New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors

Combs, Jacob; Bozdağ, Murat; Cravey, Lochlin D.; Kota, Anusha; McKenna, Robert; Angeli, Andrea; Carta, Fabrizio; Supuran, Claudiu T.

doi:10.3390/molecules28020890

Cited by 6 publications

(6 citation statements)

References 25 publications

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“…Data on crystals of the complexes were collected using synchrotron radiation at the XRD2 beamline at Elettra Synchrotron (Trieste, Italy) with a wavelength of 1.000 Å and a DECTRIS Pilatus 6M detector. Data were integrated and scaled using the program XDS . Data processing statistics are shown in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2023

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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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Section: Methodsmentioning

confidence: 99%

“…Data were integrated and scaled using the program XDS. 43 Data processing statistics are shown in the Supporting Information.…”

Section: Synthesis Of 4-(3-(4-(((2s3r4s5s6r)-345-trihydroxy-6-(hydrox...mentioning

confidence: 99%

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

et al. 2023

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“…Moreover, other studies identified further benzenesulfonamides possessing high hCA IX/hCA XII and improvement isoform selectivity. [11][12][13] Apart from the common zinc binding site (H94, H96, H119, T199), for the different hCAs the active site is well characterized by two distinct areas opposed each other controlling the enrolment of CO 2 and subsequent release of HCO 3 À . In more detail, the hCA IX is schematically composed of two halves: (i) the hydrophobic area is essentially lined by L91, V131, L135 and P202 residues; (ii) the hydrophilic area includes R60, R62, H64, Q67, T69, E170.…”

Section: Introductionmentioning

confidence: 99%

“…Among them, the compound named SLC‐0111 completed Phase II clinical trials for the treatment of hypoxic tumours and as adjuvant agent in advanced solid tumours. Moreover, other studies identified further benzenesulfonamides possessing high hCA IX/hCA XII and improvement isoform selectivity [11–13] …”

Section: Introductionmentioning

confidence: 99%

Screening Campaign and Docking Investigations in Identifying New Hit Compounds as Inhibitors of Human Carbonic Anhydrases Expressed In Tumour Cells

Ricci,

Angeli,

Mancuso

et al. 2023

ChemMedChem

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The tumor‐expressed human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII have been extensively studied to develop anticancer agents targeting solid tumors in combined therapy. These CA isoforms are considered key factors in controlling tumor microenvironment (TME) of cancer lines that develop high metastatic activity. Herein, we report the discovery of potent hCA IX/hCA XII inhibitors that were disclosed through a screening campaign on an in‐house collection of arylsulfonamides preliminary tested toward other hCAs. Among them, the N‐(4‐sulfamoylphenyl)naphthalene‐2‐carboxamide (12) and N‐(4‐sulfamoylphenyl)‐3,4‐dihydroisoquinoline‐2(1H)‐carbothioamide (15) proved to be the most intriguing hCA IX/hCA XII inhibitors displaying favourable selectivity ratios over widespread hCA I and hCA II isoforms. To explore their binding mode, we conducted docking studies that described the poses of the best inhibitors in the catalytic site of hCA IX and hCA XII, thus suggesting the privileged pattern of interactions. These structural findings might further improve the knowledge for a successful identification of new sulfonamides as adjuvant agents in cancer management.

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“…The structure of SLC-0111, a selective hCA IX inhibitor in phase I/II clinical trials for the treatment of advanced metastatic hypoxic solid tumors, was recently employed in our group for the preparation of a new class of 4-sulfamoylbenzoylpiperidine analogs with the aim of obtaining potent and selective hCA IX and XII molecules. − With the intent to increase the knowledge about tail modification effects on the CA inhibitory activity and selectivity, in this study we present a small library of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamide derivatives (Figure ). In these compounds, the benzenesulfonamide group is connected through a carbonyl group to a piperidine ring, facing the two tails with both the hydrophilic and hydrophobic regions of the active site.…”

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confidence: 99%

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

Moi,

Vittorio,

Angeli

et al. 2024

ACS Med. Chem. Lett.

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A series of 1-(4-sulfamoylbenzoyl)piperidine-4-carboxamides deriving from substituted piperazines/benzylamines was designed, synthesized, and tested on human carbonic anhydrase (hCA). The inhibitory activity of the new sulfonamides was analyzed using acetazolamide (AAZ) as a standard inhibitor against hCA I, II, IX, and XII. Several sulfonamides showed both inhibitory activity at low nanomolar concentrations and selectivity against the cytosolic hCA II isoform, and the same trend was observed on the tumor-associated hCA IX and XII. The benzenesulfonamido carboxamides 11 and 15 were the most potent of the piperazino- and benzylamino-based series, respectively. Docking and molecular dynamics studies related the high selectivity of compound 11 toward the tumor-associated hCA isoforms to its capability to participate in favorable interactions within hCA IX and hCA XII active sites, whereas no such interactions were detected within both hCA I and hCA II isoforms.

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New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors

Cited by 6 publications

References 25 publications

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

Screening Campaign and Docking Investigations in Identifying New Hit Compounds as Inhibitors of Human Carbonic Anhydrases Expressed In Tumour Cells

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

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