Carbonic anhydrase inhibitors as emerging agents for the treatment and imaging of hypoxic tumors

Expert Opinion on Investigational Drugs, Journal Year: 2018, Volume and Issue: 27(12), P. 963 - 970

Published: Nov. 14, 2018

Introduction: Hypoxic tumors overexpress two carbonic anhydrases (CA, EC 4.2.1.1), CA IX and XII, involved in complex processes connected to tumorigenesis (pH regulation, metabolism, invasion, dissemination of the tumor). The biochemical rationale behind these is orchestrated by transcription factor hypoxia inducible 1 (HIF-1).Areas covered: XII have been validated as antitumor/antimetastatic drug targets may be used for imaging hypoxic tumors. Many inhibitors (CAIs) belonging sulfonamide, coumarin sulfocoumarin classes selectively inhibit isoforms. IX/XII growth primary formation metastases deplete cancer stem cell population, alone or combination with other agents. These are three beneficial antitumor mechanisms that make them unique among anticancer drugs available.Expert opinion: Indisulam entered clinical trials an sulfonamide; it progressed Phase II but was terminated 2016. However, SLC-0111, a sulfonamide inhibitor 1, recently completed successful I trial treatment advanced, metastatic solid This compound now Ib/II being assessed monotherapy agents such gemcitabine. synergistic (cisplatin, proton pump inhibitors, doxorubicin, temozolamide) versatile, emerging class drugs.

Language: Английский

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Benzothiazole derivatives as anticancer agents

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2019, Volume and Issue: 35(1), P. 265 - 279

Published: Dec. 2, 2019

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The scaffolds showed a crucial role in inhibition metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over last decade discloses mainly anticancer agents. Such compounds are effective against various types cancer cell lines through multitude mechanisms, some which poorly studied or understood. tumour associated CAs by is on other hand better investigated may serve leads for development agents hypoxic tumours.

Language: Английский

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Carbonic anhydrase inhibitors as antitumor/antimetastatic agents: a patent review (2008–2018)

Expert Opinion on Therapeutic Patents, Journal Year: 2018, Volume and Issue: 28(10), P. 729 - 740

Published: Aug. 3, 2018

Introduction: Human carbonic anhydrases (CA, EC 4.2.1.1) IX and XII are tumor-associated proteins, being part of the molecular machinery that tumor cells build as adaptive responses to hypoxia acidic conditions characteristic ‘glycolytic shift’ many tumors. A wealth research depicts CA biomarkers therapeutic targets for various cancer types.Areas covered: The review presents an overview role in hypoxic tumors physio-pathology well principal molecular, structural, catalytic features both isozymes. then covers patent literature medically relevant inhibitors CAs produced during period 2008–2018.Expert opinion: variety approaches design strategies were reported which afford IX/XII-specific avoid compromising effects isoforms-promiscuous compounds. Access crystal structures human isoforms have improved structure-based drug campaigns related zinc-binder chemotypes. Nevertheless, great potential still resides non-classical CAIs exhibit alternative binding mechanisms able further distinguish active sites architecture. hybrids/conjugates increasingly emerging field promising tools combine inhibition anticancer other moieties or antitumor drugs.

Language: Английский

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Carbonic anhydrase inhibitors and their potential in a range of therapeutic areas

Expert Opinion on Therapeutic Patents, Journal Year: 2018, Volume and Issue: 28(10), P. 709 - 712

Published: Sept. 16, 2018

KEYWORDS: Carbonic anhydraseinhibitoractivatordiureticsulfonamideepilepsysleep apneaneuropathic paincerebral ischemiacancermetastasisanti-infectivesbacterial enzymes

Language: Английский

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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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Advances in the structural annotation of human carbonic anhydrases and impact on future drug discovery

Expert Opinion on Drug Discovery, Journal Year: 2019, Volume and Issue: 14(11), P. 1175 - 1197

Published: Aug. 22, 2019

Introduction: Of the 15 human carbonic anhydrase (CA, EC 4.2.1.1) isoforms known to date, for 11 crystal structure is known. Many different classes of CA inhibitors (CAIs) were reported in last decade, with a wealth inhibition mechanisms, where apart from classical one, do not bind zinc ion active site. The binders (sulfonamides, dithiocarbamates and their isosteres, thiols, selenols, carboxylates, hydroxamates, carbamates) are isoform-selective inhibitors, but specificity action may be achieved by decorating scaffolds tails that interact amino acids at entrance site.Areas covered: Herein, authors review advances structural annotation CAs. Furthermore, look impact on drug discovery efforts as well providing expert perspectives.Expert opinion: CAs unique example among metalloenzymes which all regions spacious sites used inhibitor/activator binding, leading variety mechanisms profiles many chemotypes modulating activity. This exploited design increasingly efficient useful pharmacological applications.

Language: Английский

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Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Metabolites, Journal Year: 2020, Volume and Issue: 10(10), P. 412 - 412

Published: Oct. 14, 2020

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence outcome anticancer therapies. rationale behind many these phenomena resides in activation transcription factors such as hypoxia-inducible factor 1 2 (HIF-1/2). In turn, HIF pathway activates a number genes including those involved glucose metabolism, angiogenesis, pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, CA IX XII, actively participate processes were validated antitumor/antimetastatic drug targets. Here, we review field inhibitors (CAIs), selectively inhibit cancer-associated isoforms. Particular focus was on identification lead compounds various inhibitor classes, measurement inhibitory on-/off-target effects. addition, preclinical data that resulted SLC-0111, sulfonamide Phase Ib/II clinical trials treatment hypoxic, advanced solid tumors, are detailed.

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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Investigation of inhibitory properties of some hydrazone compounds on hCA I, hCA II and AChE enzymes

Bioorganic Chemistry, Journal Year: 2019, Volume and Issue: 86, P. 316 - 321

Published: Feb. 4, 2019

Language: Английский

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Carbonic anhydrase 9 confers resistance to ferroptosis/apoptosis in malignant mesothelioma under hypoxia

Redox Biology, Journal Year: 2019, Volume and Issue: 26, P. 101297 - 101297

Published: Aug. 10, 2019

Hypoxia and acidity provide microenvironment for selection under evolutionary pressure proliferation in cancer cells. Carbonic anhydrases (CAs) are a superfamily of metalloenzymes present all life kingdoms, equilibrating the reactions among CO2, bicarbonate H+. CA9, membrane-associated α-CA, has been drug target various cancers. Whereas iron is essential not only cells but also lives on earth, little known association hypoxia, metabolism, extracellular redox regulation. Malignant mesothelioma (MM), an aggressive tumor with poor prognosis, intriguing model that asbestos-associated pathogenesis includes excess environment during carcinogenesis. Re-analysis rat asbestos-induced MM revealed inverse between high CA9 expression survival. Here we used human MMs to identify molecular events surrounding from viewpoint metabolism. was significantly higher than MeT-5A mesothelial cells, which further amplified hypoxia (1%O2) increased catalytic Fe(II). suppression by inhibitors (S4 U104) decreased viability migration accompanied overexpression TFRC, IREB1/2 FPN1(SLC40A1) downregulation FTH/FTL. This expressional pattern similar erastin-induced ferroptosis same Furthermore, observed mitochondrial fission enhanced autophagy Fe(II) both mitochondria lysosomes after inhibition, peroxides, O2- lipid peroxidation. The eventual cell death inhibited deferoxamine, ferrostatin-1 Z-VAD-FMK, suggesting mixed apoptosis. Therefore, plays role metabolism regulation

Language: Английский

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