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Title: Design and synthesis of some CUP26 and CYP24 inhibitors as indirect differentiating agents for prostate and breast cancer
Author: Gomaa, Mohamed Sayed Mohamed
ISNI:       0000 0004 2746 872X
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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Prostate and breast cancer are 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 focus on the development of differentiation agents for the treatment of solid tumours, e.g. prostate and breast cancer, was stimulated by the ability of ATRA to inhibit cellular growth and restore normal differentiation of neoplastic cells, ATRA was also shown to be successful in the treatment of acute promelocytic leukemia. The use of differentiating agents to suppress prostate and breast cancer cell proliferation is now one of the new therapeutic strategies. However, the use of 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 or CYP24A1 with ATRA or la, 25-(OH)2-D3 respectively may be a new strategy for the treatment of prostate and breast cancer. To date, the crystal structures of human CYP26A1 or CYP24A1 have not been resolved and there is no single theoretical model published. Homology models of cytochrome P450 RA1 (CYP26A1) and cytochrome P450 24 (CYP24A1) were constructed using three human P450 structures, CYP2C8, CYP2C9 and CYP3A4 as templates for the model building. Using MOE software the lowest energy CYP26A1 and CYP24A1 models were then assessed and showed good stereochemical quality and side chain environment comparable with the templates. Further active site optimisation of the CYP26A1 and CYP24A1 models built using the CYP3A4 template was performed by molecular dynamics using Gromax software to generate final CYP26A1 and CYP24A1 models. The docking studies carried out on the final models showed that the models accommodated the natural substrates ATRA and vitamin D3 as well as the potent inhibitors Rl 15866 and ( )-VID-400 for CYP26A1 and CYP24A1 respectively. To design inhibitors as potent as Rl 15866 and VID-400, for CYP26A1 and CYP24A1 respectively, the virtual screening of a designed library of compounds based on the structure of potent inhibitors, natural substrate and intuition was performed. The results revealed good interaction with the active site of several compounds and therefore potentially good CYP26A1 and CYP24A1 inhibition activity. Two series were synthesised for CYP26A1 inhibition, including a substituted 4-(l,2,4)triazol- and imidazol-l-ylmethylphenylaryl and heteroarylamine and aryl and heteroaryl substituted 3-(4-aminophenyl)-3-imidazol-l-yl-2,2-dimethylpropionic acid methyl ester derivatives. The synthesised compounds were biologically evaluated using a MCF-7 breast cancer cell assay, from which some have shown potent inhibitory activity, with IC5O in the low nanomolar range (20 nM), and others less active but still much more active then the well known inhibitor liarozole. A series of 4 or 5 substituted l-(3-benzenesulfonyl propyl)-l,1-indoles was synthesised and biologically tested for CYP24A1 inhibition. The series showed moderate inhibition activity with a good structure-activity relationship, for further evaluation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available