Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Caroline P Owen; Sachin Dhanani; Chirag H Patel; Imran Shahid; Sabbir Ahmed

doi:10.1016/j.bmcl.2006.05.070

Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Caroline P Owen, Sachin Dhanani, Chirag H Patel, Imran Shahid, Sabbir Ahmed

Research output: Contribution to journal › Article › peer-review

Abstract

The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).

Original language	English
Pages (from-to)	4011-4015
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2006.05.070
Publication status	Published - 1 Aug 2006
Externally published	Yes

Keywords

lyase
hydroxylase
p-45017 alpha
inhibitors
substrate-haem complex
prostate-cancer
chemotherapy
target
Chemistry

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10.1016/j.bmcl.2006.05.070

http://dx.doi.org/10.1016/j.bmcl.2006.05.070

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Owen, C. P., Dhanani, S., Patel, C. H., Shahid, I., & Ahmed, S. (2006). Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). Bioorganic and Medicinal Chemistry Letters, 16(15), 4011-4015. https://doi.org/10.1016/j.bmcl.2006.05.070

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title = "Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])",

abstract = "The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).",

keywords = "lyase, hydroxylase, p-45017 alpha, inhibitors, substrate-haem complex, prostate-cancer, chemotherapy, target, Chemistry",

author = "Owen, \{Caroline P\} and Sachin Dhanani and Patel, \{Chirag H\} and Imran Shahid and Sabbir Ahmed",

year = "2006",

month = aug,

day = "1",

doi = "10.1016/j.bmcl.2006.05.070",

language = "English",

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Owen, CP, Dhanani, S, Patel, CH, Shahid, I & Ahmed, S 2006, 'Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])', Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 15, pp. 4011-4015. https://doi.org/10.1016/j.bmcl.2006.05.070

Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). / Owen, Caroline P; Dhanani, Sachin; Patel, Chirag H et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 15, 01.08.2006, p. 4011-4015.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

AU - Owen, Caroline P

AU - Dhanani, Sachin

AU - Patel, Chirag H

AU - Shahid, Imran

AU - Ahmed, Sabbir

PY - 2006/8/1

Y1 - 2006/8/1

N2 - The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).

AB - The cytochrome P-450 enzyme, 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), is a potential target in hormone-dependent cancers. Here, we report the synthesis and biochemical evaluation of a range of benzyl imidazole-based compounds which have been targeted against the two components of this enzyme, that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results from the biochemical testing suggest that the compounds synthesised are good inhibitors, with N-4-iodobenzyl imidazole (5) (IC50=10.06 microM against 17alpha-OHase and IC50=1.58 microM against lyase) showing equipotent activity against lyase compared to the standard compound, ketoconazole (KTZ) (IC50=3.76+/-0.01 microM against 17alpha-OHase and IC50=1.66+/-0.15 microM against lyase). Furthermore, the compounds tested are less potent towards the 17alpha-OHase component, a desirable property in the development of novel inhibitors of P450(17alpha).

KW - lyase

KW - hydroxylase

KW - p-45017 alpha

KW - inhibitors

KW - substrate-haem complex

KW - prostate-cancer

KW - chemotherapy

KW - target

KW - Chemistry

UR - http://www.ncbi.nlm.nih.gov/pubmed/16750362

U2 - 10.1016/j.bmcl.2006.05.070

DO - 10.1016/j.bmcl.2006.05.070

M3 - Article

C2 - 16750362

SN - 0960-894X

VL - 16

SP - 4011

EP - 4015

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 15

ER -

Synthesis and biochemical evaluation of a range of potent benzyl imidazole-based compounds as potential inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

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