14949-00-9Relevant articles and documents
Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging
Iikuni, Shimpei,Kitano, Anna,Watanabe, Hiroyuki,Shimizu, Yoichi,Ono, Masahiro
, (2020)
Carbonic anhydrase-IX (CA-IX) is an attractive target for detecting tumors associated with a poor prognosis. We previously reported a [99mTc]hydroxamamide complex based on ureidosulfonamide as a CA-IX ligand ([99mTc]URB2A), which showed a favorable affinity for CA-IX high-expressing cells in vitro and tumors in vivo; however, radioactivity retention in the blood pool suggested a high background signal on imaging. To improve the pharmacokinetics of [99mTc]URB2A, in this study, we designed and synthesized [99mTc]ISB2 based on imidazothiadiazole sulfonamide, which exhibited greater CA-IX affinity and faster clearance from the blood pool than ureidosulfonamide in studies using corresponding 111In-labeled compounds, and evaluated its utility for CA-IX imaging. In an in vitro cell binding assay, [99mTc]ISB2 markedly bound to CA-IX high-expressing (HT-29) cells; moreover, its binding was greater than that of [99mTc]URB2A. In an in vivo biodistribution assay, [99mTc]ISB2 showed faster clearance from the blood pool than [99mTc]URB2A; however, lower HT-29 tumor accumulation was observed. Further structural modification of [99mTc]ISB2 to improve its stability may lead to the development of a useful [99mTc]hydroxamamide complex for CA-IX imaging.
An Original Aspirin-Containing Carbonic Anhydrase 9 Inhibitor Overcomes Hypoxia-Induced Drug Resistance to Enhance the Efficacy of Myocardial Protection
Zhou, Wen,Zhang, Bin,Fan, Keyu,Yin, Xiaojian,Liu, Jinfeng,Gou, Shaohua
, (2021)
Purpose: Hypoxic microenvironment plays a vital role in myocardial ischemia injury, generally leading to the resistance of chemotherapeutic drugs. This induces an intriguing study on mechanism exploration and prodrug design to overcome the hypoxia-induced drug resistance. Methods: In this study, we hypothesized that the overexpression of carbonic anhydrase 9 (CAIX) in myocardial cells is closely related to the drug resistance. Herein, bioinformatics analysis, gene knockdown, and overexpression assay certificated the correlation between CAIX overexpression and hypoxia. An original aspirin-containing CAIX inhibitor AcAs has been developed. Results: Based on the downregulation of CAIX level, both in vitro and in vivo, AcAs can overcome the acquired resistance and more effectively attenuate myocardial ischemia and hypoxia injury than that of aspirin. CAIX inhibitor is believed to recover the extracellular pH value so as to ensure the stable effect of aspirin. Conclusion: Results indicate great potential of CAIX inhibitor for further application in myocardial hypoxia injury therapy.
Carbonic anhydrase inhibitors. V: Pyrylium salts in the synthesis of isozyme-specific inhibitors
Supuran,Manole,Dinculescu,Schiketanz,Gheorghiu,Puscas,Balaban
, p. 716 - 719 (1992)
Syntheses and physicochemical properties of 2,4,6-tri-,2,3,4,6-tetra-, or 2,3,4,5,6-pentasubstituted 1-(2-sulfonamido-1,3,4-thiadiazol-5-yl)pyridinium perchlorates are presented. The new compounds, putative inhibitors of membrane-bound carbonic anhydrase, were tested for inhibitory action on the bovine red cell enzyme.
Synthesis of sulfonamide conjugates of Cu(ii), Ga(iii), In(iii), Re(v) and Zn(ii) complexes: Carbonic anhydrase inhibition studies and cellular imaging investigations
Dilworth, Jonathan R.,Pascu, Sofia I.,Waghorn, Philip A.,Vullo, Daniela,Bayly, Simon R.,Christlieb, Martin,Sun, Xin,Supuran, Claudiu T.
