- Synthesis and evaluation of novel technetium-99m-hydroxamamide complex based on imidazothiadiazole sulfonamide targeting carbonic anhydrase-IX for tumor imaging
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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.
- Iikuni, Shimpei,Kitano, Anna,Watanabe, Hiroyuki,Shimizu, Yoichi,Ono, Masahiro
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- An Original Aspirin-Containing Carbonic Anhydrase 9 Inhibitor Overcomes Hypoxia-Induced Drug Resistance to Enhance the Efficacy of Myocardial Protection
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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.
- Zhou, Wen,Zhang, Bin,Fan, Keyu,Yin, Xiaojian,Liu, Jinfeng,Gou, Shaohua
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- Carbonic anhydrase inhibitors. V: Pyrylium salts in the synthesis of isozyme-specific inhibitors
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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.
- Supuran,Manole,Dinculescu,Schiketanz,Gheorghiu,Puscas,Balaban
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- 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
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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
- Dilworth, Jonathan R.,Pascu, Sofia I.,Waghorn, Philip A.,Vullo, Daniela,Bayly, Simon R.,Christlieb, Martin,Sun, Xin,Supuran, Claudiu T.
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- Improved molecular recognition of Carbonic Anhydrase IX by polypeptide conjugation to acetazolamide
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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.
- Yang, Jie,Koruza, Katarina,Fisher, Zo?,Knecht, Wolfgang,Baltzer, Lars
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- Structural Basis of Nanomolar Inhibition of Tumor-Associated Carbonic Anhydrase IX: X-Ray Crystallographic and Inhibition Study of Lipophilic Inhibitors with Acetazolamide Backbone
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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.
- Andring, Jacob T.,Fouch, Mallorie,Akocak, Suleyman,Angeli, Andrea,Supuran, Claudiu T.,Ilies, Marc A.,McKenna, Robert
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- Preformulation studies of acetazolamide: effect of pH, two buffer species, ionic strength, and temperature on its stability.
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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.
- Parasrampuria,Gupta
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- 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
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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.
- El-Gohary, Nadia S.,Shaaban, Mona I.
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- 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
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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.
- Diaz, Jorge R. A.,Camí, Gerardo Enrique,Liu-González, Malva,Vega, Daniel R.,Vullo, Daniela,Juárez, Américo,Pedregosa, José C.,Supuran, Claudiu T.
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- Carbonic anhydrase inhibitors with dual-tail moieties to match the hydrophobic and hydrophilic halves of the carbonic anhydrase active site
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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.
- Tanpure, Rajendra P.,Ren, Bin,Peat, Thomas S.,Bornaghi, Laurent F.,Vullo, Daniela,Supuran, Claudiu T.,Poulsen, Sally-Ann
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- A red-shifted photochromic sulfonylurea for the remote control of pancreatic beta cell function
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Azobenzene photoresponsive elements can be installed on sulfonylureas, yielding optical control over pancreatic beta cell function and insulin release. An obstacle to such photopharmacological approaches remains the use of ultraviolet-blue illumination. Herein, we synthesize and test a novel yellow light-activated sulfonylurea based on a heterocyclic azobenzene bearing a push-pull system.
- Broichhagen,Frank,Johnston,Mitchell,?mid,Marchetti,Bugliani,Rutter,Trauner,Hodson
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- Copper-free ‘click’ chemistry-based synthesis and characterization of carbonic anhydrase-IX anchored albumin-paclitaxel nanoparticles for targeting tumor hypoxia
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Triple negative breast cancer (TNBC) is a difficult to treat disease due to the absence of the three unique receptors estrogen, progesterone and herceptin-2 (HER-2). To improve the current therapy and overcome the resistance of TNBC, there is unmet need to develop an effective targeted therapy. In this regard, one of the logical and economical approaches is to develop a tumor hypoxia-targeting drug formulation platform for selective delivery of payload to the drug-resistant and invasive cell population of TNBC tumors. Toward this, we developed a Carbonic Anhydrase IX (CA IX) receptor targeting human serum albumin (HSA) carriers to deliver the potent anticancer drug, Paclitaxel (PTX). We used Acetazolamide (ATZ), a small molecule ligand of CA IX to selectively deliver HSA-PTX in TNBC cells. A novel method of synthesis involving copper free ‘click’ chemistry (Dibenzocyclooctyl, DBCO) moiety with an azide-labeled reaction partner, known as Strain-Promoted Alkyne Azide Cycloaddition (SPAAC) along with a desolvation method for PTX loading were used in the present study to arrive at the CA IX selective nano-carriers, HSA-PTX-ATZ. The anticancer effect of HSA-PTX-ATZ is higher compared to HSA, PTX and non-targeted HSA-PTX in MDA-MB-231 and MDA-MB-468 cells. The cell killing effect is associated with induction of early and late phases of apoptosis. Overall, our proof-of-concept study shows a promising avenue for hypoxia-targeted drug delivery that can be adapted to several types of cancers.
