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Title: Small molecule inhibitors of CYP24A1 for the treatment of various cancers
Author: Ferla, Salvatore
ISNI:       0000 0004 2752 3389
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2013
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In the last three decades vitamin D, or calcitriol, has been found to have important anticancer role in different cancer types. Unfortunately, a therapy using calcitriol remains a challenge due to increased drug resistance as a consequence of the up-regulation of CYP24A1, which metabolises and inactivates calcitriol. Moreover, the hypercalcaemia associated with an elevated dose of calcitriol does not allow the use of vitamin D at a high concentration. Analogues of calcitriol have enhanced anti-tumour activity, reducing the calcaemic undesired effect. The use of CYP24A1 selective inhibitors could be the appropriate strategy to increase the lifetime and thereby! the anti-cancer functions of calcitriol and its derivatives. Consequently, the aim of this project is to develop new, potent and selective inhibitors of CYP24A1 that could be used in the treatment of different types of cancer in order to enhance endogenous vitamin D levels and favour its anti-tumour activity. Through molecular modelling studies, a new CYP24A1 homology model has been prepared and the active site has been characterised examining the disposition of (R)-VID400, a CYP24 inhibitor, (E)-N-(2-(1H-imidazol-1-yl)2-phenylethyl)-4-styrylbenzamide (MCC165), a compound previously synthesised in our laboratory that showed a potent CYP24A1 inhibitory activity (IC50= 0.3μM), and the natural substrate calcitriol. Different series of potential CYP24A1 inhibitors were designed in order to mimic completely the calcitriol disposition in the binding pocket and to interact with the haem iron of the enzyme catalytic site. For each series a synthetic pathway was developed. The synthesis was followed by a CYP24A1/CYP27B1 inhibition assay. All the compounds occupy the same hydrophobic tunnel as calcitriol and access the active site through the same channel. Moreover the substituents in the lateral chain bind directly to the haem iron via a lone pair of electrons. The different syntheses were obtained after several optimisations of reactions and routes. The CYP24A1/CYP27B1 inhibitory activity (IC50) using a cell-free assay and the value of the Ki (dissociation constant) of the different series of compounds, compared with ketoconazole (Ki= 0.030 μM, IC50= 0.47 μM) as the standard, were evaluated. Selectivity of CYP24A1 over CYP27B1 was also calculated. New potent CYP24A1 inhibitors were found.!Selectivity gave a range from poor to moderate results with selectivity improved in some case compared with ketoconazole (selectivity: 1.6).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; RC0254 Neoplasms. Tumors. Oncology (including Cancer)