Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance

Ibidapo S Williams; Prashant Joshi; Linda Gatchie; Mohit Sharma; Naresh K Satti; Ram A Vishwakarma; Bhabatosh Chaudhuri; Sandip B Bharate

doi:10.1016/j.bmcl.2017.07.010

Synthesis and biological evaluation of pyrrole-based chalcones as CYP1 enzyme inhibitors, for possible prevention of cancer and overcoming cisplatin resistance

Bioorg Med Chem Lett. 2017 Aug 15;27(16):3683-3687. doi: 10.1016/j.bmcl.2017.07.010. Epub 2017 Jul 4.

Authors

Ibidapo S Williams¹, Prashant Joshi², Linda Gatchie¹, Mohit Sharma³, Naresh K Satti⁴, Ram A Vishwakarma², Bhabatosh Chaudhuri⁵, Sandip B Bharate⁶

Affiliations

¹ Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK; CYP Design Limited, Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK.
² Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
³ Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
⁴ Natural Product Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
⁵ Leicester School of Pharmacy, De Montfort University, Leicester LE1 9BH, UK; CYP Design Limited, Innovation Centre, 49 Oxford Street, Leicester LE1 5XY, UK. Electronic address: bchaudhuri@dmu.ac.uk.
⁶ Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India; Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India. Electronic address: sbharate@iiim.ac.in.

PMID: 28711350
DOI: 10.1016/j.bmcl.2017.07.010

Abstract

Inhibitors of CYP1 enzymes may play vital roles in the prevention of cancer and overcoming chemo-resistance to anticancer drugs. In this letter, we report synthesis of twenty-three pyrrole based heterocyclic chalcones which were screened for inhibition of CYP1 isoforms. Compound 3n potently inhibited CYP1B1 with an IC₅₀ of ∼0.2μM in Sacchrosomes™ and CYP1B1-expressing live human cells. However, compound 3j which inhibited both CYP1A1 and CYP1B1 with an IC₅₀ of ∼0.9µM, using the same systems, also potently antagonized B[a]P-mediated induction of AhR signaling in yeast (IC₅₀, 1.5µM), fully protected human cells from B[a]P toxicity and completely reversed cisplatin resistance in human cells that overexpress CYP1B1 by restoring cisplatin's cytotoxicity. Molecular modeling studies were performed to rationalize the observed potency and selectivity of enzyme inhibition by compounds 3j and 3n.

Keywords: AhR antagonism; CYP1A1; CYP1B1; Chemoprevention; Cisplatin chemo-resistance; Heterocyclic chalcones.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Binding Sites
Cell Line, Tumor
Cell Survival / drug effects
Chalcones / chemical synthesis*
Chalcones / pharmacology*
Cisplatin / pharmacology
Cytochrome P-450 CYP1B1 / antagonists & inhibitors*
Cytochrome P-450 CYP1B1 / genetics
Cytochrome P-450 CYP1B1 / metabolism
Drug Resistance, Neoplasm / drug effects*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
HEK293 Cells
Humans
Inhibitory Concentration 50
Molecular Dynamics Simulation
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Pyrroles / chemical synthesis
Pyrroles / pharmacology
Structure-Activity Relationship

Substances

Antineoplastic Agents
Chalcones
Enzyme Inhibitors
Protein Isoforms
Pyrroles
CYP1B1 protein, human
Cytochrome P-450 CYP1B1
Cisplatin