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.
Natural Products Laboratory, Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
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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