Emerging role of carbonic anhydrase inhibitors

Clinical Science, Journal Year: 2021, Volume and Issue: 135(10), P. 1233 - 1249

Published: May 1, 2021

Abstract Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) was clinically exploited for decades, as most modern diuretics were obtained considering lead molecule acetazolamide, the prototypical CA inhibitor (CAI). The discovery and characterization multiple human (hCA) isoforms, 15 which being known today, led to new applications their inhibitors. They include widely used antiglaucoma, antiepileptic antiobesity agents, antitumor drugs in clinical development, well management acute mountain sickness idiopathic intracranial hypertension (IIH). Emerging roles several isoforms areas not generally connected these enzymes recently documented, such neuropathic pain, cerebral ischemia, rheumatoid arthritis, oxidative stress Alzheimer’s disease. Proof-of-concept studies thus emerged by using isoform-selective inhibitors, may areas. Relevant preclinical models are available pathologies due availability CAIs all belonging novel classes compounds, coumarins, sulfocoumarins, dithiocarbamates, benzoxaboroles, apart classical sulfonamide inhibition CAs from pathogenic bacteria, fungi, protozoans or nematodes started be considered obtaining anti-infectives with a mechanism action.

Language: Английский

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The importance of sulfur-containing motifs in drug design and discovery

Expert Opinion on Drug Discovery, Journal Year: 2022, Volume and Issue: 17(5), P. 501 - 512

Published: Feb. 23, 2022

Sulfur-containing functional groups are privileged motifs that occur in various pharmacologically effective substances and several natural products. Various functionalities found with a sulfur atom at diverse oxidation states, as illustrated by thioether, sulfoxide, sulfone, sulfonamide, sulfamate, sulfamide functions. They valuable scaffolds the field of medicinal chemistry part large array approved drugs clinical candidates.Herein, authors review current research on development organosulfur-based drug discovery. This article also covers details their roles new lead compounds reported literature over past five years 2017-2021.Given its prominent role importance discovery, has attracted continuing interest been used design demonstrate variety biological pharmacological feature activities. Overall, sulfur's continues to grow. However, many remain underused small-molecule discovery deserve special attention armamentarium for treating diseases. Research efforts still required synthetic methodology direct access these functions late-stage functionalization.

Language: Английский

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Exploration of 1,2,3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase

Bioorganic & Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 77, P. 117111 - 117111

Published: Nov. 29, 2022

Language: Английский

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Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1278 - 1298

Published: May 4, 2022

Carbonic anhydrases IX and CAXII (CAIX/CAXII) are transmembrane zinc metalloproteins that catalyze a very basic but crucial physiological reaction: the conversion of carbon dioxide into bicarbonate with release proton. CA, especially CAIX isoforms gained attention many researchers interested in anticancer drug design due to pivotal functions enzymes cancer cell metastasis response hypoxia, their expression restricted malignant cells. This offers an opportunity develop new targeted therapies fewer side effects. Continuous efforts led discovery series diverse compounds most abundant sulphonamide derivatives. Here we review current knowledge considering small molecule antibody-based targeting CAIX/CAXII cancer.

Language: Английский

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

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 93, P. 129411 - 129411

Published: July 27, 2023

Language: Английский

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Carbonic anhydrase IX: An atypical target for innovative therapies in cancer

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(4), P. 189120 - 189120

Published: May 25, 2024

Carbonic anhydrases (CAs), are metallo-enzymes implicated in several pathophysiological processes where tissue pH regulation is required. CA IX a tumor-associated isoform induced by hypoxia and involved the adaptation of tumor cells to acidosis. Indeed, tumor-driving pathways can induce expression, this turn has been associated cancer invasion metastatic features as well induction stem-like features, drug resistance recurrence. After its functional structural characterization targeting approaches have developed inhibit activity neoplastic tissues, date field seen an incredible acceleration terms therapeutic options biological readouts. Small molecules inhibitors, hybrid/dual drugs, antibodies adoptive (CAR-T based) cell therapy at preclinical level, whereas sulfonamide inhibitor antibody entered Phase Ib/II clinical trials for treatment imaging different solid tumors. Here recent advances on biology pharmacology cancer, will be discussed.

