2H-chromene and 7H-furo-chromene derivatives selectively inhibit tumour associated human carbonic anhydrase IX and XII isoforms

Abstract

Tumour associated carbonic anhydrases (CAs) IX and XII have been recognised as potential targets for the treatment of hypoxic tumours. Therefore, considering the high pharmacological potential of the chromene scaffold as selective ligand of the IX and XII isoforms, two libraries of compounds, namely 2H-chromene and 7H-furo-chromene derivatives, with diverse substitution patterns were designed and synthesised. The structure of the newly synthesised compounds was characterised and their inhibitory potency and selectivity towards human CA off target isoforms I, II and cancer-associated CA isoforms IX and XII were evaluated. Most of the compounds inhibit CA isoforms IX and XII with no activity against the I and II isozymes. Thus, while the potency was influenced by the substitution pattern along the chromene scaffold, the selectivity was conserved along the series, confirming the high potential of both 2H-chromene and 7H-furo-chromene scaffolds for the design of isozyme selective inhibitors.

Graphical Abstract

Keywords:

• Human carbonic anhydrase IX and XII
• coumarin derivatives
• selective inhibitors
• cancer
• docking

Author contributions

Lisa Sequeira: investigation, data curation, formal analysis, and writing – original draft. Simona Distinto: investigation, data curation, formal analysis, methodology, supervision, and writing – review and editing. Rita Meleddu: methodology, supervision, and writing – review and editing. Marco Gaspari: investigation. Andrea Angeli: investigation. Filippo Cottiglia: supervision and writing – review and editing. Daniela Secci: investigation. Alessia Onali: investigation. Erica Sanna: investigation. Fernanda Borges: funding acquisition, resourses, supervision, writing – review & editing. Eugenio Uriarte: resources, supervision, writing – review & editing. Stefano Alcaro: conceptualization, resources. Claudiu T. Supuran: conceptualization, resources. Elias Maccioni: conceptualization, funding acquisition, methodology, project administration, resources, supervision, writing – review & editing.

Disclosure statement

All authors declare no conflict of interest except CTS. CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this paper. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

The authors wish to acknowledge for funding part of the research: PRIN 201744BN5T_002 program; UIDB/00081/2020 (CIQUP); LA/P/0056/2020 (IMS); PT-OPENSCREEN-NORTE-01-0145-FEDER-085468.