Salen and tetrahydrosalen derivatives act as effective inhibitors of the tumor-associated carbonic anhydrase XII--a new scaffold for designing isoform-selective inhibitors

Simone Carradori; Celeste De Monte; Melissa D'Ascenzio; Daniela Secci; Gulsah Celik; Mariangela Ceruso; Daniela Vullo; Andrea Scozzafava; Claudiu T Supuran

doi:10.1016/j.bmcl.2013.10.026

Salen and tetrahydrosalen derivatives act as effective inhibitors of the tumor-associated carbonic anhydrase XII--a new scaffold for designing isoform-selective inhibitors

Bioorg Med Chem Lett. 2013 Dec 15;23(24):6759-63. doi: 10.1016/j.bmcl.2013.10.026. Epub 2013 Oct 26.

Authors

Simone Carradori¹, Celeste De Monte, Melissa D'Ascenzio, Daniela Secci, Gulsah Celik, Mariangela Ceruso, Daniela Vullo, Andrea Scozzafava, Claudiu T Supuran

Affiliation

¹ Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: simone.carradori@uniroma1.it.

PMID: 24189056
DOI: 10.1016/j.bmcl.2013.10.026

Abstract

Salen and tetrahydrosalen derivatives possess metal-chelating properties and have been used as ligands in organic synthesis and as scaffolds for developing therapeutic agents. Fourteen such compounds were synthesized in order to explore their ability to inhibit the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Human (h) isoforms hCA I, hCA II, hCA IX and hCA XII were included in the investigation. Several aliphatic and aromatic spacers were introduced between the two chelating groups from salen/tetrahydrosalen in order to explore a diverse chemical space for designing CA inhibitors, which incorporate both phenol and polyamine fragments in their molecule. Some of these compounds showed CA inhibitory activity in the low micromolar-nanomolar range and a pronounced selectivity for inhibiting an isoform over-expressed in hypoxic tumors, hCA XII, over hCA I, II and IX.

Keywords: Carbonic anhydrase inhibitor; Phenol; Polyamine; Salen; Tetrahydrosalen; Tumor over-expressed CA XII.

Publication types

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

MeSH terms

Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry*
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Drug Design
Enzyme Activation / drug effects
Ethylenediamines / chemical synthesis
Ethylenediamines / chemistry*
Ethylenediamines / metabolism
Humans
Neoplasms / enzymology
Neoplasms / pathology
Phenol / chemistry
Polyamines / chemistry
Protein Binding
Protein Isoforms / antagonists & inhibitors
Protein Isoforms / metabolism
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Ethylenediamines
Polyamines
Protein Isoforms
Phenol
disalicylaldehyde ethylenediamine
Carbonic Anhydrases
carbonic anhydrase XII