The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells

Ketan C Ruparelia; Sabahat Lodhi; Dyan N Ankrett; Nicola E Wilsher; Randolph R J Arroo; Gerard A Potter; Kenneth J M Beresford

doi:10.1016/j.bmcl.2019.03.030

The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells

Bioorg Med Chem Lett. 2019 Jun 1;29(11):1403-1406. doi: 10.1016/j.bmcl.2019.03.030. Epub 2019 Mar 22.

Authors

Ketan C Ruparelia¹, Sabahat Lodhi¹, Dyan N Ankrett¹, Nicola E Wilsher¹, Randolph R J Arroo¹, Gerard A Potter¹, Kenneth J M Beresford²

Affiliations

¹ Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
² Leicester School of Pharmacy, Faculty of Health and Life Sciences, De Montfort University, The Gateway, Leicester LE1 9BH, UK. Electronic address: kberesford@dmu.ac.uk.

PMID: 30935796
DOI: 10.1016/j.bmcl.2019.03.030

Abstract

As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6-60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds.

Keywords: 4,6-Diaryl-2-pyridones; Antiproliferative; CYP1B1; Chalcones; Prodrug.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cytochrome P-450 CYP1A1 / antagonists & inhibitors*
Cytochrome P-450 CYP1A1 / genetics
Cytochrome P-450 CYP1A1 / metabolism
Cytochrome P-450 CYP1B1 / antagonists & inhibitors*
Cytochrome P-450 CYP1B1 / genetics
Cytochrome P-450 CYP1B1 / metabolism
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Female
Humans
MCF-7 Cells
Molecular Structure
Pyridones / chemical synthesis
Pyridones / chemistry
Pyridones / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Pyridones
CYP1A1 protein, human
CYP1B1 protein, human
Cytochrome P-450 CYP1A1
Cytochrome P-450 CYP1B1