Small-molecule inhibitors of 25-hydroxyvitamin D-24-hydroxylase (CYP24A1): synthesis and biological evaluation.

The synthesis of imidazole styrylbenzamide, tert-butyl styrylimidazole, and tert-butyl styrylsulfonate derivatives is described. Evaluation of binding affinity and inhibitory activity against CYP24A1 identified the imidazole styrylbenzamides as potent inhibitors of CYP24A1, having selectivity with respect to CYP27B1 comparable with or greater than that of the standard ketoconazole. Further evaluation of the 3,5-dimethoxy and 3,4,5-trimethoxy derivatives in chronic lymphocytic leukemia cells revealed that co-treatment of 1α,25-dihydroxyvitamin D3 plus inhibitor coordinately upregulated GADD45α and CDKN1A. Docking experiments on the inhibitors in the CYP24A1 enzyme active site suggest the compounds reach the active site through the vitamin D access tunnel and are exposed to multiple hydrophobic residues. The imidazole styrylbenzamides are optimally positioned to allow interaction of the imidazole with the heme, and, in the case of the methoxy derivatives, a hydrogen bond between the 3-methoxy group and Gln82 stabilizes the molecule in a favorable active conformation.

[1]  M. Cantorna.  Vitamin D, multiple sclerosis and inflammatory bowel disease. , 2012, Archives of biochemistry and biophysics.

[2]  Glenville Jones,et al.  25-Hydroxyvitamin D-24-hydroxylase (CYP24A1): its important role in the degradation of vitamin D. , 2012, Archives of biochemistry and biophysics.

[3]  A. Ascherio,et al.  Vitamin D and multiple sclerosis: epidemiology, immunology, and genetics. , 2012, Current opinion in neurology.

[4]  P. Kimmel,et al.  The immunoregulatory function of vitamin D: implications in chronic kidney disease , 2012, Nature Reviews Nephrology.

[5]  A. Bianucci,et al.  Synthesis and biological activities of vitamin D-like inhibitors of CYP24 hydroxylase , 2012, Steroids.

[6]  D. Feldman,et al.  Vitamin D metabolism and action in the prostate: Implications for health and disease , 2011, Molecular and Cellular Endocrinology.

[7]  Dean E Brenner,et al.  CYP24A1 Is an Independent Prognostic Marker of Survival in Patients with Lung Adenocarcinoma , 2010, Clinical Cancer Research.

[8]  H. DeLuca,et al.  Screening of selective inhibitors of 1α,25-dihydroxyvitamin D3 24-hydroxylase using recombinant human enzyme expressed in Escherichia coli. , 2010, Biochemistry.

[9]  Chris Oostenbrink,et al.  Computational Prediction of Binding Affinity for CYP1A2-Ligand Complexes Using Empirical Free Energy Calculations , 2010, Drug Metabolism and Disposition.

[10]  S. Yee,et al.  Synthesis and CYP24A1 inhibitory activity of N-(2-(1H-imidazol-1-yl)-2-phenylethyl)arylamides. , 2010, Bioorganic & medicinal chemistry.

[11]  C. Helvig,et al.  Vitamin D analogues targeting CYP24 in chronic kidney disease , 2010, The Journal of Steroid Biochemistry and Molecular Biology.

[12]  Eric F. Johnson,et al.  Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. , 2010, Journal of molecular biology.

[13]  M. Yasuda,et al.  Indium-Catalyzed Coupling Reaction Between Silyl Enolates and Alkyl Chlorides or Alkyl Ethers. , 2009 .

[14]  S. Hameed,et al.  (E)-4-(4-Fluorostyryl)benzoic acid , 2008, Acta crystallographica. Section E, Structure reports online.

[15]  M. Mizutani,et al.  Structure-activity relationship of uniconazole, a potent inhibitor of ABA 8'-hydroxylase, with a focus on hydrophilic functional groups and conformation. , 2008, Bioorganic & medicinal chemistry.

[16]  Carsten Kutzner,et al.  GROMACS 4:  Algorithms for Highly Efficient, Load-Balanced, and Scalable Molecular Simulation. , 2008, Journal of chemical theory and computation.

