Design, synthesis & biological evaluation of ferulic acid-based small molecule inhibitors against tumor-associated carbonic anhydrase IX

Babita Aneja; Aarfa Queen; Parvez Khan; Farheen Shamsi; Afzal Hussain; Phool Hasan; M Moshahid A Rizvi; Constantin G Daniliuc; Mohamed F Alajmi; Mohd Mohsin; Md Imtaiyaz Hassan; Mohammad Abid

doi:10.1016/j.bmc.2020.115424

Design, synthesis & biological evaluation of ferulic acid-based small molecule inhibitors against tumor-associated carbonic anhydrase IX

Bioorg Med Chem. 2020 May 1;28(9):115424. doi: 10.1016/j.bmc.2020.115424. Epub 2020 Mar 17.

Authors

Affiliations

¹ Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
² Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India; Department of Chemistry, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
³ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁴ Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
⁵ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁶ Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, 48149, Germany.
⁷ Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address: mihassan@jmi.ac.in.
⁸ Department of Biosciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India. Electronic address: mabid@jmi.ac.in.

PMID: 32209296
DOI: 10.1016/j.bmc.2020.115424

Abstract

Carbonic anhydrase IX (CAIX) is an emerging drug target for hypoxia associated cancers. To identify potent and selective inhibitors of CAIX, a small library of ferulic acid (FA) derivatives bearing triazole moiety has been designed, synthesized and evaluated against different human CA isoforms (CAII, CAVA & CAIX). Though most of the compounds showed CAIX inhibition in the micromolar range, compound 7i selectively inhibits CAIX in the nanomolar range (IC₅₀ = 24 nM). In silico analysis revealed binding of 7i with the catalytically important amino acid residues of CAIX. Further, cell-based studies indicate that 7i inhibits the activity of CAIX, decreases the epithelial to mesenchymal transitions, induces apoptosis, inhibits cell migration and colonization potential of cancer cells. Taken together, these results emphasized the use of 7i as a prospective pharmacological lead molecule in CAIX targeted anticancer therapeutics.

Keywords: Anticancer; Apoptosis; Carbonic anhydrase IX (CAIX) inhibitors; Ferulic acid.

Publication types

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

MeSH terms

Antigens, Neoplasm
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Coumaric Acids / chemical synthesis
Coumaric Acids / chemistry
Coumaric Acids / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Epithelial-Mesenchymal Transition / drug effects
Humans
Molecular Structure
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Coumaric Acids
Small Molecule Libraries
ferulic acid
CA9 protein, human
Carbonic Anhydrase IX