| Autor: |
Hassani, M., Cai, W., Holley, D. C., Lineswala, J. P., Maharjan, B. R., Ebrahimian, G. R., Seradj, H., Stocksdale, M. G., Mohammadi, F., Marvin, C. C., Gerdes, J. M., Beall, H. D., Behforouz, M. |
| Zdroj: |
Journal of Medicinal Chemistry; December 2005, Vol. 48 Issue: 24 p7733-7749, 17p |
| Abstrakt: |
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 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. |
| Databáze: |
Supplemental Index |
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