ANTI-AIDS AGENTS .15. SYNTHESIS AND ANTI-HIV ACTIVITY OF DIHYDROSESELINS AND RELATED ANALOGS

Forty-two dihydroseselins based on the structure of suksdorfin (1) wer e synthesized in order to evaluate their anti-HIV activity. These synt hetic derivatives include 3',4'-di-O-acyl- and 3'- or 4'-O-acyl-cis-di hydroseselins (8-21) and 3',4'-trans-dihydroseselins with O-acyl and/o r O-alkyl groups at the 3' and 4' positions (6, 22-43). Two 4'-azido ( 44, 45) and three 4'-alkylamido (46, 48, 49) derivatives were also pre pared. By using optically pure reagents, three pairs of diastereoisome rs were synthesized and separated as optically pure compounds (14, 15; 16, 17; 38, 39). Together with the above synthetic derivatives, sesel in (3) and (+/-)-cis(4), (+)-cis- (5), and (+/-)-trans-dihydroseselin- 3',4'-diol (7) were also tested for their in vitro anti-HIV activity. An optically pure compound, 3',4'-di-O-(-)-camphanoyl-(+)-cis-khellact one (16), showed potent inhibitory activity and remarkable selectivity against HIV replication. The EC(50) value and in vitro therapeutic in dex (TI) of 16 are 4 x 10(-4) mu M and 136 719, respectively, which ar e better than those shown by AZT in the same assay. In addition, compo und 16 is also active against HIV replication in a monocytic cell line and in peripheral blood mononuclear cells (PBMCs). Our in vitro assay indicated that, like compound 1, compound 16 is not an inhibitor of H IV-1 reverse transcriptase. Moreover, the anti-HIV activity of 16 is s tereoselective as its three diastereoisomers (17, 38, 39) are at least 10 000 times less active. Since other synthetic dihydroseselin deriva tives with different substituents or without any substituents are inac tive or are active only at much higher concentrations, the antiviral p otency of 16 could be associated with the camphanoyl moieties of its s tructure. Therefore, compound 16 represents a unique coumarin structur e with promising anti-HIV activity.