title: Lavendamycin antitumor agents: structure-based design, synthesis, and NAD(P)H:quinone oxidoreductase 1 (NQO1) model validation with molecular docking and biological studies.
abstract: A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogues were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metabolism and cytotoxicity studies were performed on the analogues with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biological data were found to be correlated where analogues 12, 13, 14, 15, and 16 were categorized as good, poor, poor, poor, and good NQO1 substrates, respectively. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The observed consistency between the docking and biological data suggests that the model possesses practical predictive power.
authors.affiliation: Center for Environmental Health Sciences, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Hassani
authors.forename: Wen
authors.initials: W
authors.lastname: Cai
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Koelsch
authors.forename: David C
authors.initials: DC
authors.lastname: Holley
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Rose
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Olang
authors.forename: Jayana P
authors.initials: JP
authors.lastname: Lineswala
authors.forename: William G
authors.initials: WG
authors.lastname: Holloway
authors.forename: John M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Mohammad
authors.initials: M
authors.lastname: Behforouz
authors.forename: Howard D
authors.initials: HD
authors.lastname: Beall
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry*; D011485:Protein Binding; D013308:Streptonigrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D013308:Streptonigrin; C034566:lavendamycin; D045304:Cytochromes c; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human