunodeficiency Virus