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.
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.
Xu
Shi-Qing
SQ
Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
Yan
Xin
X
Chen
Ying
Y
Xia
Peng
P
Qian
Keduo
K
Yu
Donglei
D
Xia
Yi
Y
Yang
Zheng-Yu
ZY
Morris-Natschke
Susan L
SL
Lee
Kuo-Hsiung
KH
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
C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; D019380:Anti-HIV Agents; D007783:Lactones; D002164:Camphor