Language: Английский

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Synthesis, biological evaluation, and in silico studies of phenyl naphthalene-2-sulfonate derived thiosemicarbazones as potential carbonic anhydrase inhibitors

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 155, P. 108118 - 108118

Published: Jan. 4, 2025

Language: Английский

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Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 36(1), P. 561 - 580

Published: Jan. 1, 2021

Inorganic anions inhibit the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) generally by coordinating to active site metal ion. Cyanate was reported as a non-coordinating CA inhibitor but those erroneous results were subsequently corrected another group. We review anion inhibitors (CAIs) in more general context of drug design studies and discovery large number classes inhibition mechanisms, including zinc binders (sulphonamides isosteres, dithiocabamates thiols, selenols, benzoxaboroles, ninhydrins, etc.); anchoring zinc-coordinated water molecule (phenols, polyamines, sulfocoumarins, thioxocoumarins, catechols); CAIs occluding entrance (coumarins derivatives, lacosamide), well compounds that bind outside site. All these new chemotypes integrated with procedure for obtaining isoform-selective (the tail approach) has resulted, through guidance rigorous X-ray crystallography experiments, development highly selective all human isoforms many pharmacological applications.

Language: Английский

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<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

Journal of Experimental Pharmacology, Journal Year: 2020, Volume and Issue: Volume 12, P. 603 - 617

Published: Dec. 1, 2020

Abstract: Carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are overexpressed in many hypoxic tumors as a consequence of the hypoxia inducible factor (HIF) activation cascade, being present limited amounts normal tissues. These enzymes together with others involved pH regulation metabolism cancer cells, were validated antitumor targets recently. A multitude targeting strategies against these have been proposed reviewed this article. The small molecule inhibitors, drug conjugates (SMDCs), antibody-drug (ADACs) or cytokine-drug but not monoclonal antibodies CA IX/XII will be discussed. Relevant synthetic chemistry efforts, coupled preclinical studies, demonstrated that inhibition leads to growth primary metastases depletes stem cell populations, all factors highly relevant clinical settings. One inhibitor, sulfonamide SLC-0111, is most advanced candidate, having completed Phase I now Ib/II trials for treatment solid tumors. Keywords: carbonic anhydrase, hypoxia, conjugates, anticancer drug, SLC-0111

Language: Английский

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Carbonic anhydrase inhibitors: an update on experimental agents for the treatment and imaging of hypoxic tumors

Expert Opinion on Investigational Drugs, Journal Year: 2021, Volume and Issue: 30(12), P. 1197 - 1208

Published: Dec. 2, 2021

Hypoxic tumors, unlike normal tissues, overexpress proteins involved in oxygen sensing, metabolism, pH regulation, angiogenesis, immunological response, and other survival mechanisms, which are under investigation as antitumor drug targets.Carbonic anhydrase (CA) isoforms CA IX XII among these validated antitumor/antimetastatic targets, with several of their inhibitors undergoing preclinical or clinical-stage investigations. Alone combination chemotherapeutic agents radiotherapy, IX/XII inhibitors, such SLC-0111, SLC-149, S4, 6A10, etc., were shown to inhibit the growth primary tumor, metastases, invasiveness many tumor types, being also amenable for development imaging agents.SLC-0111 is most investigated agent, Phase Ib/II clinical trials. In addition its interference extracellular acidifications, it has been promote ferroptosis cancer cells, another mechanism this compound entire class. A large number sulfonamide non-sulfonamide have developed using SLC-0111 lead last three years, together hybrid incorporating anticancer chemotypes, including cytotoxins, telomerase, thioredoxin P-glycoprotein adenosine A2A receptor antagonists, pyrophosphatase/phosphodiesterase-3 antimetabolites. All them showed significant activity.

Language: Английский

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