Synthesis and biological evaluation of novel 4,7-disubstituted coumarins as selective tumor-associated carbonic anhydrase IX and XII inhibitors

K Muni Chandra; Nerella Sridhar Goud; Mohammed Arifuddin; Mallika Alvala; Ravi Alvala; Andrea Angeli; Claudiu T Supuran

doi:10.1016/j.bmcl.2021.127877

Synthesis and biological evaluation of novel 4,7-disubstituted coumarins as selective tumor-associated carbonic anhydrase IX and XII inhibitors

Bioorg Med Chem Lett. 2021 May 1:39:127877. doi: 10.1016/j.bmcl.2021.127877. Epub 2021 Feb 26.

Authors

K Muni Chandra¹, Nerella Sridhar Goud¹, Mohammed Arifuddin², Mallika Alvala³, Ravi Alvala⁴, Andrea Angeli⁵, Claudiu T Supuran⁶

Affiliations

¹ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India.
² Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India; Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India.
³ Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India; School of Pharmacy & Technology Management, SVKM'S NMIMS (Deemed to be University), Hyderabad Campus, Plot No. B4, Green Industrial Park, Polepally SEZ, TSIIC, Jadcherla, Telangana 509 301, India. Electronic address: mallikaalvala@yahoo.in.
⁴ G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad, India.
⁵ Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy.
⁶ Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 33640442
DOI: 10.1016/j.bmcl.2021.127877

Abstract

With an aim to develop novel potential anti-cancer agents we have designed a series of novel 4,7-disubstituted coumarin hybrids synthesis and evaluated for their inhibitory activity against the human carbonic anhydrase isoforms namely CA I, CA II, CA IX and CA XII. The results of CA inhibition clearly showed that the novel 4, 7-disubstituted coumarin hybrids (7a-i & 8a-j) exhibited selective inhibition towards tumor associated isoforms, CA IX and CA XII without inhibiting CA I and CA II isoforms. Among all the compound 8b showed a significant inhibition against hCA IX with a K_i of 0.58 µM whereas, the compound 7c showed a significant inhibition against hCA XII with a K_i of 0.36 µM respectively. All other compounds have shown a good inhibition against hCA IX and hCA XII over hCA I and hCA II within the range of 0.46 to 9.35 µM. Therefore, compound 8b and 7c would be the potential leads for developing selective cytotoxic agents targeting hCA IX and XII.

Keywords: 4,7-disubstituted coumarin hybrids; Cancer; Carbonic anhydrase; hCAsI, II, IX and XII.

Publication types

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

MeSH terms

Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Coumarins / chemical synthesis
Coumarins / chemistry
Coumarins / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Structure-Activity Relationship

Substances

Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Coumarins
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII