Article

Synthesis and biological evaluation of imidazolylmethylacridones as cytochrome P-450 enzymes inhibitors

Medicinal Chemistry Communication (Impact Factor: 2.72). 04/2012;

ABSTRACT Two positional isomers with the general formula 1H-imidazol-1-ylmethylacridin-9(10H)-one were synthesized (5, 6) and evaluated for their inhibitory activity versus CYP11B1, CYP11B2, CYP17 and CYP19. Compound 5 was more effective than letrozole in inhibiting CYP19 (aromatase). Interestingly, compound 5 also inhibited CYP11B1 with an IC 50 of 21.2 nM. On the other hand compound 6 was almost completely inactive against all CYPs; this indicates that the positioning and spatial orientation of the imidazolylmethyl moiety is of paramount importance to activity. Sequence alignment of the four steroidogenic CYP enzymes and docking studies with 5, 6 and letrozole supported this finding and suggested Ser478 to be an essential residue for both inhibition and selectivity. These novel compounds may have benefits for the treatment of Cushing's syndrome, hypertension, congestive heart failure and myocardial fibrosis and breast cancer.

2 Bookmarks
 · 
116 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Imidazole ring is an important five-membered aromatic heterocycle widely present in natural products and synthetic molecules. The unique structural feature of imidazole ring with desirable electron-rich characteristic is beneficial for imidazole derivatives to readily bind with a variety of enzymes and receptors in biological systems through diverse weak interactions, thereby exhibiting broad bioactivities. The related research and developments of imidazole-based medicinal chemistry have become a rapidly developing and increasingly active topic. Particularly, numerous imidazole-based compounds as clinical drugs have been extensively used in the clinic to treat various types of diseases with high therapeutic potency, which have shown the enormous development value. This work systematically gives a comprehensive review in current developments of imidazole-based compounds in the whole range of medicinal chemistry as anticancer, antifungal, antibacterial, antitubercular, anti-inflammatory, antineuropathic, antihypertensive, antihistaminic, antiparasitic, antiobesity, antiviral, and other medicinal agents, together with their potential applications in diagnostics and pathology. It is hoped that this review will be helpful for new thoughts in the quest for rational designs of more active and less toxic imidazole-based medicinal drugs, as well as more effective diagnostic agents and pathologic probes.
    Medicinal Research Reviews 06/2013; · 9.58 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.
    International Journal of Molecular Sciences 01/2013; 14(7):13958-78. · 2.46 Impact Factor

Full-text

View
81 Downloads
Available from
May 22, 2014