Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Sachin Dhanani; Caroline P. Owen; Chirag H. Patel; Sabbir Ahmed

doi:10.1016/j.bmcl.2006.06.092

Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Sachin Dhanani, Caroline P. Owen, Chirag H. Patel, Sabbir Ahmed

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

Abstract

We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 microM against 17alpha-OHase and IC50 = 0.33 microM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 microM against 17alpha-OHase and IC50 = 1.66 microM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C3 area of the steroid backbone, thereby increasing potency.

Original language	English
Pages (from-to)	4752-4756
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2006.06.092
Publication status	Published - 15 Sept 2006
Externally published	Yes

Keywords

imidazole
17 [alpha]-hydroxylase/17
20-lyase
inhibitors
prostate cancer
molecular modeling perspective
prostate-cancer
potential therapeutics
aromatase
mechanism
Chemistry

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Dhanani, S., Owen, C. P., Patel, C. H., & Ahmed, S. (2006). Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). Bioorganic and Medicinal Chemistry Letters, 16(18), 4752-4756. https://doi.org/10.1016/j.bmcl.2006.06.092

Dhanani, Sachin ; Owen, Caroline P. ; Patel, Chirag H. et al. / Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). In: Bioorganic and Medicinal Chemistry Letters. 2006 ; Vol. 16, No. 18. pp. 4752-4756.

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title = "Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])",

abstract = "We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 microM against 17alpha-OHase and IC50 = 0.33 microM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 microM against 17alpha-OHase and IC50 = 1.66 microM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C3 area of the steroid backbone, thereby increasing potency.",

keywords = "imidazole, 17 [alpha]-hydroxylase/17, 20-lyase, inhibitors, prostate cancer, molecular modeling perspective, prostate-cancer, potential therapeutics, aromatase, mechanism, Chemistry",

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

year = "2006",

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day = "15",

doi = "10.1016/j.bmcl.2006.06.092",

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Dhanani, S, Owen, CP, Patel, CH & Ahmed, S 2006, 'Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])', Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 18, pp. 4752-4756. https://doi.org/10.1016/j.bmcl.2006.06.092

Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). / Dhanani, Sachin; Owen, Caroline P.; Patel, Chirag H. et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 18, 15.09.2006, p. 4752-4756.

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

TY - JOUR

T1 - Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

AU - Dhanani, Sachin

AU - Owen, Caroline P.

AU - Patel, Chirag H.

AU - Ahmed, Sabbir

PY - 2006/9/15

Y1 - 2006/9/15

N2 - We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 microM against 17alpha-OHase and IC50 = 0.33 microM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 microM against 17alpha-OHase and IC50 = 1.66 microM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C3 area of the steroid backbone, thereby increasing potency.

AB - We report the preliminary results of the synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a number of phenyl alkyl imidazole-based compounds as inhibitors of the two components of 17alpha-hydroxylase/17,20-lyase (P450(17alpha)), that is, 17alpha-hydroxylase (17alpha-OHase) and 17,20-lyase (lyase). The results show that N-3-(4-bromophenyl) propyl imidazole (12) (IC50 = 2.95 microM against 17alpha-OHase and IC50 = 0.33 microM against lyase) is the most potent compound within the current study, in comparison to ketoconazole (KTZ) (IC50 = 3.76 microM against 17alpha-OHase and IC50 = 1.66 microM against lyase). Modelling of these compounds suggests that the length of the alkyl chain enhances the interaction between the inhibitor and the area of the active site corresponding to the C3 area of the steroid backbone, thereby increasing potency.

KW - imidazole

KW - 17 [alpha]-hydroxylase/17

KW - 20-lyase

KW - inhibitors

KW - prostate cancer

KW - molecular modeling perspective

KW - prostate-cancer

KW - potential therapeutics

KW - aromatase

KW - mechanism

KW - Chemistry

UR - http://www.ncbi.nlm.nih.gov/pubmed/16870430

U2 - 10.1016/j.bmcl.2006.06.092

DO - 10.1016/j.bmcl.2006.06.092

M3 - Article

C2 - 16870430

SN - 0960-894X

VL - 16

SP - 4752

EP - 4756

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

Dhanani S, Owen CP, Patel CH, Ahmed S. Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha]). Bioorganic and Medicinal Chemistry Letters. 2006 Sept 15;16(18):4752-4756. doi: 10.1016/j.bmcl.2006.06.092

Synthesis, biochemical evaluation and rationalisation of the inhibitory activity of a range of 4-substituted phenyl alkyl imidazole-based inhibitors of the enzyme complex 17[alpha]-hydroxylase/17,20-lyase (P450[sub]17[alpha])

Abstract

Keywords

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