Novel lavendamycin analogues as antitumor agents: Synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1

Mary Hassani, Wen Cai, David C. Holley, Jayana P. Lineswala, Babu R. Maharjan, G. Reza Ebrahimian, Hassan Seradj, Mark G. Stocksdale, Farahnaz Mohammadi, Christopher C. Marvin, John M. Gerdes, Howard D. Beall, Mohammad Behforouz

Research output: Contribution to journalArticlepeer-review

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′-CH 2OH-7-NH2 derivative) and 31 (2′-CONH 2-7-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 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.

Original languageEnglish
Pages (from-to)7733-7749
Number of pages17
JournalJournal of Medicinal Chemistry
Volume48
Issue number24
DOIs
StatePublished - Dec 1 2005

Fingerprint

Dive into the research topics of 'Novel lavendamycin analogues as antitumor agents: Synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1'. Together they form a unique fingerprint.

Cite this