tretinoin and imidazole

All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10-19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22 μM and 0.46 μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure-activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs.

Topics: Amides; Cell Differentiation; Cell Proliferation; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Design; HL-60 Cells; Humans; Imidazoles; Models, Molecular; Molecular Structure; Retinoic Acid 4-Hydroxylase; Structure-Activity Relationship

The role of all-trans-retinoic acid (ATRA) in the development and maintenance of many epithelial and neural tissues has raised great interest in the potential of ATRA and related compounds (retinoids) as pharmacological agents, particularly for the treatment of cancer, skin, neurodegenerative and autoimmune diseases. The use of ATRA or prodrugs as pharmacological agents is limited by a short half-life in vivo resulting from the activity of specific ATRA hydroxylases, CYP26 enzymes, induced by ATRA in liver and target tissues. For this reason retinoic acid metabolism blocking agents (RAMBAs) have been developed for treating cancer and a wide range of other diseases. The synthesis, CYP26A1 inhibitory activity and molecular modeling studies of novel methyl 3-[4-(arylamino)phenyl]-3-(azole)-2,2-dimethylpropanoates are presented. From this series of compounds clear SAR can be derived for 4-substitution of the phenyl ring with electron-donating groups more favourable for inhibitory activity. Both the methylenedioxyphenyl imidazole (17, IC(50) = 8 nM) and triazole (18, IC(50) = 6.7 nM) derivatives were potent inhibitors with additional binding interactions between the methylenedioxy moiety and the CYP26 active site likely to be the main factor. The 6-bromo-3-pyridine imidazole 15 (IC(50) = 5.7 nM) was the most active from this series compared with the standards liarozole (IC(50) = 540 nM) and R116010 (IC(50) = 10 nM).

Topics: Aminopyridines; Azoles; Binding Sites; Catalytic Domain; Cell Survival; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Humans; Imidazoles; MCF-7 Cells; Microsomes; Molecular Docking Simulation; Phenylpropionates; Propionates; Retinoic Acid 4-Hydroxylase; Structure-Activity Relationship; Tretinoin; Triazoles

The effect of retinoic acid on the induction of tyrosinase (EC 1:14.18.1) by imidazole was determined in cultured B16/C3 melanoma cells. Retinoic acid could block the induction of enzyme activity within 3 hours of addition to the culture medium at a physiological concentration (10nM). The blockade was similar to that of 3,3',5-L-triiodothyronine (T3) already reported. mRNA hybridizable to a tyrosinase DNA probe was induced by imidazole while retinoic acid and T3 blocked that increase. These observations suggest that retinoic acid can mimic the action of T3 in B16 melanoma cells in culture.

Topics: Animals; Catechol Oxidase; Cell Line; Enzyme Induction; Imidazoles; Melanoma; Mice; Monophenol Monooxygenase; RNA, Messenger; Tretinoin; Triiodothyronine; Tumor Cells, Cultured