title: Synthetic methods for the preparation of ARQ 501 (beta-Lapachone) human blood metabolites.
abstract: ARQ 501 (3,4-dihydro-2,2-dimethyl-2H-naphthol[1,2-b] pyran-5,6-dione), a synthetic version of beta-Lapachone, is a promising anti-cancer agent currently in multiple Phase II clinical trials. Promising anti-cancer activity was observed in Phase I and Phase II trials. Metabolism by red blood cells of drugs is an understudied area of research and the metabolites arising from oxidative ring opening (M2 and M3), decarbonylation/ring contraction (M5), and decarbonylation/oxidation (M4 and M6) of ARQ 501 offer a unique opportunity to provide insight into these metabolic processes. Since these metabolites were not detected in in vitro incubations of ARQ 501 with liver microsomes and were structurally diverse, confirmation by chemical synthesis was considered essential. In this report, we disclose the synthetic routes employed and the characterization of the reference standards for these blood metabolites as well as additional postulated structures, which were not confirmed as metabolites.
authors.affiliation: ArQule Inc., 19 Presidential Way, Woburn, MA 01801, USA.
authors.forename: Rui-Yang
authors.initials: RY
authors.lastname: Yang
authors.forename: Darin
authors.initials: D
authors.lastname: Kizer
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.forename: Erika
authors.initials: E
authors.lastname: Volckova
authors.forename: Xiu-Sheng
authors.initials: XS
authors.lastname: Miao
authors.forename: Syed M
authors.initials: SM
authors.lastname: Ali
authors.forename: Manish
authors.initials: M
authors.lastname: Tandon
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Savage
authors.forename: Thomas C K
authors.initials: TC
authors.lastname: Chan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ashwell
mesh_terms: D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: D009285:Naphthoquinones; C014638:beta-lapachone