Carbonic Anhydrase Inhibitors:  Synthesis and Inhibition of Cytosolic/Membrane-Associated Carbonic Anhydrase Isozymes I, II, and IX with Sulfonamides Incorporating Hydrazino Moieties

Winum, Jean‐Yves; Dogné, Jean-Michel; Casini, Angela; Leval, Xavier de; Montéro, Jean-Louis; Scozzafava, Andrea; Vullo, Daniela; Innocenti, Alessio; Supuran, Claudiu T.

doi:10.1021/jm0494826

Cited by 69 publications

(60 citation statements)

References 27 publications

(73 reference statements)

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“…Flourophenylsulphamate adducts were reported that the sulphomates possess a rather variable binding pattern within the hCA active site 42,43 . It should also be mentioned that among the nitro substituted compounds, o-nitro substituted compound (5i) seems to be much less effective inhibitors as compared to the meta (5j) 44 , this may be due to the sterical impairment of the ortho-substituent for the binding of the compounds to the Zn(II) ion within the enzyme active site. K i values of the compounds for hCA I (K i ¼ 0.33-1.21) are close to the clinically used sulfonamide AZA (acetazolamide, K i ¼ 0.250 mM) whereas the values of the compounds for hCA II (K i ¼ 0.11-1.99 mM) are higher than AZA (K i ¼ 0.012 mM) 26 .…”

Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Kilicaslan

Arslan

Ruya

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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Sulfonamide-bearing thiazole compounds were synthesized and their inhibitory effects on the activity of purified human carbonic anhydrase I and II were evaluated. Human carbonic anhydrase isoenzymes (hCA-I and hCA-II) were purified from erythrocyte cells by affinity chromatography. The inhibitory effects of the 12 synthesized sulfonamide (5a-l) on the hydratase and esterase activities of these isoenzymes (hCA-I and hCA-II) were studied in vitro. In relation to these activities, the inhibition equilibrium constants (Ki) were determined. The results showed that all the synthesized compounds inhibited the CA isoenzyme activity. Among them 5b was found to be the most active (IC 50 ¼ 0.35 mM; Ki: 0.33 mM) for hCA I and hCA II.

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Section: Resultsmentioning

confidence: 99%

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Kilicaslan

Arslan

Ruya

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…40 We reported recently a series of sulfonamide derivatives incorporating hydrazine moiety in their structure, prepared from 2-carbohydrazido-and 4-carbohydrazido-benzenesulfonamides, which were further derivatized by reaction with aryl isocyanates or arylsulfonyl isocyanates. 44 The hydrazine moiety was considered in this study to be beneficial for CA IX targeting compounds, for several reasons: (i) the facile synthesis and subsequent derivatization of such compounds, leading to a chemical diversity necessary when such new targets are considered (ii) the hydrazine moiety is susceptible to redox chemistry which may be advantageous in the hypoxic environment present in some tumors. Several low nanomolar CA IX inhibitors were detected in this way.…”

Section: C a I X I N H I B I T O R S I N T H E S U L F O N A M I D mentioning

confidence: 99%

Carbonic anhydrase IX: A new druggable target for the design of antitumor agents

Winum

Rami

Scozzafava

et al. 2007

Medicinal Research Reviews

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209

113

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Carbonic anhydrases (CAs, EC 4.2.1.1) are a family of enzymes widespread in all life kingdoms. In mammals, isozyme CA IX is highly overexpressed in many cancer types being present in few normal tissues. Its expression is strongly induced by hypoxia present in many tumors, being regulated by the HIF transcription factor and correlated with a poor response to classical chemo- and radiotherapies. CA IX was recently shown to contribute to acidification of the tumor environment, by efficiently catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site, leading both to the acquisition of metastasic phenotypes and to chemoresistance with weakly basic anticancer drugs. Inhibition of this enzymatic activity by specific and potent inhibitors was shown to revert these acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of potent and selective CA IX inhibitors belonging to diverse chemical classes, such as membrane-impermeant, fluorescent or metal-containing such agents, could thus provide useful tools for highlighting the exact role of CA IX in hypoxic cancers, to control the pH (im)balance of tumor cells, and to develop novel diagnostic or therapeutic applications for the management of tumors. Indeed, both fluorescent inhibitors or positively charged, membrane impermeant sulfonamides have been recently developed as potent CA IX inhibitors and used as proof-of-concept tools for demonstrating that CA IX constitutes a novel and interesting target for the anticancer drug development.

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“…Reaction yields less than Ͻ1 g were purified with Varian mega bond elut (Palo Alto, CA) solid-phase extraction columns (normal phase silica). Building block 1 was synthesized from 4-carboxybenzene sulfonamide [42]. Aldehyde building blocks A-E were synthesized in two steps from commercially available amino acid methyl esters.…”

Section: Chemistrymentioning

confidence: 99%

Direct screening of a dynamic combinatorial library using mass spectrometry

Poulsen

2006

J. Am. Soc. Mass Spectrom.

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A dynamic combinatorial library (DCL) screening approach is described that permits direct identification of the effective (from ineffective) combination of building blocks in the equilibrating DCL. The approach uses Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) together with sustained off-resonance irradiation collision activated dissociation (SORI-CAD) to detect noncovalent protein-DCL ligand complexes under native conditions. It was shown that in a single, rapid experiment one could concurrently identify all the ligands of interest from the DCL against a background of inactive DCL ligands while still in the presence of the target protein. This result has demonstrated that mass spectrometry may provide a fast preliminary screening approach to identify DCL candidates for later verification with more traditional but time-consuming analysis. The MS/MS enables DCL mixtures to be effectively deconvoluted without the need for either chromatography, synthesis of DCL sub-libraries, conversion of the DCL to a static library, or disruption of the protein-ligand complexes before analysis-all typically necessary for the current screening method for DCLs. ( -3]. The benefit of this additional dimension becomes readily evident when dynamic combinatorial libraries (DCLs) are prepared in the presence of a therapeutic target molecule. The reversible chemistry, together with the target acting as a template, permits self-screening owing to selection and amplification of the "best binders" by molecular recognition events between DCL constituents and the target. There are now multiple examples of ligand discovery from dynamic combinatorial libraries (DCLs) generated in the presence of protein targets [4 -20]. In principle, DCC has the potential to circumvent the need to individually synthesize, characterize, and screen each possible library constituent, however rapid detection of the enriched DCL product(s) still poses a serious analytical problem and is a critical limitation to DCC taking a prominent place in drug discovery [21]. The standard DCL screening approach must carry out the screening of identical DCLs twice-with and without the targetand then compare the equilibrium concentration profiles of all library ligands when generated in both the absence and presence (following disruption of the ligand-target complexes) of target protein [4, 7, 10, 14 -17]-the detection of ligand enrichment in the targeted DCL is the basis of identifying the "best binders". Unfortunately, this screening approach typically necessitates synthesis of individual library components to validate chromatographic (e.g., HPLC) or spectral (e.g., NMR) assignments; this is both labor-and time-intensive and has the effect of undermining the promoted advantages of DCC. The complexity of screening with this indirect method also increases with the size of the DCL owing to chromatographic and/or spectral overlap so that the preparation and screening of DCL sub-libraries becomes necessary for deconvolution of larger DCLs. For DCC to have ...

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Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of Cytosolic/Membrane-Associated Carbonic Anhydrase Isozymes I, II, and IX with Sulfonamides Incorporating Hydrazino Moieties

Cited by 69 publications

References 27 publications

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

Carbonic anhydrase IX: A new druggable target for the design of antitumor agents

Direct screening of a dynamic combinatorial library using mass spectrometry

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