Molecular modelling and synthesis of novel ligands related to cellular differentiation.

Mohamed, Ahmed Safwat Mohamed. 2009. Molecular modelling and synthesis of novel ligands related to cellular differentiation. PhD Thesis, Cardiff University.

PDF - Accepted Post-Print Version Download (11MB)

Abstract

Cancer is a leading cause of death all over the world. Retinoic acid and vitamin D3 play an important role in cellular proliferation and differentiation and as such have potential therapeutic value as differentiating agents in the treatment of cancer and hyperkeratinising diseases. The use of differentiating agents to suppress prostate and breast cancer proliferation is now one of the new therapeutic strategies. However, the use of all trans retinoic acid (ATRA) and vitamin D3 as differentiating agents is limited by their rapid metabolism through the self induction of the cytochrome P450 enzymes that are involved in their catabolism. The P450 enzymes responsible for the metabolism of ATRA and la,25-(OH)2-D3 (calcitriol) are cytochrome P450 26 (CYP26A1) and cytochrome P450 24 (CYP24A1) respectively. Therefore the use of potent and selective inhibitors of CYP26A1 and CYP24A1 with ATRA and la,25-(OH)2-D3 respectively may represent a new strategy for the treatment of cancer. The pharmacophore model of CYP26A1 inhibitors was constructed using MOE software. A database of 71 inhibitors with different conformations have been built and arranged according to activity. The resulting pharmacophore model has 8 features of which 5 features are essential to get the CYP26A1 inhibitory activity. The designed model was used to build new inhibitors, which have reasonable activity. Two series were synthesised for CYP26A1 inhibition. The first series was designed to investigate the effect of changing the structure of the lead compound on the inhibitory activity against CYP26A1 and was depending mainly on presence of imidazole moiety, and the second series was a result of the pharmacophore search and was mainly oxadiazole derivatives. These two series were biologically evaluated using a MCF-7 breast cancer cell assay previously described by our group and also some of the compounds were tested in the biochemical assay. Changing of the structure could be tolerated to a certain limit as long as the imidazole ring is included which is the main part responsible for the binding with the haem in CYP26A1 enzyme. Some of the resulting compounds has good activity, specially methyl anti-3-(1H-1-imidazolyl)-3-[4-(phenylamino)phenyl]-2-methylpropanoate which should IC50 of 26 nM in the biochemical CYP26A1 assay. The oxadiazole derivatives did not show very good activity against CYP26A1 cell based assay, may be owing to the decrease in the flexibility of the molecules. Further investigation in the first series, i.e. the imidazole containing compounds, is being continued in our group. As for CYP24A1 inhibition, two series; the azoles and the tetralones, were synthesised and biologically evaluated. The tetralones do not seem to have a very good activity against CYP24A1, as the most active compound, which is 2-[l-(2-ethylphenyl)methylidene]-6-methoxy-1,2,3,4-tetrahydro-1-naphthalenone showed IC50 of 1.92 pM which about 4 folds less potent than ketoconazole (IC50 = 0.52 pM). As for the azoles, it seems that the azoles would be much more active than the tetralone derivatives as N-[2-( 1H-1 -imidazolyl)-2-phenylethyl]-4-[(£)-2-phenyl-1 -ethenyl] benzamide displayed greater inhibitory activity (IC50 = 0.3 pM) than the standard ketoconazole (IC50 = 0.52 pM). As a result of this work, it seems that the azole type of these compounds could be of interest for future development.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	Q Science > QD Chemistry R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) R Medicine > RS Pharmacy and materia medica
ISBN:	9781303197055
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:30
URI:	https://orca.cardiff.ac.uk/id/eprint/54516

Actions (repository staff only)

Edit Item