Novel lavendamycin analogues as antitumor agents: synthesis, in vitro cytotoxicity, structure-metabolism, and computational molecular modeling studies with NAD(P)H:quinone oxidoreductase 1.
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 micromol/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.
Hassani
Mary
M
Department of Chemistry, Ball State University, Muncie, Indiana 47306, USA.
Cai
Wen
W
Holley
David C
DC
Lineswala
Jayana P
JP
Maharjan
Babu R
BR
Ebrahimian
G Reza
GR
Seradj
Hassan
H
Stocksdale
Mark G
MG
Mohammadi
Farahnaz
F
Marvin
Christopher C
CC
Gerdes
John M
JM
Beall
Howard D
HD
Behforouz
Mohammad
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry* / Q000378:metabolism*; D010084:Oxidation-Reduction; D013308:Streptonigrin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; C507720:decarboxy-2'-(hydroxymethyl)-demethyllavendamycin; D013308:Streptonigrin; C034566:lavendamycin; D016660:NAD(P)H Dehydrogenase (Quinone)