title: Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1.
abstract: Novel lavendamycin analogues with various substituents were synthesized and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1)-directed antitumor agents. Pictet-Spengler condensation of quinoline- or quninoline-5,8-dione aldehydes with tryptamine or tryptophans yielded the lavendamycins. Metabolism studies with recombinant human NQO1 revealed that addition of NH2 and CH2OH groups at the quinolinedione-7-position and indolopyridine-2'-position had the greatest positive impact on substrate specificity. The best and poorest substrates were 37 (2'-CH2OH-7-NH2 derivative) and 31 (2'-CONH2-7-NHCOC3H7-n derivative) with reduction rates of 263 +/- 30 and 0.1 +/- 0.1 micromol/min/mg NQO1, respectively. Cytotoxicity toward human colon adenocarcinoma cells was determined for the lavendamycins. The best substrates for NQO1 were also the most selectively toxic to the NQO1-rich BE-NQ cells compared to NQO1-deficient BE-WT cells with 37 as the most selective. Molecular docking supported a model in which the best substrates were capable of efficient hydrogen-bonding interactions with key residues of the active site along with hydride ion reception.
authors.affiliation: Department of Chemistry, Ball State University, Muncie, Indiana 47306, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Hassani
authors.forename: Wen
authors.initials: W
authors.lastname: Cai
authors.forename: David C
authors.initials: DC
authors.lastname: Holley
authors.forename: Jayana P
authors.initials: JP
authors.lastname: Lineswala
authors.forename: Babu R
authors.initials: BR
authors.lastname: Maharjan
authors.forename: G Reza
authors.initials: GR
authors.lastname: Ebrahimian
authors.forename: Hassan
authors.initials: H
authors.lastname: Seradj
authors.forename: Mark G
authors.initials: MG
authors.lastname: Stocksdale
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Mohammadi
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Marvin
authors.forename: John M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Howard D
authors.initials: HD
authors.lastname: Beall
authors.forename: Mohammad
authors.initials: M
authors.lastname: Behforouz
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry* / Q000378:metabolism*; D010084:Oxidation-Reduction; D013308:Streptonigrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C507720:decarboxy-2'-(hydroxymethyl)-demethyllavendamycin; D013308:Streptonigrin; C034566:lavendamycin; D016660:NAD(P)H Dehydrogenase (Quinone)