, p. 4859 - 4873 (2015)
Carbonic anhydrase IX (CA IX) is currently generating great interest as a marker of tumour hypoxia and a potential chemotherapeutic target. In order to test the principle that a CA IX inhibitor could be used for targeting PET or SPECT metallic radioisotopes to tumours we have prepared a number of conjugates involving aryl-sulfonamides or an acetazolamide derivative linked to a range of copper, indium, rhenium, 99m-technetium and zinc complexes. Radiolabelled 64Cu and 99mTc analogues of the 'cold' Cu and some of the Re complexes were prepared in good radiochemical incorporation. Inhibition of various human carbonic anhydrase isoforms (I, II, IX and XII) was tested with the 'cold', non-radiolabelled complexes, and compared with an acetazolamide standard (AZA). The molecular structure of a new, tri-sulfonated porphyrin-labeled sulfonamide was determined using synchrotron X-ray crystallography. This journal is
Improved molecular recognition of Carbonic Anhydrase IX by polypeptide conjugation to acetazolamide
Yang, Jie,Koruza, Katarina,Fisher, Zo?,Knecht, Wolfgang,Baltzer, Lars
, p. 5838 - 5848 (2017)
The small molecule inhibitor acetazolamide (AZM) was conjugated to a set of designed polypeptides and the resulting conjugates were evaluated for their affinity to Human Carbonic Anhydrase II (HCA II) using surface plasmon resonance. The dissociation constant of the AZM-HCA II complex was 38 nM and that of the AZM conjugated polypeptide (4-C10L17-AZM) to HCA II was found to be 4 nM, an affinity enhancement of a factor of 10 due to polypeptide conjugation. For Human Carbonic Anhydrase IX (HCA IX) the dissociation constant of AZM was 3 nM, whereas that of the 4-C10L17-AZM conjugate was 90 pM, a 33-fold affinity enhancement. This dramatic affinity increase due to polypeptide conjugation was achieved for a small molecule ligand with an already high affinity to the target protein. This supports the concept that enhancements due to polypeptide conjugation are not limited to small molecule ligands that bind proteins in the mM to μM range but may be used also for nM ligands to provide recognition elements with dissociation constants in the pM range. Evaluations of two HCA IX constructs that do not carry the proteoglycan (PG) domain did not show significant affinity differences between AZM and the polypeptide conjugate, providing evidence that the improved binding of 4-C10L17-AZM to HCA IX emanated from interactions between the polypeptide segment and the PG domain found only in one carbonic anhydrase, HCA IX.
Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X-Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone
Andring, Jacob T.,Fouch, Mallorie,Akocak, Suleyman,Angeli, Andrea,Supuran, Claudiu T.,Ilies, Marc A.,McKenna, Robert
, p. 13064 - 13075 (2020)
This study provides a structure-Activity relationship study of a series of lipophilic carbonic anhydrase (CA) inhibitors with an acetazolamide backbone. The inhibitors were tested against the tumor-expressed CA isozyme IX (CA IX), and the cytosolic CA I, CA II, and membrane-bound CA IV. The study identified several low nanomolar potent inhibitors against CA IX, with lipophilicities spanning two log units. Very potent pan-inhibitors with nanomolar potency against CA IX and sub-nanomolar potency against CA II and CA IV, and with potency against CA I one order of magnitude better than the parent acetazolamide 1 were also identified in this study, together with compounds that displayed selectivity against membrane-bound CA IV. A comprehensive X-ray crystallographic study (12 crystal structures), involving both CA II and a soluble CA IX mimetic (CA IX-mimic), revealed the structural basis of this particular inhibition profile and laid the foundation for further developments toward more potent and selective inhibitors for the tumor-expressed CA IX.
Preformulation studies of acetazolamide: effect of pH, two buffer species, ionic strength, and temperature on its stability.
Parasrampuria,Gupta
, p. 855 - 857 (1989)
Using an HPLC method, the effect of pH, two buffer species (phosphate and citrate), ionic strength, and temperature on the stability of acetozolamide has been studied. The optimum pH of stability appears to be 4. The buffers and ionic strength did not affect the decomposition constant. There was a direct relationship between the activation energies and pH values, with an energy of activation (Ea) value of 16.61 kcal/mol at pH 4. The un-ionized acetazolamide is subject to specific acid-base catalysis. The KH and KOH values have been estimated to be 0.23 and 1.56 d-1, respectively. These preformulation studies can be used to develop a stable oral liquid dosage form of acetazolamide.
