A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation

Supuran, Claudiu T.

doi:10.1016/j.bmcl.2023.129411

Cited by 55 publications

(20 citation statements)

References 504 publications

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“…[2] Among the appealing avenues for the development of these innovative anticancer agents lies the realm of carbonic anhydrase isoenzymes. [3][4][5] Carbonic anhydrases (CAs, EC 4.2.1.1), classified as metalloenzymes, play a pivotal role in modulating the equilibrium between carbon dioxide and bicarbonate ions through a hydration-dehydration mechanism. [6][7][8] While seemingly straightforward, this physiological reaction is pivotal and underpins various essential processes, encompassing CO 2 and pH homeostasis, respiratory functions, gluconeogenesis, calcification, bone remodeling, fluid secretion, and even the intricate mechanisms of tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Yapar,

Lolak,

Bonardi

et al. 2024

ChemMedChem

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This study introduces a series of ten hybrid molecules DK(1‐10), which combine diazo and coumarin moieties along with diverse aromatic substitutions. The primary objective was to evaluate the inhibitory capabilities of these compounds against four prominent isoforms: the cytosolic hCA I and II, as well as the tumor‐associated membrane‐bound hCA IX and XII. Impressively, the majority of the tested compounds exhibited significant inhibition activity against the tumor‐associated isoforms hCA IX and XII, with KI values ranging from 29.2 to 293.3 nM. Notably, compound DK‐8 displayed particularly robust inhibitory activity against the tumor‐associated membrane‐bound isoforms, hCA IX and XII, yielding KI values of 32.5 and 29.2 nM, respectively. Additionally, another derivative, DK‐9, containing a primary sulfonamide, exhibited notable inhibition against hCA XII with a KI value of 36.4 nM. This investigation aimed to explore the structure‐activity relationships within these compounds, shedding light on how various substitutions and structural components influence their inhibitory potential. As a result, these compounds present promising candidates for further exploration in medicinal and pharmacological research. Their ability to selectively inhibit specific isoforms, particularly those associated with hypoxic tumors, suggests their potential as foundational compounds for the development of novel therapeutic agents.

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Section: Introductionmentioning

confidence: 99%

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Yapar,

Lolak,

Bonardi

et al. 2024

ChemMedChem

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“…Overexpression of this protein on the cell surface of solid tumors is associated with hypoxia, which is regulated by the transcription factor HIF-1α. Furthermore, CA IX overexpression is frequently associated with poor reactivity to conventional radio- and chemotherapies. , Strived by the formerly reported findings, tremendous efforts have been made to develop potent and selective hCA IX inhibitors. Acetazolamide (AAZ) is the best-known such pharmacological agent (hCA IX; K I = 0.025 μM).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

Hefny,

El-Moselhy,

El-Din

et al. 2024

J. Med. Chem.

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A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles (5a−h, 6, and 7a−e) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a, 5d, and 5e can effectively inhibit both targets. 5a, 5d, and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3). Further mechanistic investigation disclosed the ability of 5e to interrupt the PANC1 cell progression in the S stage by triggering the apoptotic cascade, as seen by increased levels of caspases 3, 9, and BAX, alongside the Bcl-2 decline. Moreover, the in vivo efficacy of compound 5e as an antitumor agent was evaluated. Also, molecular docking and dynamics displayed distinctive interactions between 5e and CA IX and VEGFR-2 binding pockets.

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“…[10][11][12] These metalloenzymes are found in diverse organisms ranging from bacteria to archaea and vertebrates and they play a pivotal role in regulating acid-base balance and maintaining physiological pH, in several metabolic pathways and CO 2 / bicarbonate sensing. [13][14][15] The primary function of CAs is to catalyze the reversible hydration of carbon dioxide (CO 2 ) to bicarbonate ion (HCO 3 À ) and a proton (H + ), a critical step in numerous physiological processes. [16,17] Structurally, the several classes of CAs exhibit remarkable diversity and, in humans, 15 isoforms are identified with various tissues and cellular distribution.…”

Section: Introductionmentioning

confidence: 99%

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

Angeli,

Ferraroni,

Capasso

et al. 2024

Chemistry An Asian Journal

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The inhibitory effects of veralipride, a benzamide‐class antipsychotic acting as dopamine D2 receptors antagonist incorporates a primary sulfonamide moiety and was investigated for its interactions with carbonic anhydrase (CA) isoforms. In vitro profiling using the stopped‐flow technique revealed that veralipride exhibited potent inhibitory activity across all tested hCA isoforms, with exception of hCA III. Comparative analysis with standard inhibitors, acetazolamide (AAZ), and sulpiride, provided insights for understanding the relative efficacy of veralipride as CA inhibitor. The study reports the X‐ray crystal structure analysis of the veralipride adduct with three human (h) isoforms, hCA I, II, and CA XII mimic, allowing the understanding of the molecular interactions rationalizing its inhibitory effects against each isoform. These findings contribute to our understanding of veralipride pharmacological properties and for the design of structural analogs endowed with polypharmacological properties.

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A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation

Cited by 55 publications

References 504 publications

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

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

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A simple yet multifaceted 90 years old, evergreen enzyme: Carbonic anhydrase, its inhibition and activation

Cited by 55 publications

References 504 publications

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Exploring the potency of diazo‐coumarin containing hybrid molecules: Selective inhibition of tumor‐associated carbonic anhydrase isoforms IX and XII

Discovery and Mechanistic Studies of Dual-Target Hits for Carbonic Anhydrase IX and VEGFR-2 as Potential Agents for Solid Tumors: X-ray, In Vitro, In Vivo, and In Silico Investigations of Coumarin-Based Thiazoles

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

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