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

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.

Novel Carbonic Anhydrase Inhibitors with Dual-Tail Core Sulfonamide Show Potent and Lasting Effects for Glaucoma Therapy

“…To elucidate the molecular underpinnings of CA inhibition by our derivatives, we determined the X-ray structures of hCA II in complex with compounds 25a , 25f , 26a , and 14b , the latter interacting with an engineered hCA II protein designed to mimic the active site of hCA XII (Figure ). In all studied inhibitors, a well-defined electron density map (Figure S1) inside the active site showed the benzene­sulfon­amide directly binds to the zinc ion, featuring the characteristic deprotonated sulfonamide group typical to this compound class , (Figure ). Moreover, we observed a hydrogen bond between the amide backbone of Thr199 and one of the sulfonamide oxygen, along with hydrophobic interactions involving the side chains of Val121 and Leu198, stabilizing the benzene­sulfon­amide moiety within the active site.…”

The dopamine D2 receptors antagonist Veralipride inhibits carbonic anhydrases: solution and crystallographic insights on human isoforms

“…[24] K group, characteristic typical of this compound class (Figure 2 and 3). [25] In the hCA I complex with Veralipride, one of the oxygen atoms of the sulfonamide group forms a hydrogen bond with the backbone amide of Thr199 (Figure 2B). Additionally, the benzenesulfonamide is engaged in several van der Waals interactions with the side chains of Ala121, Val143, and Leu198.…”

Discovery of a New Class of 1-(4-Sulfamoylbenzoyl)piperidine-4-carboxamides as Human Carbonic Anhydrase Inhibitors

“…Currently 15 CAs have been discovered and described in humans and are involved in several physiological and biochemical processes, such as pH homeostasis, gluco­neogenesis, liquid secretion, and tumor­genicity. The active site of human CAs (hCAs) contains zinc ions in a tetrahedral geometric shape, coordinated by three amino acid residues, H94, H96, and H119, in addition to a H 2 O molecule or OH – ion. − The hCA IX and hCA XII isoenzymes have been deeply studied due to their important role in cancer cell survival. − Although small metabolic changes are tolerated in cancer cells, strong pH control is necessary for their survival and proliferation . Hydrogen carbonate ions, which are important pH buffers, are imported by transporters such as Cl – /HCO 3 – anion exchanger and Na + /HCO 3 – co-transporter, consuming cytosolic protons to give a new molecule of CO 2 which leaves the cytoplasm to be hydrated by hCA IX and XII .…”