title: Anti-AIDS agents. 52. Synthesis and anti-HIV activity of hydroxymethyl (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone derivatives.
abstract: To enhance the water solubility and oral bioavailability of DCK analogues, 12 new mono- and disubstituted (3'R,4'R)-3',4'-di-O-(S)-camphanoyl-(+)-cis-khellactone (DCK) analogues were synthesized and evaluated for inhibition of HIV-1 replication in H9 lymphocytes. 3-Hydroxymethyl-4-methyl-DCK (4c) exhibited significant anti-HIV activity in H9 lymphocytes and primary peripheral blood mononuclear cells with EC(50) values of 0.004 and 0.024 microM, respectively. Although this compound was not as potent as 4-methyl-DCK (2) and 3-bromomethyl-4-methyl-DCK (4a), it provides increased water solubility and possible linkage to other moieties. Of particular note, 4c exhibits moderate oral bioavailability (15%) when administered as a carboxymethylcellulose suspension to rats, whereas 2 is not orally bioavailable in the same formulation. Further studies on mechanism of action suggest that 4c inhibits the production of double-stranded viral DNA from the single-stranded DNA intermediate. In addition, 4a is the most potent compound in this series of new analogues, with EC(50) and TI values of 0.00011 microM and 189,600, respectively. Thus, further modification at the 3-position of the coumarin ring can improve the potency of new DCK analogues.
authors.affiliation: Natural Products Laboratory, School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
authors.forename: Donglei
authors.initials: D
authors.lastname: Yu
authors.forename: Carl
authors.initials: C
authors.lastname: Wild
authors.forename: Graham
authors.initials: G
authors.lastname: Allaway
authors.forename: Jim
authors.initials: J
authors.lastname: Turpin
authors.forename: Philip C
authors.initials: PC
authors.lastname: Smith
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D002164:Camphor / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014779:Virus Replication
chemical_list: C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; D019380:Anti-HIV Agents; D007783:Lactones; D002164:Camphor