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

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.
Ibidapo S Williams 1,  Prashant Joshi 2,  Linda Gatchie 1,  Mohit Sharma 3,  Naresh K Satti 4,  Ram A Vishwakarma 2,  Bhabatosh Chaudhuri 5,  Sandip B Bharate 6
Affiliations

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.

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