title: Anti-AIDS agents. 60. Substituted 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP) analogues as potent anti-HIV agents.
abstract: Synthesis of positional isomers is a commonly used technique in drug design. Accordingly, based on prior SAR studies of 3'R,4'R-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK, 1) analogues, a series of mono- and disubstituted chromone derivatives of 3'R,4'R-di-O-(-)-camphanoyl-2',2'-dimethyldihydropyrano[2,3-f]chromone (DCP, 4) were designed and synthesized. Together with 1 and 4-methyl DCK (2), all newly synthesized DCP analogues (4-21) were screened for anti-HIV-1 activity against a non-drug-resistant strain in H9 lymphocytes and a multiple reverse transcriptase (RT) inhibitor-resistant strain in the MT4 cell line. Several DCP analogues (4, 5, 7, 8, 13, and 17) exhibited extremely high anti-HIV activity in the non-drug-resistant strain assay, with EC(50) values ranging from 0.00032 to 0.0057 microM and remarkable therapeutic indexes (TI) ranging from 5.6 x 10(3) to 1.16 x 10(5), which were similar to those of 2 (EC(50) 0.0059 microM, TI > 6.6 x 10(3)) and better than those of 1 (EC(50) 0.049 microM, TI > 328). Even more promisingly, some DCP analogues also showed activity against a multi-RT inhibitor-resistant strain, HIV-1 RTMDR1, whereas most DCK analogues did not. The most significant compound was 8, with an EC(50) value of 0.06 microM and TI of 718 against the multi-RT inhibitor-resistant HIV-1 strain. Compounds 9 and 10 also showed good activity with an EC(50) value of 0.14 microM, and TIs of 272 and >111, respectively. 2-Ethyl DCP (8) exhibited the best anti-HIV activity in both assays. Further development of 8-related compounds as clinical trial candidates is warranted.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Chin-Ho
authors.initials: CH
authors.lastname: Chen
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
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; D002478:Cells, Cultured; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024921:Drug Resistance, Multiple, Viral; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C488671:3',4'-di-O-camphanoyl-2',2'-dimethyl-2-ethyldihydropyrano(2,3-f)chromone; D019380:Anti-HIV Agents; D002867:Chromones; D018894:Reverse Transcriptase Inhibitors; D002164:Camphor