Synthesis of Novel CYP1 Activated Heterocyclic Anticancer Prodrugs
type: CreativeWork
description: The cytochrome P450 superfamily of enzymes are critical in the metabolism of endogenous and exogenous substrates. CYP1A1 and CYP1B1 have been found to be over-expressed in tumour cells whilst undetected or present in very low levels in corresponding normal tissue. This presented a novel target for the development of anti-cancer prodrugs, which would remain non-toxic until undergoing metabolism to toxic species by CYP1 enzymes over-expressed at tumour sites. The chalcones have been shown to exhibit effective anti-cancer prodrug activity, but are labile to photoisomerisation reactions converting the potent trans isomer to the less toxic cis isomer. Several heterocyclic ring systems were incorporated across the α,β-unsaturated moiety of the chalcones to produce rigid structures, eliminating the possibility of photoisomerisation occurring whilst maintaining the substituted phenyl groups in a trans like geometry. Lead compounds were identified using an in vitro MTT screening assay against a panel of tumour cell lines characterised for their constitutive or inducible CYP1 expression. These were the MDA 468, MCF7 and MDA 231 cell lines. The non-tumour MCF10A cell line which has no basal CYP1 expression was used as the control. A library of eighteen 3,5-diarylpyrazoles were synthesised. The lead pyrazole DMU 10107 (3-(2,3,4-trimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)pyrazole) gave an IC50 value of 8μM towards the MDA 468 cell line. The MCF7 cells, TCDD induced and non-induced gave IC50 values of 10μM each. Although the pyrazoles showed plausible tumour toxicity, an investigation into six membered pyrimidine heterocycles was undertaken in an attempt to obtain enhanced cytotoxicities than those observed from the five membered pyrazoles. Therefore, a library of fifteen 2-amino-4,6-diarylpyrimidines was synthesised. The lead amino-pyrimidine DMU 10212 (2-amino-4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine) showed significant cytotoxicity towards the MDA 468 …
abstract: The cytochrome P450 superfamily of enzymes are critical in the metabolism of endogenous and exogenous substrates. CYP1A1 and CYP1B1 have been found to be over-expressed in tumour cells whilst undetected or present in very low levels in corresponding normal tissue. This presented a novel target for the development of anti-cancer prodrugs, which would remain non-toxic until undergoing metabolism to toxic species by CYP1 enzymes over-expressed at tumour sites. The chalcones have been shown to exhibit effective anti-cancer prodrug activity, but are labile to photoisomerisation reactions converting the potent trans isomer to the less toxic cis isomer. Several heterocyclic ring systems were incorporated across the α,β-unsaturated moiety of the chalcones to produce rigid structures, eliminating the possibility of photoisomerisation occurring whilst maintaining the substituted phenyl groups in a trans like geometry. Lead compounds were identified using an in vitro MTT screening assay against a panel of tumour cell lines characterised for their constitutive or inducible CYP1 expression. These were the MDA 468, MCF7 and MDA 231 cell lines. The non-tumour MCF10A cell line which has no basal CYP1 expression was used as the control. A library of eighteen 3,5-diarylpyrazoles were synthesised. The lead pyrazole DMU 10107 (3-(2,3,4-trimethoxyphenyl)-5-(3,4-methylenedioxyphenyl)pyrazole) gave an IC50 value of 8μM towards the MDA 468 cell line. The MCF7 cells, TCDD induced and non-induced gave IC50 values of 10μM each. Although the pyrazoles showed plausible tumour toxicity, an investigation into six membered pyrimidine heterocycles was undertaken in an attempt to obtain enhanced cytotoxicities than those observed from the five membered pyrazoles. Therefore, a library of fifteen 2-amino-4,6-diarylpyrimidines was synthesised. The lead amino-pyrimidine DMU 10212 (2-amino-4-(2,4-dimethoxyphenyl)-6-(3,4-methylenedioxyphenyl)pyrimidine) showed significant cytotoxicity towards the MDA 468 …
author: Bhambra, Avninder S.
license: https://dora.dmu.ac.uk/bitstreams/3d92daa1-39db-4d79-980f-74a69854dfe4/download
date published: 2011-04
date modified: 2026-07-24T06:18:31Z
provider: De Montfort University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: De Montfort University