Overexpression of the transmembrane carbonic anhydrase isoforms IX and XII in the inflamed synovium

Medicinal Research Reviews

2020

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188

166

Carbonic anhydrases (CAs, EC 4.2.1.1) are widely distributed metalloenzymes in both prokaryotes and eukaryotes. They efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate and H + ions and play a crucial role in regulating many physiological processes. CAs are wellstudied drug target for various disorders such as glaucoma, epilepsy, sleep apnea, and high altitude sickness. In the past decades, a large category of diverse families of CA inhibitors (CAIs) have been developed and many of them showed effective inhibition toward specific isoforms, and effectiveness in pathological conditions in preclinical and clinical settings. The discovery of isoform-selective CAIs in the last decade led to diminished side effects associated with off-target isoforms inhibition. The many new classes of such compounds will be discussed in the review, together with strategies for their development. Pharmacological advances of the newly emerged CAIs in diseases not usually associated with CA inhibition (neuropathic pain, arthritis, cerebral ischemia, and cancer) will also be discussed.

Section: Ra and Osteoporosismentioning

confidence: 99%

Progress in the development of human carbonic anhydrase inhibitors and their pharmacological applications: Where are we today?

Mishra

Tiwari

Medicinal Research Reviews

2020

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188

166

“…Many such enzymes from vertebrates, protozoa, fungi, and bacteria are well-known drug targets 1–13 , and their inhibitors possess pharmacologic applications, being clinically used for the management of glaucoma 1 , 14 , edema 1 , 15 , obesity 16 , epilepsy 17 , hypoxic tumors 1 , 2 , 18 , 19 , idiopathic intracranial hypertension 20 , etc. Ultimately, some human (h) CA isoforms have also been validated as drug targets for cerebral ischemia 21 , neuropathic pain 22 , and arthritis 23 , whereas many such enzymes present in pathogenic organisms may lead to the development of anti-infectives with a new mechanism of action 24 , 25 .…”

Section: Introductionmentioning

confidence: 99%

Carbon- versus sulphur-based zinc binding groups for carbonic anhydrase inhibitors?

Journal of Enzyme Inhibition and Medicinal Chemistry

2018

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110

A set of compounds incorporating carbon-based zinc-binding groups (ZBGs), of the type PhX (X = COOH, CONH2, CONHNH2, CONHOH, CONHOMe), and the corresponding derivatives with sulphur(VI)-based ZBGs (X = SO3H, SO2NH2, SO2NHNH2, SO2NHOH, SO2NHOMe) were tested as inhibitors of all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1), CA I–XV. Three factors connected with the ZBG influenced the efficacy as CA inhibitor (CAI) of the investigated compounds: (i) the pKa of the ZBG; (ii) its geometry (tetrahedral, i.e. sulphur-based, versus trigonal, i.e. carbon-based ZBGs), and (iii) orientation of the organic scaffold induced by the nature of the ZBG. Benzenesulphonamide was the best inhibitor of all isoforms, but other ZBGs led to interesting inhibition profiles, although with an efficacy generally reduced when compared to the sulphonamide. The nature of the ZBG also influenced the CA inhibition mechanism. Most of these derivatives were zinc binders, but some of them (sulfonates, carboxylates) may interact with the enzyme by anchoring to the zinc-coordinated water molecule or by other inhibition mechanisms (occlusion of the active site entrance, out of the active site binding, etc.). Exploring structurally diverse ZBGs may lead to interesting new developments in the field of CAIs.

“…Recently Margheri et al . reported that CA IX and XII are overexpressed in the synovial fluid of patients with juvenile idiopathic arthritis, whereas in normal controls this overexpression does not occur.…”

Section: Therapeutic Applications Of Carbonic Anhydrase IX Inhibitorsmentioning

confidence: 99%

“…Recently Margheri et al 288 reported that CA IX and XII are overexpressed in the synovial fluid of patients with juvenile idiopathic arthritis, whereas in normal controls this overexpression does not occur. This was the starting point for investigating whether inhibition of CA IX (and XII) in animal models of arthritis may be a useful and innovative approach for the pharmacological intervention.…”

Section: Antiarthritis Agentsmentioning

confidence: 99%

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

Medicinal Research Reviews

Alterio

Fiore

et al. 2018

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217

160

Human carbonic anhydrase (CA) IX is a tumor-associated protein, since it is scarcely present in normal tissues, but highly overexpressed in a large number of solid tumors, where it actively contributes to survival and metastatic spread of tumor cells. Due to these features, the characterization of its biochemical, structural, and functional features for drug design purposes has been extensively carried out, with consequent development of several highly selective small molecule inhibitors and monoclonal antibodies to be used for different purposes. Aim of this review is to provide a comprehensive state-of-the-art of studies performed on this enzyme, regarding structural, functional, and biomedical aspects, as well as the development of molecules with diagnostic and therapeutic applications for cancer treatment. A brief description of additional pharmacologic applications for CA IX inhibition in other diseases, such as arthritis and ischemia, is also provided.