Back to Search
Start Over
Design and Synthesis of New α-Naphthoflavones as Cytochrome P450 (CYP) 1B1 Inhibitors To Overcome Docetaxel-Resistance Associated with CYP1B1 Overexpression.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Apr 23; Vol. 58 (8), pp. 3534-47. Date of Electronic Publication: 2015 Apr 01. - Publication Year :
- 2015
-
Abstract
- CYP1B1 is recognized as a new target in cancer prevention and therapy. Taking α-naphthoflavone as a lead, a series of 6,7,10-trimethoxy-α-naphthoflavones (4a-o) were synthesized and evaluated for their inhibitory potency against CYP1B1 and selectivity over CYP1A1 and 1A2. SAR analysis indicated that introducing methoxy groups at C(6), C(7), and C(10) on the naphthalene part and a fluoro atom at C(3') on the B-ring, could sharply increase the efficiency toward CYP1B1 inhibition. Among the prepared derivatives, compound 4c is the most potent and selective CYP1B1 inhibitor ever reported. More effort was taken to acquire water-soluble α-naphthoflavone derivatives for further cell-based study of overcoming anticancer drug-resistance. Finally, we obtained water-soluble naphthoflavone (11f) which could obviously eliminate the docetaxel-resistance caused by the enhanced expression of CYP1B1 in MCF-7/1B1 cells. It could be envisaged that the discovery of new α-naphthoflavones as CYP1B1 inhibitors is clinically important for overcoming CYP1B1-mediated drug-resistance in cancer therapeutics.
- Subjects :
- Cell Line, Tumor
Cytochrome P-450 CYP1B1 metabolism
Docetaxel
Humans
Molecular Docking Simulation
Neoplasms drug therapy
Neoplasms metabolism
Antineoplastic Agents pharmacology
Benzoflavones chemistry
Benzoflavones pharmacology
Cytochrome P-450 CYP1B1 antagonists & inhibitors
Drug Resistance, Neoplasm drug effects
Taxoids pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25799264
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b00265