Antimicrobial and Antiquorum-Sensing Studies. Part 3: Synthesis and Biological Evaluation of New Series of [1,3,4]Thiadiazoles and Fused [1,3,4]Thiadiazoles
El-Gohary, Nadia S.,Shaaban, Mona I.
, p. 283 - 297 (2015)
New series of [1,3,4]thiadiazoles and fused [1,3,4]thiadiazoles were synthesized. The newly synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Escherichia coli. Compounds 3b and 10a displayed the highest activity against E. coli with MIC value of 78.125μg/mL. In addition, compound 10a exhibited the highest activity against B. cereus with MIC value of 156.25μg/mL. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus flavus 3375. Compounds 3b, 5a, 10a, and 12b showed the best activity against A. flavus 3375 with MIC value of 19.531μg/mL. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds 3b, 5a, and 12b exhibited moderate activity. In vitro cytotoxicity testing of compounds 3b,c, 5a, 6a, 10a, and 12a,b against human normal lung fibroblast (W138) cell line was performed. The in vivo acute toxicity of the same compounds was also tested and the obtained results indicated that compound 10a is the least toxic analog. The same compounds were studied for their DNA-binding affinity and the obtained results showed that compounds 3b, 10a, and 12a,b have moderate DNA-binding affinity. New series of [1,3,4]thiadiazoles and fused [1,3,4]thiadiazoles were synthesized and screened for their antibacterial activity against Staphylococcus aureus, Bacillus cereus, and Escherichia coli, as well as their antifungal activity against Candida albicans and Aspergillus flavus 3375. The compounds were also examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472. Compounds 3b and 10a showed interesting activity in all assays.
Salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole, a structural and analog of acetazolamide, show interesting carbonic anhydrase inhibitory properties, diuretic, and anticonvulsant action
Diaz, Jorge R. A.,Camí, Gerardo Enrique,Liu-González, Malva,Vega, Daniel R.,Vullo, Daniela,Juárez, Américo,Pedregosa, José C.,Supuran, Claudiu T.
, p. 1102 - 1110 (2016)
Three salts of 5-amino-2-sulfonamide-1,3,4-thiadiazole (Hats) were prepared and characterized by physico-chemical methods. The p-toluensulfonate, the methylsulfonate, and the chlorhydrate monohydrate salts of Hats were evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) and as anticonvulsants and diuretics, since many CAIs are clinically used as pharmacological agents. The three Hats salts exhibited diuretic and anticonvulsant activities with little neurotoxicity. The human (h) isoforms hCA I, II, IV, VII, IX, and XII were inhibited in their micromolar range by these salts, whereas pathogenic beta and gamma CAs showed similar, weak inhibitory profiles.
Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site
Tanpure, Rajendra P.,Ren, Bin,Peat, Thomas S.,Bornaghi, Laurent F.,Vullo, Daniela,Supuran, Claudiu T.,Poulsen, Sally-Ann
, p. 1494 - 1501 (2015)
We present a new approach to carbonic anhydrase II (CA II) inhibitor design that enables close interrogation of the regions of the CA active site where there is the greatest variability in amino acid residues among the different CA isozymes. By appending dual tail groups onto the par excellence CA inhibitor acetazolamide, compounds that may interact with the distinct hydrophobic and hydrophilic halves of the CA II active site were prepared. The dual-tail combinations selected included (i) two hydrophobic moieties, (ii) two hydrophilic moieties, and (iii) one hydrophobic and one hydrophilic moiety. The CA enzyme inhibition profile as well as the protein X-ray crystal structure of compound 3, comprising one hydrophobic and one hydrophilic tail moiety, in complex with CA II is described. This novel dual-tail approach has provided an enhanced opportunity to more fully exploit interactions with the CA active site by enabling these molecules to interact with the distinct halves of the active site. In addition to the dual-tail compounds, a corresponding set of single-tail derivatives was synthesized, enabling a comparative analysis of the single-tail versus dual-tail compound CA inhibition profile.
