Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms

Sharonova, Tatiana; Paramonova, Polina; Kalinin, Stanislav; Bunev, Alexander S.; Gasanov, Rovshan E.; Nocentini, Alessio; Sharoyko, Vladimir V.; Tennikova, Tatiana; Dar’in, Dmitry; Krasavin, Mikhail

doi:10.1016/j.ejmech.2021.113352

Cited by 8 publications

(5 citation statements)

References 72 publications

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“…Most HCAs, including HCA II, are unstable below pH 5.0. Recent research on HCAs thus emphasizes the isozyme specific inhibition of HCA IX by novel molecules at nano- to picomolar concentrations ,− for optimum therapeutic applications. However, a molecular level understanding of the observed pH dependence of activity of HCA II and IX is largely incomplete.…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

2022

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Human carbonic anhydrases (HCAs) are responsible for the pH control and sensing in our body and constitute key components in the central pH paradigm connected to cancer therapeutics. However, little or no molecular level studies are available on the pH-dependent stability and functional dynamics of the known isozymes of HCA. The main objective of this Article is to report the first bench-marking study on the structure and dynamics of the two most efficient isozymes, HCA II and IX, at neutral pH using classical molecular dynamics (MD) and constant pH MD (CpHMD) simulations combined with umbrella sampling, transition path sampling, and Markov state models. Starting from the known crystal structures of HCA II and the monomeric catalytic domain of HCA IX (labeled as HCA IX-c), we have generated classical MD and CpHMD trajectories (of length 1 μs each). In all cases, the overall stability, RMSD, and secondary structure segments of the two isozymes are found to be quite similar. Functionally important dynamics of these two enzymes have been probed in terms of active site hydration, coordination of the Zn(II) ion to a transient excess water, and the formation of putative proton transfer paths. The most important difference between the two isozymes is observed for the side-chain fluctuations of His-64 that is expected to shuttle an excess proton out of the active site as a part of the rate-determining intramolecular proton transfer reaction. The relative stability of the stable inward and outward conformations of the His-64 side-chain and the underlying free energy surfaces are found to depend strongly on the isozyme. In each case, a lower free energy barrier is detected between predominantly inward conformations from predominantly outward ones when simulated under constant pH conditions. The kinetic rate constants of interconversion between different free energy basins are found to span 10 7 –10 8 s –1 with faster conformational transitions predicted at constant pH condition. The estimated rate constants and free energies are expected to validate if the fluctuation of the His-64 side-chain in HCA IX may have a significance similar to that known in the multistep catalytic cycle of HCA II.

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Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

2022

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“…The special features of the spatial structure of these diazo molecules suggests significant differences in their chemical behavior from classical vinyl diazocarbonyl reagents. We and others have already shown that, in addition to the transformations which are typical of diazocarbonyl compounds (e.g., XH-insertion), DAS enter into some less typical reactions; in particular, they form products of formal insertion into the C–O bond of ethers and S–S bond of cyclic disulfides . Recently, Bhat and Laha observed the formation of spirooxiranes upon Ag(I)-catalyzed interaction of DAS with aromatic aldehydes (Scheme , a) .…”

Section: Introductionmentioning

confidence: 99%

Diastereoselective Formal [5+2] Cycloaddition of Diazo Arylidene Succinimides-Derived Rhodium Carbenes and Aldehydes: A Route to 2-Benzoxepines

Inyutina

Kantin

et al. 2021

J. Org. Chem.

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We report on a facile method for the preparation of 2-benzoxepine derivatives as a result of Rh(II)-catalyzed decomposition of diazo arylidene succinimides in the presence of aldehydes. The process is thought to involve the formation of styryl carbonyl ylide which undergoes 1,7-electrocyclization and subsequent 1,5-hydrogen shift. In some cases, the competition of the target reaction and [3+2] dipolar cycloaddition of the intermediate carbonyl ylide to another molecule of diazo substrate was observed. Generally, the desired 2-benzoxepines were isolated in good to high yields and high diastereoselectivity. The developed original approach toward a 2-benzoxepine core via formal [5+2] cycloaddition of styryl carbenoids and aldehydes significantly expands the arsenal of synthetic methods for producing this scaffold.

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“…In our current study, we explored the potential of both the commercial pan-isoform CA inhibitor acetazolamide (AAZ) and a series of CA-inhibitory small molecules developed inhouse, referred to as Inh1-10 [ [19][20][21][22], in the context of sarcoma treatment (for structures and K i values against some therapeutically relevant CA isoforms, see SI, Table S1). Interestingly, we found that AAZ actually enhances invasion and vimentin expression in Ewing sarcoma tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells

Fayzullina,

Yakushov,

Kantserova

et al. 2023

Cancers

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Ewing sarcoma (ES) is one of the most frequent types of malignant tumors among children. The active metabolic state of ES cells presents a new potential target for therapeutic interventions. As a primary regulator of cellular homeostasis, carbonic anhydrases (CAs; EC 4.2.1.1) have emerged as promising molecular targets for the development of anticancer drugs. Within the present study, we tested the commercial drug acetazolamide and our previously discovered inhibitors to target the CAII isoform, which was overexpressed and positively correlated with ES patient relapse. We employed molecular biology tests to identify effective inhibitors of CAII that can induce ferroptosis by downregulating FTH1 expression in ES cells. In vitro, we have also demonstrated their ability to reduce cell proliferation, decrease invasion, and induce apoptosis- or autophagy-related cell death. Using Western blotting, we confirmed the induction of cathepsin B in cells treated with CA inhibitors. It was found that the suppression of cathepsin B expression during the treatment reduces the anticancer efficacy of selected CAII inhibitors. These experiments highlighted profound antitumor activity of CAII inhibitors attributive to their remarkable ability to trigger ferroptosis in Ewing sarcoma cells without causing substantial host damage. The obtained results suggest that cytosolic CAII may be a prospective target for ES treatment, and CAII inhibitors can be considered as potential single-agent or combination antitumor agents to be used in the treatment of ES.

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Insertion of metal carbenes into the anilinic N–H bond of unprotected aminobenzenesulfonamides delivers low nanomolar inhibitors of human carbonic anhydrase IX and XII isoforms

Cited by 8 publications

References 72 publications

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

Diastereoselective Formal [5+2] Cycloaddition of Diazo Arylidene Succinimides-Derived Rhodium Carbenes and Aldehydes: A Route to 2-Benzoxepines

Carbonic Anhydrase Inhibitors Induce Ferroptosis through Inhibition of AKT/FTH1 Signaling in Ewing Sarcoma Tumor Cells

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