[17]  Andrea Brancale,et al.  Homology model of 1α,25-dihydroxyvitamin D3 24-hydroxylase cytochrome P450 24A1 (CYP24A1): Active site architecture and ligand binding , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[18]  Hamed I. Ali,et al.  Analgesic agents without gastric damage: design and synthesis of structurally simple benzenesulfonanilide-type cyclooxygenase-1-selective inhibitors. , 2007, Bioorganic & medicinal chemistry.

[19]  S. Yee,et al.  Inhibition of Vitamin D3 metabolism enhances VDR signalling in androgen-independent prostate cancer cells , 2006, The Journal of Steroid Biochemistry and Molecular Biology.

[20]  E. Kallay,et al.  The Vitamin D endocrine system of the gut—Its possible role in colorectal cancer prevention , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  S. Nagpal,et al.  Noncalcemic actions of vitamin D receptor ligands. , 2005, Endocrine reviews.

[22]  AKIFUMI ODA,et al.  New AMBER force field parameters of heme iron for cytochrome P450s determined by quantum chemical calculations of simplified models , 2005, J. Comput. Chem..

[23]  H. DeLuca.  Overview of general physiologic features and functions of vitamin D. , 2004, The American journal of clinical nutrition.

[24]  T. Kensler,et al.  Potent, Selective and Low-Calcemic Inhibitors of CYP24 Hydroxylase: 24-Sulfoximine Analogues of the Hormone 1α,25-Dihydroxyvitamin D3 , 2004 .

[25]  D. Guillon,et al.  Liquid-crystalline octopus dendrimers: block molecules with unusual mesophase morphologies. , 2004, Journal of the American Chemical Society.

[26]  P. Nussbaumer,et al.  Inhibitors of vitamin D hydroxylases: Structure–activity relationships , 2003, Journal of cellular biochemistry.

[27]  John H. White,et al.  Regulation of Gene Expression by 1α,25-Dihydroxyvitamin D3 and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells , 2001 .

[28]  I. Schuster,et al.  Selective inhibitors of CYP24: mechanistic tools to explore vitamin D metabolism in human keratinocytes , 2001, Steroids.

[29]  E. Durantini.  Synthesis of meso-nitrophenylporphyrins covalently linked to a polyphenylene chain bearing methoxy groups , 2000 .

[30]  G. Han,et al.  Conceptually new sulfone analogues of the hormone 1alpha, 25-dihydroxyvitamin D(3): synthesis and preliminary biological evaluation. , 1999, Journal of medicinal chemistry.

[31]  A. Meyers,et al.  The chemistry of 2-oxazolines (1985–present) , 1994 .

[32]  T. Yeates,et al.  Verification of protein structures: Patterns of nonbonded atomic interactions , 1993, Protein science : a publication of the Protein Society.

[33]  J. Ylikoski,et al.  A New Simple and Mild Synthesis of 2-Substituted 2-Oxazolines , 1988 .

[34]  H. L. Wehrmeister.  Reactions of Aromatic Thiols with Oxazolines , 1963 .

[35]  T. Kensler,et al.  Potent, selective and low-calcemic inhibitors of CYP24 hydroxylase: 24-sulfoximine analogues of the hormone 1alpha,25-dihydroxyvitamin D(3). , 2004, Journal of medicinal chemistry.

[36]  S. Miettinen,et al.  Antiproliferative action of vitamin D. , 2002, Vitamins and hormones.

[37]  T. Sano,et al.  Luminescent supramolecular assemblies based on hydrogen-bonded complexes of stilbenecarboxylic acids and dithieno[3,2-b:2′,3′-d]thiophene-2-carboxylic acids with a tris(imidazoline) base , 2001 .

[38]  D. Feldman,et al.  Liarozole acts synergistically with 1alpha,25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity. , 1999, Endocrinology.

[39]  Johan Åqvist,et al.  Ligand binding affinity prediction by linear interaction energy methods , 1998, J. Comput. Aided Mol. Des..

[40]  D. Eisenberg,et al.  A method to identify protein sequences that fold into a known three-dimensional structure. , 1991, Science.

[41]  D. D. Perrin,et al.  Purification of Laboratory Chemicals , 2022 .