Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497588
Title: Synthesis and biochemical evaluation of novel non-steroidal inhibitors of the cytochrome P450 enzyme 17α-hydroxylase/17,20-lyase in the treatment of hormone-dependent prostate cancer
Author: Shahid, Imran
Awarding Body: Kingston University
Current Institution: Kingston University
Date of Award: 2008
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Abstract:
A high proportion of prostate cancers have been shown to be androgen-dependent. The biosynthesis of the androgens is catalysed by the cytochrome P450 enzyme 17[alpha]-hydroxylase/17, 20-lyase (P450[sub]17[alpha]), which is responsible for the conversion of C[sub]21 steroids (for example pregnenolone and progesterone) to the androgens (for example dehydroepiandrosterone and androstenedione respectively). The inhibition of this enzyme would therefore lead to the overall reduction in the level of androgens and thus result in an overall decrease in the stimulation of androgen-dependent cancer cells. The compounds synthesised within the current study were designed such that the compounds were able to donate a lone pair of electrons to the Fe atom within the haem group of the active site of P450[sub]17[alpha]. As such, compounds based on benzyl imidazole backbone were synthesised as the major range of compounds with a small number of phenyl alkyl imidazole based compounds synthesised in an effort to evaluate physicochemical factors such as hydrophobicity. In general, the results of the study show that of the benzyl imidazole-based compounds were weak inhibitors of P450[sub]17[alpha] in comparison to the standard compound, namely ketoconazole (3) (IC[sub]50=1.66[plus or minus]0.15[mu]M against 17,20-lyase and IC[sub]50=3.76[plus or minus]0.01[mu]M against 17[alpha]-hydroxylase). The most potent benzyl imidazole-based compounds synthesised were: 4- iodobenzyl imidazole (224) (IC[sub]50=1.58[plus or minus]0.17[mu]M against 17,20-lyase and IC[sub]50=10.06[plus or minus]0.96[mu]M against 17[alpha]-OHase); 1-(3,4-dichloro-benzyl)-1H-imidazole (215) (IC[sub]50=2.07[plus or minus]0.07[mu]M against 17,20-lyase and IC[sub]50=12.22[plus or minus]0.88[mu]M against 17[alpha]-hydroxylase); 1-(3,5-dichloro-benzyl)-1H-imidazole (216) (IC[sub]50=3.34[plus or minus]0.11[mu]M against 17,20-lyase and IC[sub]50=22.56[plus or minus]0.34[mu]M against 17[alpha]-hydroxylase); 1-(3,5-dibromo-benzyl)-1H-imidazole (221) (IC[sub]50=3.16[plus or minus]0.11[mu]M against 17,20-lyase and IC[sub]50=25.95[plus or minus]0.91[mu]M against 17[alpha]-hydroxylase). The phenyl alkyl imidazole based compounds were found to be more potent than the benzyl imidazole-based compounds and 3 and included: phenylheptyl imidazole (318) (IC[sub]50=0.10[plus or minus]0.02[mu]M against 17,20-lyase and IC[sub]50=0.32[plus or minus]0.05[mu]M against 17[alpha]-hydroxylase); phenyloctyl imidazole (321) (IC[sub]50=0.21[plus or minus]0.02[mu]M against 17,20-lyase and IC[sub]50=0.25[plus or minus]0.01[mu]M against 17[alpha]-hydroxylase); and phenylnonyl imidazole (324) (IC[sub]50=0.35[plus or minus]0.01[mu]M against 17,20-lyase and IC[sub]50=1.06[plus or minus]0.03[mu]M against 17[alpha]-hydroxylase). Consideration of the structure-activity relationship determination and the molecular modeling of the synthesised compounds using the substrate-haem complex (SHC) approach shows that the disubstituted derivatives of benzyl imidazole were able to utilise both hydrogen bonding groups which are presumed to exist at the active site of P450[sub]17[alpha]. These compounds were found to be considerably more potent than the mono-substituted derivatives, as such, it suggests that the increase in the number of interactions between the inhibitor and the enzyme is the key feature which results in the increase in potency. The inhibitory data obtained for the phenyl alkyl imidazole-based compounds show that hydrophobicity (logP) of the inhibitor plays a major role in determining the overall inhibitory activity of these compounds. As such, the study suggests that in the design of further novel inhibitors of this enzyme, the interaction with the active site and logP are two factors which would allow for the synthesis of highly potent inhibitors of this enzyme.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.497588  DOI: Not available
Keywords: Pharmacy
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