- Tatiparti, Katyayani,Sau, Samaresh,Gawde, Kaustubh A.,Iyer, Arun K.
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- Infrared and raman spectra of 5-amino-1,3,4-thiadiazole-2-sulfonamide (Hats). Experimental data and quantum chemistry calculations
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The infrared and Raman spectra in the range 4000-50 cm-@ were obtained for 5-amino-1,3,4-thiadiazole-2-sulfonamide. The molecular geometry was optimized by means of the DFT methods of quantum chemistry (B3LYP/6-31G**), resulting in a structure which agrees quite well with that obtained by X-ray diffraction. The wavenumbers corresponding to the normal modes of vibration were calculated using the same approximation and the associated force field converted to a set of local symmetry coordinates, with subsequent calculation of the potential energy distribution. An assignment of the observed bands is proposed on the basis of such calculations and the comparison with related molecules.
- Camí,Chufán,Pedregosa,Varetti
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- Acetazolamide-based [18F]-PET tracer: In vivo validation of carbonic anhydrase IX as a sole target for imaging of CA-IX expressing hypoxic solid tumors
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Carbonic anhydrase IX is overexpressed in many solid tumors including hypoxic tumors and is a potential target for cancer therapy and diagnosis. Reported imaging agents targeting CA-IX are successful mostly in clear cell renal carcinoma as SKRC-52 and no candidate was approved yet in clinical trials for imaging of CA-IX. To validate CA-IX as a valid target for imaging of hypoxic tumor, we designed and synthesized novel [18F]-PET tracer (1) based on acetazolamide which is one of the well-known CA-IX inhibitors and performed imaging study in CA-IX expressing hypoxic tumor model as 4T1 and HT-29 in vivo models other than SKRC-52. [18F]-acetazolamide (1) was found to be insufficient for the specific accumulation in CA-IX expressing tumor. This study might be useful to understand in vivo behavior of acetazolamide PET tracer and can contribute to the development of successful PET imaging agents targeting CA-IX in future. Additional study is needed to understand the mechanism of poor targeting of CA-IX, as if CA-IX is not reliable as a sole target for imaging of CA-IX expressing hypoxic solid tumors.
- More, Kunal N.,Lee, Jun Young,Kim, Dong-Yeon,Cho, Nam-Chul,Pyo, Ayoung,Yun, Misun,Kim, Hyeon Sik,Kim, Hangun,Ko, Kwangseok,Park, Jeong-Hoon,Chang, Dong-Jo
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- Synthesis and properties of two new membrane-impermeant high-molecular-weight carbonic anhydrase inhibitors
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The synthesis and inhibitory properties and stability of two nontoxic high-molecular-weight carbonic anhydrase inhibitors (F 3500 and POBUMS) are reported. F 3500 was prepared by the covalent linkage of aminobenzolamide, a potent carbonic anhydrase (CA) inhibitor, to polyoxyethylene bisacetic acid (MW 3350). Linkage of the same inhibitor to polybutadiene maleic acid copolymer (MW 20,000) gave POBUMS. They contained on a mole percentage basis 0.11-0.28% unreacted aminobenzolamide as contaminant. F 3500 and POBUMS were approximately equipotent as carbonic anhydrase inhibitors on a weight basis with K(i) at 37°C for CA II and CA IV of approximately 0.5 and 10 μg/ml, respectively. They showed a maximum release of 28% aminobenzolamide when heated at 70°C for 3 days at pH 10.5 and were completely stable toward enzymatic hydrolysis (protease and peptidase at 25°C). They were not membrane permeable as judged by their inability to bind to intracellular CA II in intact red cells, nor were they actively uptaken in rat kidney slices. Rats injected with F 3500 (200 mg/kg) showed no toxicity and excreted 93% of the polymer unchanged in the urine in 3 h. The two polymers should prove useful for in vivo and in vitro studies of selective CA IV inhibition in membranes.
