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Title: Selective inhibitors of the cytochrome p450 enzyme CYP1B1
Author: Tan, Hoon Leong
ISNI:       0000 0004 2669 5082
Awarding Body: De Montfort University
Current Institution: De Montfort University
Date of Award: 2006
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The cytochrome P450 CYP1 ezymes, CYP1A1, CYP1A2 and CYP1B1, are members of the cytochrome P450 superfamily which catalyse the oxidative metabolism of a wide range of endogenous and exogenous compounds. CYP1B1 is highly overexpressed in different malignancies but not in the corresponding normal tissues. This significant discovery has provided an opportunity to develop tumour specific intracellular activated anticancer prodrugs, using CYP1B1 as molecular target. As part of the continuing CYP1B1 activated anticancer prodrugs discovery programme at Leicester School of Pharmacy, this research was set up to delineate the structure-activity relationship of the CYP1 enzymes. This was achieved by studying a range of inhibitors designed and synthesised during this Ph. D. project. The inhibitor's ability to inhibit CYP1 enzymes was quantified using a fluorometric high throughput ethoxyresorufin O-deethylase assay. DMU968 and DMU2157 were identified as inhibitors of CYP1A1. These inhibitors have low intrinsic toxicity and therefore, have potential applications for in vivo and cell line based in vitro experiments. 9-Acetylphenanthrene was identified as CYP1A2 inhibitor. It was demonstrated that 9-acetylphenahthrene has better potency and selectivity profiles compared with the known CYP1A2 inhibitor furafylline. Fourteen CYP1B1 inhibitors were identified. DMU778 and DMU2103 may have potential applications in cell based assays due to low intrinsic toxicity. DMU2123 and DMU2127 have been shown to possess tumour specific anticancer properties. These compounds were selectively activated by CYP1A1 and may have the potential as anticancer prodrug since some cancers also highly expressed CYP1A1. It was also found that residual insect P450, present in control microsomes, also bioactivated these compounds. Although the identity of the insect P450 has not been identified, DMU2123 and DMU2127 have a double potential as insect selective pesticides as well as tumour selective anticancer agents. Currently, more detailed studies are being performed on these compounds. Combining drug metabolism data obtained elsewhere and enzyme inhibition results, pharmacophore models for the CYP1 enzymes were constructed. The pharmacophore models for each CYP1 enzymes have shown distinct structural requirements for selective inhibitors and substrates. These pharmacophore models have contributed towards better prodrug design. Inhibitors synthesised in this research may be used for studying other P450s structure-activity relationships. Selective inhibitors identified in this project also provided valuable molecular probes for drug metabolism and pharmacokinetic studies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available