2. Academic Validation
  3. First-in-Class Dual Targeting Compounds for the Management of Seizures in Glucose Transporter Type 1 Deficiency Syndrome

First-in-Class Dual Targeting Compounds for the Management of Seizures in Glucose Transporter Type 1 Deficiency Syndrome

  • J Med Chem. 2023 Jul 27;66(14):10010-10026. doi: 10.1021/acs.jmedchem.3c00938.
Andrea Angeli 1,  Marta Ferraroni 2,  Carlotta Granchi 3,  Filippo Minutolo 3,  Xiaozhuo Chen 4,  Pratik Shriwas 4,  Emilio Russo 5,  Antonio Leo 5,  Silvia Selleri 1,  Fabrizio Carta 1,  Claudiu T Supuran 1
Affiliations

Affiliations

  • 1 NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, University of Florence, Via Ugo Schiff 6, Sesto Fiorentino, Florence 50019, Italy.
  • 2 Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3-13, Sesto Fiorentino, Florence I-50019, Italy.
  • 3 Department of Pharmacy, University of Pisa, Via Bonanno 6, Pisa 56126, Italy.
  • 4 Edison Biotechnology Institute, Department of Biological Sciences, Molecular and Cellular Biology Program, Ohio University, Athens, Ohio 45701, United States.
  • 5 School of Medicine, Science of Health Department, FAS@UMG Research Center, University of Catanzaro, 88100 Catanzaro, Italy.
PMID: 37436184 DOI: 10.1021/acs.jmedchem.3c00938
Abstract

The genetic disorder glucose transporter type 1 deficiency syndrome (GLUT1-DS) heavily affects the main intake of energy in tissues and determines the most relevant outcomes at the central nervous system (CNS) district, which is highly dependent on glucose. Herein, we report the design and development of a set of compounds bearing the glucosyl and galactosyl moieties. We assessed their ability to enhance the GLUT1 mediated glucose intake in non-small-cell lung Cancer (NSCLC) cells and to inhibit the Carbonic Anhydrase (CA; EC 4.2.1.1) isoforms implicated in the physiopathology of uncontrolled seizures associated to epilepsy (i.e., I, II, IV, VA, VB, and XII). The binding mode of 8 in adduct with hCA II was determined by X-ray crystallography. Among the selected derivatives, compound 4b proved effective in suppressing the occurrence of uncontrolled seizures on the in vivo induced maximal electroshock (MES) model and thus gives sustainment of an unprecedently reported pharmacological approach for the management of GLUT1-DS associated diseases.

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