- Conroy, Curtis W.,Wynns, George C.,Maren, Thomas H.
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- Synthesis and investigation of inhibition effects of new carbonic anhydrase inhibitors
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Three new derivatives of 2-substituted 1,3,4-thiadiazole-5-sulfonamide have been synthesized. These compounds are 2-(3-chloropropionylamino)- 1,3,4-thiadiazole-5-sulfonamide (1); 2-(2,2-dichloroacetylamino)-1,3,4-thiadiazole-5-sulfonamide (2); and 2-(3-phenylpropionylamino)-1,3,4-thiadiazole-5-sulfonamide (3). Inhibition effects of these compounds on carbonic anhydrase I and II have been investigated. By comparing 150 and K(i) values of the compounds, it has been found that compound 1 is a more potent inhibitor than acetazolamide (b) on carbonic anhydrase II.
- Arslan, Oktay,Kuefrevioglu, Oe. Irfan,Nalbantoglu, Barbaros
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- Synthesis, molecular docking analysis and biological evaluations of saccharide-modified thiadiazole sulfonamide derivatives
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A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors.
- Zhang, Zuo-Peng,Zhong, Ye,Han, Zhen-Bin,Zhou, Lin,Su, Hua-Sheng,Wang, Jian,Liu, Yang,Cheng, Mao-Sheng
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- N-aryl sulfanilamide-N-beta-D-glucopyranose diamide compound and application thereof
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The invention belongs to the technical field of medicines, and relates to a preparation method and medical application of an N1-aryl sulfanilamide-N4-beta-D-glucopyranose diamide compound. The compound is shown in a general formula (I), substituent groups are described in the specification, and the compound shown in the general formula (I) and an optical active body, a diastereoisomer and a pharmaceutically acceptable salt thereof are applied to preparation of anti-tumor drugs. Based on pharmacophore characteristics and subcellular localization of CA IX and XII, a selective CA IX and XII inhibitor is designed and synthesized, polyhydroxy high-polarity glucose is selected as a tail end, a classical pharmacophore aryl sulfanilamide fragment of a targeted CAs active center is introduced through a flexible aliphatic chain and a rigid aromatic structure, the overall structure can selectively inhibit catalytic activity of extracellular CA IX and XII, an anti-tumor effect is achieved, and therefore, the compound has a good application prospect.
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Paragraph 0029; 0036
(2021/06/26)
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- RADIOACTIVE IMIDAZOTHIADIAZOLE DERIVATIVE COMPOUND
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The present invention provides a radiolabeled compound represented by the following formula (1), which is a radioactive imidazothiadiazole derivative compound having an affinity for CA-IX, or a salt thereof. wherein n is an integer of 1 to 4, and L represents a radionuclide or a mono- to tetravalent group containing a radionuclide.
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Paragraph 0085-0087; 0112; 0113
(2021/10/22)
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- DUAL-TARGETED CARBONIC ANHYDRASE IX COMPLEX AND CONTRAST AGENT THEREOF
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Disclosed herein are a dual-targeted carbonic anhydrase IX complex, a contrast agent comprising the same, and a synthesizing method thereof. The dual-targeted carbonic anhydrase IX complex includes a carbonic anhydrase IX (CA9) binding peptide, a sulfonamide derivative, and a metal chelating agent. The dual-targeted carbonic anhydrase IX complex has potential for use as a molecular nuclear drug.
