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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 μmol/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 …