Anti-AIDS agents. 37. Synthesis and structure-activity relationships of (3'R,4'R)-(+)-cis-khellactone derivatives as novel potent anti-HIV agents.
To explore the structural requirements of (+)-cis-khellactone derivatives as novel anti-HIV agents, 24 monosubstituted 3', 4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) derivatives were synthesized asymmetrically. These compounds included 4 isomeric monomethoxy analogues (3-6), 4 isomeric monomethyl analogues (7-10), 4 4-alkyl/aryl-substituted analogues (11-14), and 12 4-methyl-(+)-cis-khellactone derivatives (15-26) with varying 3', 4'-substituents. These (+)-cis-khellactone derivatives were screened against HIV-1 replication in acutely infected H9 lymphocytes. The results demonstrated that the (3'R,4'R)-(+)-cis-khellactone skeleton, two (S)-(-)-camphanoyl groups at the 3'- and 4'-positions, and a methyl group on the coumarin ring, except at the 6-position, were optimal structural moieties for anti-HIV activity. 3-Methyl- (7), 4-methyl- (8), and 5-methyl- (9) 3',4'-di-O-(S)-camphanoyl-(3'R, 4'R)-(+)-cis-khellactone showed EC(50) and therapeutic index values of <5.25 x 10(-5) microM and >2.15 x 10(6), respectively, in H9 lymphocytes, which are much better than those of DCK and AZT in the same assay. Furthermore, 8 and 9 also showed potent inhibitory activity against HIV-1 replication in the CEM-SS cell line, and most monosubstituted DCK analogues were less toxic than DCK in both assays.
Xie
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Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Takeuchi
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Cosentino
L M
LM
Lee
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KH
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000821:virology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
C120314:3',4'-di-O-camphanoyl-4-methylkhellactone; C120315:3',4'-di-O-camphanoyl-5-methylkhellactone; D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003374:Coumarins