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Paragraph 0027
(2021/05/29)
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- Acetazolamide derivative, preparation method thereof and application thereof in preparation of medicine for treating coronary heart disease
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The invention relates to an acetazolamide derivative, a preparation method thereof and an application of the acetazolamide derivative in preparation of a medicine for treating coronary heart disease.The acetazolamide derivative is an acetazolamide derivative I obtained by bonding a carbonic anhydrase inhibitor acetazolamide Ac and a non-steroidal anti-inflammatory drug which is represented by aspirin As and has a carboxylic acid group through a linking group, and the structural general formula is shown as a formula 1 shown in the specification, wherein in the formula 1, OOC-NSAID represents anon-steroidal anti-inflammatory drug in which one carboxylic acid proton is lost, representative are acetazolamide derivatives containing aspirin or indomethacin, and the acetazolamide derivative I has good activity of inhibiting carbonic anhydrase 9, can effectively improve myocardial anoxia injury in an anoxia microenvironment, and is applied to preparation of the medicine for treating coronaryheart disease.
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Paragraph 0022-0023
(2020/12/05)
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- CARBONIC ANHYDRASE INHIBITORS AND ANTIBIOTICS AGAINST MULTIDRUG RESISTANT BACTERIA
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The invention described herein generally relates to novel therapeutic compounds, and in particular to carbonic anhydrase inhibitors as a narrow spectrum antibiotics against drug resistant bacteria and methods for treating those infection diseases in mammals using the described carbonic anhydrase inhibitors or a pharmaceutical formulation thereof.
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Paragraph 0082-0084
(2020/07/14)
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- Optimization of Acetazolamide-Based Scaffold as Potent Inhibitors of Vancomycin-Resistant Enterococcus
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Vancomycin-resistant enterococci (VRE) are the second leading cause of hospital-acquired infections (HAIs) attributed to a drug-resistant bacterium in the United States, and resistance to the frontline treatments is well documented. To combat VRE, we have repurposed the FDA-approved carbonic anhydrase drug acetazolamide to design potent antienterococcal agents. Through structure-activity relationship optimization we have arrived at two leads possessing improved potency against clinical VRE strains from MIC = 2 μg/mL (acetazolamide) to MIC = 0.007 μg/mL (22) and 1 μg/mL (26). Physicochemical properties were modified to design leads that have either high oral bioavailability to treat systemic infections or low intestinal permeability to treat VRE infections in the gastrointestinal tract. Our data suggest the intracellular targets for the molecules are putative α-carbonic and γ-carbonic anhydrases, and homology modeling and molecular dynamics simulations were performed. Together, this study presents potential anti-VRE therapeutic options to provide alternatives for problematic VRE infections.
- Kaur, Jatinder,Cao, Xufeng,Abutaleb, Nader S.,Elkashif, Ahmed,Graboski, Amanda L.,Krabill, Aaron D.,Abdelkhalek, Ahmed Hassan,An, Weiwei,Bhardwaj, Atul,Seleem, Mohamed N.,Flaherty, Daniel P.
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p. 9540 - 9562
(2020/10/19)
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- Synthesis and evaluation of indium-111-labeled imidazothiadiazole sulfonamide derivative for single photon emission computed tomography imaging targeting carbonic anhydrase-IX
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Carbonic anhydrase-IX (CA-IX) is a zinc enzyme overexpressed in the hypoxic regions of many types of solid tumors; therefore, in vivo imaging of CA-IX may contribute to cancer diagnosis. In this study, we newly designed and synthesized an 111In-labeled CA-IX imaging agent based on an imidazothiadiazole sulfonamide (IS) scaffold conjugated with a chelating moiety, DO3A ([111In]DO3A-IS1), and evaluated its utility for imaging of CA-IX high-expressing tumors. [111In]DO3A-IS1 was successfully synthesized at a 76% radiochemical yield by reacting its precursor with 111InCl3 in acetate buffer. In in vitro assays, [111In]DO3A-IS1 showed marked stability in murine plasma and greater binding to CA-IX high-expressing (HT-29) cells (118 ± 21% initial dose/mg protein) than CA-IX low-expressing (MDA-MB-231) cells (1.4 ± 0.3% initial dose/mg protein). Moreover, in an in vivo biodistribution assay, [111In]DO3A-IS1 showed marked accumulation in the HT-29 tumor (8.71 ± 1.41% injected dose/g at 24 h postinjection). In addition, in a single photon emission computed tomography (SPECT) study, [111In]DO3A-IS1 clearly and selectively visualized the HT-29 tumor as compared with the MDA-MB-231 tumor. These results indicate that [111In]DO3A-IS1 may serve as a useful SPECT imaging agent with the novel scaffold targeting CA-IX.
- Iikuni, Shimpei,Okada, Yuya,Ono, Masahiro,Shimizu, Yoichi,Watanabe, Hiroyuki
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supporting information
(2020/05/22)
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- Selective carbonic anhydrase inhibitor, synthesis method and application thereof
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The invention discloses a selective carbonic anhydrase inhibitor. The compound adopts acetazolamide as a lead compound, and is designed and synthesized by introducing a side chain for structural modification. The structure comprises a monosubstituted compound and a disubstituted compound; the selective inhibition effect of the compound on carbonic anhydrase is evaluated by esterase method; the neuroprotective effect of the compound is evaluated through a sodium nitroprusside oxidative stress model; and the toxicity of the compound is tested through cytotoxicity experiment. Research results show that in terms of the inhibition effect of the compound on carbonic anhydrase, monosubstitution is superior to disubstitution; the selectivity to carbonic anhydrase II is superior to that of carbonicanhydrase IX; the monosubstituted compound presents certain protective effect on sodium nitroprusside damaged PC12 cells; the IC50 of the optimal compound to carbonic anhydrase II is 16.7nM, the IC50to carbonic anhydrase IX is 4757nM, the selectivity is 285 times, which is remarkably superior to that of acetazolamide; the neuroprotective effect on PC12 is close to that of acetazolamide, and thetoxicity is lower than that of acetazolamide. The compound has the characteristics of good selectivity, effectiveness and safety, and is expected to be applied to drugs for preventing and treating neurological diseases.
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Paragraph 0048; 0049; 0054; 0055
(2020/03/06)
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- 5-[2-(N-(Substituted phenyl)acetamide)]amino-1,3,4-thiadiazole-2-sulfonamides as Selective Carbonic Anhydrase II Inhibitors with Neuroprotective Effects
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In this study, 22 novel compounds were designed and synthesized by acetamide bridge chains, among which 5 a–5 k were monosubstituted compounds, and 6 a–6 k were disubstituted. A series of biological evaluations was then carried out to determine the carbonic anhydrase inhibitory activity, neuroprotective effects and cytotoxicity of 5 a–5 k and 6 a–6 k. The results showed that some compounds could protect PC12 cells from sodium nitroprusside (SNP)-induced damage. In terms of the neuroprotection and inhibitory activity against carbonic anhydrase II, monosubstituted compounds were better than disubstituted. Compound 5 c exhibited better protective effect in PC12 cells than that of edaravone, and 5 c also showed less cytotoxicity. In addition, compound 5 c was found to be the most effective selective carbonic anhydrase II inhibitor (IC50=16.7 nM, CAI/CAII=54.3), which was similar to the inhibitory effect of acetazolamide. Moreover, the selectivity of compound 5 c was better than that of acetazolamide (IC50=12.0 nM, CAI/CAII=20.8). Molecular docking presented that the binding effect of compound 5 c with carbonic anhydrase II was superior to that of 5 c with carbonic anhydrase I and IX, which was consistent with the inhibitory results. Based on above findings, compound 5 c may be a potential candidate for selective carbonic anhydrase II inhibitor, and it had obviously neuroprotective effect and great advantages in drug safety.
- Jiang, Caibao,Lao, Yaoqiang,Liao, Liping,Liu, Jiayong,Shi, Jinguo,Wang, Yang,Zhang, Jingxia,Zhang, Liantao
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- With deficiency oxygen target tropism of polyvalent ligand drug conjugates (by machine translation)
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The invention discloses a deficiency oxygen target tropism of polyvalent ligand drug conjugates, through containing mercapto homeotropic deficiency oxygen target drug derivative molecule ligand and with the maleimide derivatized dextran of connected, can realize the corresponding drug molecules on tumor tissues to [...], has good anti-tumor activity. . (by machine translation)
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Paragraph 0051; 0063-0065
(2019/06/05)
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- Organic Photodynamic Nanoinhibitor for Synergistic Cancer Therapy
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Despite its great potential in cancer treatment, photodynamic therapy (PDT) often exacerbates hypoxia and subsequently compromises its therapeutic efficacy. To overcome this issue, an organic photodynamic nanoinhibitor (OPNi) has been synthesized that has the additional ability to counteract carbonic anhydrase IX (CA-IX), a molecular target in the hypoxia-mediated signalling cascade. OPNi is composed of a metabolizable semiconducting polymer as the photosensitizer and a CA-IX antagonist conjugated amphiphilic polymer as the matrix. This molecular structure allows OPNi not only to selectively bind CA-IX positive cancer cells to facilitate its tumor accumulation but also to regulate the CA-IX-related pathway. The integration of CA-IX inhibition into the targeted PDT process eventually has a synergistic effect, leading to superior antitumor efficacy over that of PDT alone, as well as the reduced probability of hypoxia-induced cancer metastasis. This study thus proposes a molecular strategy to devise simple yet amplified photosensitizers to conquer the pitfalls of traditional PDT.
- Jiang, Yuyan,Li, Jingchao,Zeng, Ziling,Xie, Chen,Lyu, Yan,Pu, Kanyi
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supporting information
p. 8161 - 8165
(2019/05/21)
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- METHOD OF TREATMENT FOR SOLID TUMORS CONTAINING HYPOXIA AND/OR STROMA FEATURES
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Advancements in solid tumor (e.g., renal cell carcinoma) treatments and imaging are described. The advancements are based on nanoformulations that: (i) overcome deliverability issues associated with anti-cancer compounds; (ii) have increased targeted delivery to tumors, and hypoxic cores of tumors due to the presence of targeting ligands; (iii) have increased delivery to the hypoxic cores of tumors due to engineered shapes; (iv) provide synergistic treatment combinations; and/or (v) overcome cancer cell resistance to therapeutic treatments.
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Paragraph 0020; 0042; 0054; 0292; 0304
(2019/07/17)
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- CARBONIC ANHYDRASE IX INHIBITOR CONJUGATES AND USES THEREOF
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The present disclosure relates to compositions and methods of carbonic anhydrase IX inhibitors. The present disclosure also relates to targeting conjugates of carbonic anhydrase IX inhibitors as therapeutics and imaging agents. The present disclosure also relates to the use of targeting conjugates of carbonic anhydrase IX inhibitors in imaging methods and cancer therapy.
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Page/Page column 68
(2017/10/13)
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- CA IX-TARGET NIR DYES AND THEIR USES
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The present disclosure relates to compounds that are useful as near-infrared fluorescence probes, wherein the compounds include i) a ligand that binds to the active site of carbonic anhydrase, ii) a dye molecule, and iii) a linker molecule that comprises an amino acid, amide, ureido, or polyethylene glycol derivative thereof. The disclosure further describes methods and compositions for making and using the compounds, methods incorporating the compounds, and kits incorporating the compounds.
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Paragraph 00292; 00293; 00294; 00318; 00319; 00320
(2017/10/11)
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- PHOTO-SWITCHABLE SULFONYLUREAS AND THEIR USES
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The present invention relates to sulfonylurea analogous compounds comprising a sulfonylurea moiety and a photoresponsive moiety. The present invention further relates to methods for generating the sulfonylurea analogous compounds of the invention and to pharmaceutical compositions comprising at least one sulfonylurea analogous compound of the invention. The present invention relates to the sulfonylurea analogous compounds or the phamiaceutical composition of the invention for use in medicine, in particular for use as anti-diabetic agent and/or in the prevention and/or treatment of diabetes conditions or a disease state requiring modulation of ATP-sensitive potassium (K+) (KATP) channels. The present invention also relates to the use of the sulfonylurea analogous compounds for regulating ATP-sensitive potassium (K+) (KATP) channels and/or for assessing the functional role and/or activation of KATP channels.
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Page/Page column 39
(2016/05/24)
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- Compositions and methods for the suppression of carbonic anhydrase activity
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, and methods for treating or preventing or modulating carbonic anhydrase activity in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dural ectasia, congestive heart failure, drug induced edema, diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia.
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Page/Page column 28
(2016/04/05)
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- Novel inhibitors of bacterial biofilms and related methods
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Multi-cyclic compounds of chemical structure represented by formula given below and compositions thereof are useful for reducing or inhibiting the growth of bacterial biofilms and for controlling bacterial biofilm infections. Such compounds and compositions are also useful in methods for reducing or inhibiting the growth of biofilms and for controlling bacterial biofilm infections involving biofilms.
