title: Anti-AIDS agents 84. Synthesis and anti-human immunodeficiency virus (HIV) activity of 2'-monomethyl-4-methyl- and 1'-thia-4-methyl-(3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogs.
abstract: In a continuing investigation into the pharmacophores and structure-activity relationship (SAR) of (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) as a potent anti-HIV agent, 2'-monomethyl substituted 1'-oxa, 1'-thia, 1'-sulfoxide, and 1'-sulfone analogs were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. Among them, 2'S-monomethyl-4-methyl DCK (5a)(‡) and 2'S-monomethyl-1'-thia-4-methyl DCK (7a) exhibited potent anti-HIV activity with EC(50) values of 40.2 and 39.1 nM and remarkable therapeutic indexes of 705 and 1000, respectively, which were better than those of the lead compound DCK in the same assay. In contrast, the corresponding isomeric 2'R-monomethyl-4-methyl DCK (6) and 2'R-monomethyl-1'-thia-4-methyl DCK (8) showed much weaker inhibitory activity against HIV-1 replication. Therefore, the bioassay results suggest that the spatial orientation of the 2'-methyl group in DCK analogs can have important effects on anti-HIV activity of this compound class.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Shi-Qing
authors.initials: SQ
authors.lastname: Xu
authors.forename: Xin
authors.initials: X
authors.lastname: Yan
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Yang
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D002164:Camphor / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D018360:Crystallography, X-Ray; D004261:DNA Replication / Q000187:drug effects; D015195:Drug Design; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
chemical_list: C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; D019380:Anti-HIV Agents; D007783:Lactones; D002164:Camphor