Correction to Screening of Selective Inhibitors of 1α,25-Dihydroxyvitamin D<sub>3</sub> 24-Hydroxylase Using Recombinant Human Enzyme Expressed in <i>Escherichia coli</i>

Zhu, Jiang; Barycki, Rafał; Chiellini, Grazia; DeLuca, Hector F.

doi:10.1021/bi200997n

Cited by 2 publications

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“…The CYP24A1 enzymatic assay followed methodology previously described . In short, human CYP24A1 with an N-terminal fusion to maltose binding protein (MBP) was overexpressed in Escherichia coli and purified to homogeneity.…”

Section: Resultsmentioning

confidence: 99%

“…1,25(OH) 2 D 3 and 25(OH)D 3 were purchased from SAFC-Pharma (Madison, WI). Human MBP-CYP24A1, mouse CYP27B1, bovine adrenodoxin (Adx), and adrenodoxin reductase (AdR) were purified as described previously …”

Section: Methodsmentioning

confidence: 99%

“…Both classes have their challenges: calcitriol therapy is limited by hypercalcemia, and this side effect can be associated with vitamin D derivatives, whereas for the azole inhibitors the challenge is selectivity for CYP24A1 over the other major vitamin D 3 -metabolizing enzyme CYP27B1. Successes in developing vitamin D derivatives with reduced hypercalcemic effects have been reported, , including the sulfone CTA018, , sulfoximine CTA091, , sulfonate TS17, imidazole VIMI, and cyclopropylamine CPA1 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

et al. 2014

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“…25-Hydroxyvitamin D 3 was purchased from SAFC-Pharma (Madison, WI). Mouse CYP27B1, bovine adrenodoxin (Adx), and adrenodoxin reductase (AdR) were purified as described previously . The reconstituted CYP27B1 enzymatic assay was carried out in a buffer containing 20 mM Tris (pH 7.7), 125 mM NaCl, 0.1% CHAPS, 2 μM Adx, 0.2 μM AdR, 0.05 μM CYP27B1, and 0–5 μM vitamin D substrate.…”

Section: Methodsmentioning

confidence: 99%

“…Mouse CYP27B1, bovine adrenodoxin (Adx), and adrenodoxin reductase (AdR) were purified as described previously. 28 The reconstituted CYP27B1 enzymatic assay was carried out in a buffer containing 20 mM Tris (pH 7.7), 125 mM NaCl, 0.1% CHAPS, 2 μM Adx, 0.2 μM AdR, 0.05 μM CYP27B1, and 0−5 μM vitamin D substrate. All the vitamin D analogues were dissolved in ethanol, and the concentrations were determined based on UV absorption at appropriate wavelengths (ε 254 = 42 mM −1 cm −1 for 4; ε 265 = 18.2 mM −1 cm −1 for 25-OH-D 3 ; ε 270 = 18.0 mM −1 cm −1 for 8 and 9).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D₃ Analogues Monohydroxylated in the A-ring

et al. 2014

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The 20R- and 20S-isomers of 25-hydroxy-2-methylene-vitamin D3 and 3-desoxy-1α,25-dihydroxy-2-methylene-vitamin D3 have been synthesized. Two alternative synthetic routes were devised for preparation of the required A-ring synthons, starting from the chiral compound derived from the (-)-quinic acid and, alternatively, from the commercially available achiral precursor, monoprotected 1,4-cyclohexanedione. The A-ring dienynes were coupled by the Sonogashira process with the respective C,D-ring fragments, the enol triflates derived from the protected (20R)- or (20S)-25-hydroxy Grundmann ketones. All four compounds possessed significant in vivo activity on bone calcium mobilization and intestinal calcium transport. The presence of a 2-methylene group increased intestinal calcium transport activity of all four analogues above that of the native hormone, 1α,25-dihydroxyvitamin D3. In contrast, bone calcium mobilization was equal to that produced by 1α,25-dihydroxyvitamin D3 in compounds having a (20S)-configuration or diminished to one-tenth that of 1α,25-dihydroxyvitamin D3 in compounds with a (20R)-configuration.

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Correction to Screening of Selective Inhibitors of 1α,25-Dihydroxyvitamin D₃ 24-Hydroxylase Using Recombinant Human Enzyme Expressed in Escherichia coli

Cited by 2 publications

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Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D₃ Analogues Monohydroxylated in the A-ring

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Correction to Screening of Selective Inhibitors of 1α,25-Dihydroxyvitamin D3 24-Hydroxylase Using Recombinant Human Enzyme Expressed in Escherichia coli

Cited by 2 publications

References 0 publications

Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

Small-Molecule Inhibitors of 25-Hydroxyvitamin D-24-Hydroxylase (CYP24A1): Synthesis and Biological Evaluation

Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D3 Analogues Monohydroxylated in the A-ring

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Product

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Correction to Screening of Selective Inhibitors of 1α,25-Dihydroxyvitamin D₃ 24-Hydroxylase Using Recombinant Human Enzyme Expressed in Escherichia coli

Synthesis and Biological Activity of 25-Hydroxy-2-methylene-vitamin D₃ Analogues Monohydroxylated in the A-ring