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Novel Inhibitors of NRH:Quinone Oxidoreductase 2 (NQO2): Crystal Structures, Biochemical Activity, and Intracellular Effects of Imidazoacridin-6-ones.
- Source :
-
Journal of Medicinal Chemistry . Oct2011, Vol. 54 Issue 19, p6597-6611. 15p. - Publication Year :
- 2011
-
Abstract
- Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of NQO2 containing two of the imidazoacridin-6-ones have been solved. To generate compounds with reduced off-target (DNA binding) effects, an N-oxide moiety was introduced into the tertiary aminoalkyl side chain of the imidazoacridin-6-ones. This resulted in substantially less toxicity in a panel of eight cancer cell lines, decreased protein binding, and reduced DNA binding and nuclear accumulation. Finally, one of the N-oxides showed potent ability to inhibit the enzymatic function of NQO2 in cells, and therefore, it may be useful as a pharmacological probe to study the properties of the enzyme in vitro and in vivo. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00222623
- Volume :
- 54
- Issue :
- 19
- Database :
- Academic Search Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 66418099
- Full Text :
- https://doi.org/10.1021/jm200416e