title: Anti-AIDS agents 65: investigation of the in vitro oxidative metabolism of 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone derivatives as potent anti-hiv agents.
abstract: 3',4'-Di-O-(-)-camphanoyl-(+)-cis-khellactone (DCK) is a synthetic khellactone ester that exhibits potent in vitro anti-human immunodeficiency virus (HIV) activity with a mechanism distinct from clinically used anti-HIV agents. Several series of mono- and di-substituted DCK derivatives (DCKs) have previously been synthesized, and their structure-activity relationships are well established. To optimize DCK as a drug lead and to guide further structural modifications, metabolic stabilities and metabolite structures were analyzed. In vitro metabolic stabilities of DCKs in human liver microsomes were assessed using high performance liquid chromatography (HPLC) with UV detection to establish structure-metabolism relationships (SMRs). HPLC coupled with ion trap mass spectrometry was used to identify the metabolite structures. The results indicated that DCKs undergo rapid oxidation on the lipophilic camphanoyl moieties and the substituents on the khellactone do not alter the rate or the metabolic pathways for this compound type. Our SMR and metabolite analysis study suggested that the two camphanoyl ester moieties are the determinants of the low metabolic stability and that structural alteration in the two esters may be necessary to improve metabolic profiles of DCKs.
authors.affiliation: Division of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7360, USA.
authors.forename: Madoka
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yutai
authors.initials: Y
authors.lastname: Li
authors.forename: Philip C
authors.initials: PC
authors.lastname: Smith
authors.forename: James A
authors.initials: JA
authors.lastname: Swenberg
authors.forename: David E
authors.initials: DE
authors.lastname: Martin
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 / Q000737:chemistry / Q000378:metabolism*; D002164:Camphor / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000378:metabolism*; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
chemical_list: C479985:3'R,4'R-di-O-(-)-camphanoyl-(+)-cis-khellactone; D019380:Anti-HIV Agents; D007783:Lactones; D002164:Camphor