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.
Footnotes
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This investigation was supported primarily by Grant AI-33066 from the National Institute of Allergy and Infectious Diseases, awarded to K.-H.L. The mass spectrometric work was also supported in part by the Center for Environmental Health and Susceptibility Pilot Project Program, University of North Carolina at Chapel Hill University Research Council Grant P30-CA16086 from the National Institutes of Health.
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Current address (Y.L.): Merck Research Laboratories, Department of Safety Assessment, West Point, Pennsylvania.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.004218.
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ABBREVIATIONS: DCK, 3′,4′-di-O-(–)-camphanoyl-(+)-cis-khellactone; DCKs, DCK derivatives; HPLC, high performance liquid chromatography; SMR, structure-metabolism relationship; ITMS, ion trap mass spectrometry; HIV, human immunodeficiency virus; CLint, intrinsic clearance; t1/2, half-life; MS/MS, tandem mass spectrometry; MSn, multiple stage mass spectrometry where n refers to the generation number of fragment ions being analyzed; Cl-Me-DCK, 3-chloro-4-methyl DCK; P450, cytochrome P450.
- Received February 14, 2005.
- Accepted August 8, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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