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Paragraph 0567
(2014/05/06)
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- Synthesis and evaluation of antibacterial and antitubercular activities of some novel imidazo[2,1-b][1,3,4]thiadiazole derivatives
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A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]thiadiazoles were synthesized, structures of the compounds were elucidated and evaluated for antitubercular activity against Mycobacterium tuberculosis H37Rv using microplate alamar blue assay (MABA) method, antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Vibrio cholera, and Escherichia coli by broth micro dilution assay method. Some compounds exhibited significant antibacterial and antitubercular activities. Compounds 10, 14, and 15 emerged as the most active molecules, showed significant antimicrobial activity and may serve as leads for further optimization. Graphical Abstract: Synthesis, spectral studies, and antibacterial and antitubercular activities of a novel series of imidazo[2,1-b][1,3,4]thiadiazole derivatives are described[Figure not available: see fulltext.].
- Joshi,Manish,Badiger, Aravind
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p. 869 - 878
(2013/04/23)
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- COMPOSITIONS AND METHODS FOR SUPPRESSION OF CARBONIC ANHYDRASE ACTIVITY
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Provided are the compounds of formula (I) or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula (I), and methods for treating or preventing or modulating carbonic anhydrase activity in a disease may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral admimstration, syrup, or injection. Such compositions may be used to treatment of glaucoma, epileptic seizures, Idiopathic intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, periodic paralysis and dural ectasia, congestive heart failure, drug induced edema, diuretic, intermittent claudication resulting from obstructed arteries in the limbs, and vascular dementia.
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Paragraph 00100; 00101
(2013/12/03)
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- Inhibitors of bacterial biofilms and related methods
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Certain multi-cyclic compounds and compositions thereof are useful for reducing or inhibiting the growth of bacterial biofilms and for controlling bacterial biofilm infections. Such compounds and compositions are also useful in methods for reducing or inhibiting the growth of biofilms and for controlling bacterial biofilm infections involving biofilms.
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Page/Page column 215
(2012/12/13)
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- Synthesis and evaluation of near-infrared fluorescent sulfonamide derivatives for imaging of hypoxia-induced carbonic anhydrase IX expression in tumors
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A series of human carbonic anhydrase (hCA) IX inhibitors conjugated to various near-infrared fluorescent dyes was synthesized with the aim of imaging hypoxia-induced hCA IX expression in tumor cells in vitro, ex vivo and in vivo. The resulting compounds were profiled for inhibition of transmembrane hCA IX showing a range of potencies from 7.5 to 116 nM and up to 50-fold selectivity over the cytosolic form hCA II. Some of the compounds also showed inhibition selectivity for other transmembrane forms hCA XII and XIV as well. Compounds incubated in vitro with HeLa cells cultured under normoxic and hypoxic conditions detected upregulation of hCA IX under hypoxia by fluorescence microscopy. A pilot in vivo study in HT-29 tumor bearing mice showed significant accumulation of a fluorescent acetazolamide derivative in tumor tissue with little accumulation in other tissues. Approximately 10% of injected dose was non-invasively quantified in tumors by fluorescence molecular tomography (FMT), demonstrating the promise of these new compounds for quantitative imaging of hCA IX upregulation in live animals.
- Groves, Kevin,Bao, Bagna,Zhang, Jun,Handy, Emma,Kennedy, Paul,Cuneo, Garry,Supuran, Claudiu T.,Yared, Wael,Peterson, Jeffrey D.,Rajopadhye, Milind
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scheme or table
p. 653 - 657
(2012/03/26)
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- CARBONIC ANHYDRASE TARGETING AGENTS AND METHODS OF USING SAME
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The invention provides agents that target carbonic anhydrase, which can be used as imaging agents or therapeutic agents. The agents can be used to image tumor hypoxia as well as other physiological processes in a subject.
