Direct and straightforward access to substituted alkyl selenols as novel carbonic anhydrase inhibitors

Damiano Tanini; Antonella Capperucci; Marta Ferraroni; Fabrizio Carta; Andrea Angeli; Claudiu T Supuran

doi:10.1016/j.ejmech.2019.111811

Direct and straightforward access to substituted alkyl selenols as novel carbonic anhydrase inhibitors

Eur J Med Chem. 2020 Jan 1:185:111811. doi: 10.1016/j.ejmech.2019.111811. Epub 2019 Oct 30.

Authors

Damiano Tanini¹, Antonella Capperucci¹, Marta Ferraroni¹, Fabrizio Carta², Andrea Angeli³, Claudiu T Supuran⁴

Affiliations

¹ University of Florence, Department of Chemistry "Ugo Schiff", Via della Lastruccia 3-13, I-50019, Sesto Fiorentino, Italy.
² Department of University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino (Florence), Italy.
³ Department of University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino (Florence), Italy; Centre of Advanced Research in Bionanoconjugates and Biopolymers Department,"Petru Poni" Institute of Macromolecular Chemistry, Iasi, Romania. Electronic address: andrea.angeli@unifi.it.
⁴ Department of University of Florence, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019, Sesto Fiorentino (Florence), Italy. Electronic address: claudiu.supuran@unifi.it.

PMID: 31693947
DOI: 10.1016/j.ejmech.2019.111811

Abstract

Functionalised aliphatic selenols, straightforwardly obtained through ring-opening reaction of strained heterocycles, represent a new chemotype acting as carbonic anhydrase inhibitors (CAIs). These compounds showed pronounced selectivity towards the cytosolic human (h) isoforms such as the hCA I, II and VII rather than the membrane tumor associate hCA IX. In addition, we reported for the first time the X-ray crystal structure of an aliphatic selenol bound to the hCA I zinc ion, and that afforded the opportunity to decipher in detail the inhibition mechanism underpinning such a new class of CAIs. In this context selenols are interesting leads worth developing for the obtainment of novel and efficient selective CAIs potentially useful for the management of a variety of diseases including glaucoma, retinitis pigmentosa, epilepsy and arthritis.

Keywords: Carbonic anhydrase; Inhibitor; Metalloenzymes; Selenium; Selenol.

MeSH terms

Binding Sites / drug effects
Carbonic Anhydrase I / antagonists & inhibitors*
Carbonic Anhydrase I / metabolism
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IX / antagonists & inhibitors*
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Selenium Compounds / chemical synthesis
Selenium Compounds / chemistry
Selenium Compounds / pharmacology*
Structure-Activity Relationship

Substances

Carbonic Anhydrase Inhibitors
Selenium Compounds
selenol
Carbonic Anhydrase I
Carbonic Anhydrase II
Carbonic Anhydrase IX