Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain

Akgül, Özlem; Lucarini, Elena; Mannelli, Lorenzo Di Cesare; Ghelardini, Carla; D’Ambrosio, Katia; Buonanno, Martina; Monti, Simona Maria; Simone, Giuseppina De; Angeli, Andrea; Carta, Fabrizio

doi:10.1016/j.ejmech.2021.113956

Cited by 12 publications

(9 citation statements)

References 39 publications

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“…CAIs’ efficacy against rheumatoid arthritis has emerged [ 9 , 10 , 11 ] as well as against visceral pain, and in this experiment, the CAI IV isoform has been revealed as the main actor to counteract the development of colitis in rats [ 12 ]. Moving to neuropathies induced by chemotherapeutic drugs, CAIs have been observed to possess anti-neuropathic properties in particular against oxaliplatin-induced neurotoxicity [ 13 , 14 , 33 ]. Nevertheless, no information is available regarding the pain relieving properties of CAIs against paclitaxel-induced neurotoxicity.…”

Section: Resultsmentioning

confidence: 99%

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Micheli

Testai

Angeli

et al. 2022

IJMS

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Neuropathy development is a major dose-limiting side effect of anticancer treatments that significantly reduces patient’s quality of life. The inadequate pharmacological approaches for neuropathic pain management warrant the identification of novel therapeutic targets. Mitochondrial dysfunctions that lead to reactive oxygen species (ROS) increase, cytosolic Ca2+ imbalance, and lactate acidosis are implicated in neuropathic pain pathogenesis. It has been observed that in these deregulations, a pivotal role is played by the mitochondrial carbonic anhydrases (CA) VA and VB isoforms. Hence, preclinical studies should be conducted to assess the efficacy of two novel selenides bearing benzenesulfonamide moieties, named 5b and 5d, and able to inhibit CA VA and VB against paclitaxel-induced neurotoxicity in mice. Acute treatment with 5b and 5d (30–100 mg/kg, per os – p.o.) determined a dose-dependent and long-lasting anti-hyperalgesic effect in the Cold plate test. Further, repeated daily treatment for 15 days with 100 mg/kg of both compounds (starting the first day of paclitaxel injection) significantly prevented neuropathic pain development without the onset of tolerance to the anti-hyperalgesic effect. In both experiments, acetazolamide (AAZ, 100 mg/kg, p.o.) used as the reference drug was partially active. Moreover, ex vivo analysis demonstrated the efficacy of 5b and 5d repeated treatments in reducing the maladaptive plasticity that occurs to glia cells in the lumbar portion of the spinal cord and in improving mitochondrial functions in the brain and spinal cord that were strongly impaired by paclitaxel-repeated treatment. In this regard, 5b and 5d ameliorated the metabolic activity, as observed by the increase in citrate synthase activity, and preserved an optimal mitochondrial membrane potential (ΔΨ) value, which appeared depolarized in brains from paclitaxel-treated animals. In conclusion, 5b and 5d have therapeutic and protective effects against paclitaxel-induced neuropathy without tolerance development. Moreover, 5b and 5d reduced glial cell activation and mitochondrial dysfunction in the central nervous system, being a promising candidate for the management of neuropathic pain and neurotoxicity evoked by chemotherapeutic drugs.

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Section: Resultsmentioning

confidence: 99%

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Micheli

Testai

Angeli

et al. 2022

IJMS

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“…The ubiquitous metalloenzymes carbonic anhydrases (CAs) [ 1 , 2 , 3 , 4 , 5 , 6 ] are present in bacteria [ 7 , 8 ] and fungi [ 9 , 10 , 11 , 12 ], plants and animals. Inhibitors of these enzymes have been clinically exploited for decades, and the discovery of multiple human isoforms [ 13 , 14 , 15 , 16 , 17 , 18 ] has led to many new applications and the development of new therapeutic principles, among them antiglaucoma [ 19 , 20 , 21 ] and antitumor drugs but also antiepileptic [ 22 , 23 , 24 , 25 , 26 ] and antiobesity drugs [ 27 , 28 , 29 ] as well as agents for the management of Alzheimer’s disease [ 30 , 31 ], neuropathic pain, cerebral ischemia, and some forms of arthritis [ 32 , 33 , 34 ]. Furthermore, the development of inhibitors for bacterial carbonic anhydrases is thought as a new concept to develop antibacterial drugs [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”

Section: Introductionmentioning

confidence: 99%

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates

et al. 2023

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Acetylated triterpenoids betulin, oleanolic acid, ursolic acid, and glycyrrhetinic acid were converted into their succinyl-spacered acetazolamide conjugates. These conjugates were screened for their inhibitory activity onto carbonic anhydrase II and their cytotoxicity employing several human tumor cell lines and non-malignant fibroblasts. As a result, the best inhibitors were derived from betulin and glycyrrhetinic acid while those derived from ursolic or oleanolic acid were significantly weaker inhibitors but also of diminished cytotoxicity. A betulin-derived conjugate held a Ki = 0.129 μM and an EC50 = 8.5 μM for human A375 melanoma cells.

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“…CA inhibitors can be used for the development of anti-infective agents (CAs are responsible for the survival and virulence of certain pathogens) [ 38 ], for the treatment of glaucoma [ 39 ], cerebral ischemia [ 40 ], rheumatoid arthritis [ 41 ], obesity [ 42 ], neuropathic pain [ 43 ], epilepsy [ 44 ], or cancer [ 45 ]; in this context, it is important to highlight that CA IX and XII are overexpressed in numerous tumors, where they control the microenvironment pH (acidification of the extracellular medium) [ 46 ] and certain metabolic processes connected to tumor growth and metastasis [ 47 ]. Recent evidence also correlates CA inhibition with neuroprotective effects in Alzheimer’s disease [ 48 ].…”

Section: Introductionmentioning

confidence: 99%

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

Arrighi

Puerta

Petrini

et al. 2022

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(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions.

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Sultam based Carbonic Anhydrase VII inhibitors for the management of neuropathic pain

Cited by 12 publications

References 39 publications

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates

Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations

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