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

Abstract

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.

Computer aided chemical design: using quantum chemical calculations to predict properties of a series of halochromic guaiazulene derivatives

“…ESI-TOF-MS spectra were recorded on Agilent 6210 TOF spectrometer. 4-(Hexyloxy)benzaldehyde 2  [30], 1-(hexyloxy)-4-vinylbenzene 4  [28], 7-bromo-9,9-dihexyl-9H-fluorene-2-carbaldehyde 6  [29] were prepared according to literature procedures.…”

“…The use of a method with a higher proportion of HF provided greater similarity between the calculated and experimental results for these compounds because of the presence of the large dipole moments that are more akin to charge transfer, a phenomenon that traditional DFT methods struggle to depict [28,29]. …”

The vitamin D metabolome: An update on analysis and function

“…Targeting CYP24A1 with selective inhibitors provides an opportunity to increase endogenous 1,25(OH) 2 D3. Vitamin D derivatives, azole inhibitors, arylamides, and tetralones have been described as synthetic inhibitors of CYP24A1 . Tetralones generally inhibit CYP24A1 at a lesser rate than azoles; however, tetralones have a more specific binding to the active site of CYP24A1 .…”

Synthesis, molecular modelling and CYP24A1 inhibitory activity of novel of ( E )- N -(2-(1 H -imidazol-1-yl)-2-(phenylethyl)-3/4-styrylbenzamides

“…Despite their lack of specificity towards just CYP24A1, ketoconazole and liarazole were shown to extend the half-life of calcitriol in prostate cancer cells in vitro and in vivo 21 . We have previously described azole CYP24A1 inhibitors 22,23,24,25 , of these the styrylimidazole series 24 was the most promising with potent CYP24A1 inhibitory activity observed ( Figure 2). The aim of this research was the design and synthesis of novel potent inhibitors of CYP24A1 to enhance the endogenous levels of circulating calcitriol.…”