Novel Lavendamycin Analogues as Antitumor Agents:Synthesis,in Vitro Cytotoxicity,Structure-Metabolism,and Computational Molecular Modeling Studies with NAD(P)H:Quinone Oxidoreductase 1

摘要

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 NH_2 and CH_2OH 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'-CH_2OH-7-NH_2 derivative) and 31 (2'-CONH_2-7-NHCOC_3H_7-n derivative) with reduction rates of 263+-30 and 0.1+-0.1 mumol/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.