Anti-AIDS agents. 15. Synthesis and anti-HIV activity of dihydroseselins and related analogs.
Forty-two dihydroseselins based on the structure of suksdorfin (1) were synthesized in order to evaluate their anti-HIV activity. These synthetic derivatives include 3',4'-di-O-acyl- and 3'- or 4'-O-acyl-cis-dihydroseselins (8-21) and 3',4'-trans-dihydroseselins with O-acyl and/or 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 prepared. By using optically pure reagents, three pairs of diastereoisomers were synthesized and separated as optically pure compounds (14, 15; 16, 17; 38, 39). Together with the above synthetic derivatives, seselin (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-khellactone (16), showed potent inhibitory activity and remarkable selectivity against HIV replication. The EC50 value and in vitro therapeutic index (TI) of 16 are 4 x 10(-4) microM and 136,719, respectively, which are better than those shown by AZT in the same assay. In addition, compound 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 HIV-1 reverse transcriptase. Moreover, the anti-HIV activity of 16 is stereoselective as its three diastereoisomers (17, 38, 39) are at least 10,000 times less active. Since other synthetic dihydroseselin derivatives with different substituents or without any substituents are inactive or are active only at much higher concentration, the antiviral potency of 16 could be associated with the camphanoyl moieties of its structure. Therefore, compound 16 represents a unique coumarin structure with promising anti-HIV activity.
Huang
L
L
Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill 27599.
Kashiwada
Y
Y
Cosentino
L M
LM
Fan
S
S
Chen
C H
CH
McPhail
A T
AT
Fujioka
T
T
Mihashi
K
K
Lee
K H
KH
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003374:Coumarins; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase