title: Anti-AIDS agents 86. Synthesis and anti-HIV evaluation of 2',3'-seco-3'-nor DCP and DCK analogues.
abstract: In a continuing study of novel anti-HIV agents with drug-like structures and properties, 30 1'-O-, 1'-S-, 4'-O- and 4'-substituted-2',3'-seco-3'-nor DCP and DCK analogues (8-37) were designed and synthesized. All newly synthesized seco-compounds were screened against HIV-1(NL4-3) and a multiple reverse transcriptase (RT) inhibitor-resistant (RTMDR) strain in the TZM-bl cell line, using seco-DCK (7) and 2-ethyl-DCP (4) as controls. Several compounds (14, 18, 19, 22-24, and 32) exhibited potent anti-HIV activity with EC(50) values ranging from 0.93 to 1.93 μM and therapeutic index (TI) values ranging from 20 to 39. 1'-O-Isopropoxy-2',3'-seco-3'-nor-DCP (12) showed the greatest potency among the newly synthesized compounds with EC(50) values of 0.47 and 0.88 μM, and TI of 96 and 51, respectively, against HIV-1(NL4-3) and RTMDR strains. The seco-compounds exhibited better chemical stability in acidic conditions compared with DCP and DCK compounds. Overall, the results suggested that seco-DCP analogues with simplified structures may be more favorable for development as novel anti-HIV candidates.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Ming
authors.initials: M
authors.lastname: Cheng
authors.forename: Fa-Qiang
authors.initials: FQ
authors.lastname: Liu
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: Chin-Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002164:Camphor / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; C479984:3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano(2,3-f)chromone; D019380:Anti-HIV Agents; D002867:Chromones; D007783:Lactones; D002164:Camphor