title: Identification, synthesis, and biological evaluation of metabolites of the experimental cancer treatment drugs indotecan (LMP400) and indimitecan (LMP776) and investigation of isomerically hydroxylated indenoisoquinoline analogues as topoisomerase I poisons.
abstract: Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Maris A
authors.initials: MA
authors.lastname: Cinelli
authors.forename: P V Narasimha
authors.initials: PV
authors.lastname: Reddy
authors.forename: Peng-Cheng
authors.initials: PC
authors.lastname: Lv
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liang
authors.forename: Lian
authors.initials: L
authors.lastname: Chen
authors.forename: Keli
authors.initials: K
authors.lastname: Agama
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D052117:Benzodioxoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007192:Indenes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007546:Isoquinolines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D052117:Benzodioxoles; D007192:Indenes; D007546:Isoquinolines; C553898:NSC 724998; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I; C578795:indimitecan