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Page/Page column 82; 86
(2012/12/13)
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- IN VTRO ANTIBACTERIAL AND ANTIVIRAL ACTIVITIES OF SOME NOVEL 1,3,4-THIADIAZOLE DERIVATIVES
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A series of new 2-(substituted benzoylthiocarbamido)-5-(phenyl/sulphonamido)-1,3,4-thiadiazoles 4(a-g) and 5(a-g) were synthesized as potential antibacterial and antiviral compounds. 1,3,4-Thiadiazole compounds were prepared by the reaction of 2-amino-1,3,4-thiadiazoles with a solution containing ammonium thiocyanae and substituted benzoyl chloride in acetone/tetrahydrofuran. The structures of the synthesized compounds were confirmed using the elemental analysis and spectroscopic techniques such as IR, 1H NMR and Mass. The newly synthesized compounds were evaluated for in vitro antimicrobial activities by broth micro dilution method. Evaluation of the antiviral activity of the compounds against HIV-1 strain IIIB and HIV-2 strain (ROD) in MT-4 cells was performed using the MTT assay method.
- Dixit, Sheshagiri,Gadaginamath, G. S.,Joshi, S. D.,Kulkarni, V. H.,More, Uttam A.
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p. 109 - 114
(2020/12/09)
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- Development of sulfonamide AKT PH domain inhibitors
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Disruption of the phosphatidylinositol 3-kinase/AKT signaling pathway can lead to apoptosis in cancer cells. Previously we identified a lead sulfonamide that selectively bound to the pleckstrin homology (PH) domain of AKT and induced apoptosis when present at low micromolar concentrations. To examine the effects of structural modification, a set of sulfonamides related to the lead compound was designed, synthesized, and tested for binding to the expressed PH domain of AKT using a surface plasmon resonance-based competitive binding assay. Cellular activity was determined by means of an assay for pAKT production and a cell killing assay using BxPC-3 cells. The most active compounds in the set are lipophilic and possess an aliphatic chain of the proper length. Results were interpreted with the aid of computational modeling. This paper represents the first structure-activity relationship (SAR) study of a large family of AKT PH domain inhibitors. Information obtained will be used in the design of the next generation of inhibitors of AKT PH domain function.
- Ahad, Ali Md.,Zuohe, Song,Du-Cuny, Lei,Moses, Sylvestor A.,Zhou, Li Li,Zhang, Shuxing,Powis, Garth,Meuillet, Emmanuelle J.,Mash, Eugene A.
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supporting information; experimental part
p. 2046 - 2054
(2011/05/05)
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- Synthesis and evaluation of new carbonic anhydrase inhibitors
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A series of new sulfamide derivatives have been synthesized, their structures were confirmed by 1H NMR and ESI-MS. Some target compounds were assessed by the tool of Dock6, and inhibition effects of all the new compounds on carbonic anhydrase II have been investigated. In addition, some compounds have been investigated for their antihypoxic effects in mice. Results indicated that nine target compounds exhibit as effectively as acetazolamide and 10 compounds have more potent inhibition effects on carbonic anhydrase II than acetazolamide. Three of them (I-8, I-18 and I′-3) can prolong markedly the survival time of mice in hypoxia, which are worth carrying out further studies.
- Xiao, Zhonghai,Duan, Ruifeng,Cui, Wenyu,Zhang, Yanfang,Zhang, Shouguo,Chen, Fangjin,Zhang, Yankun,Liu, Jiaying,Zhang, Dongxiang,Meng, Yuan,Wang, Lin,Wang, Hai
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experimental part
p. 3221 - 3228
(2011/06/24)
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- Synthesis and antitumor activity of new sulfonamide derivatives of thiadiazolo[3,2-a]pyrimidines
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New series of sulfonamide derivatives of [1,3,4]thiadiazolo[3,2-a] pyrimidine were synthesized and investigated as antitumor agents. Some of the newly prepared compounds were tested for their in vitro and in vivo antitumor activities. Preliminary biological studies revealed that compounds 4c, 4f, and 4j exhibited the highest affinity to DNA, while compounds 4h,i, 6a-c, 8 and 12-14 exhibited moderate activity. Also, compounds 4j, 4f and 4c showed the highest percentage increase in lifespan of mice inoculated with Ehrlich ascites cells over 5-flurouracil (positive control). The detailed synthesis, spectroscopic and biological data are reported.
- El-Sayed, Nadia S.,El-Bendary, Eman R.,El-Ashry, Saadia M.,El-Kerdawy, Mohammed M.
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experimental part
p. 3714 - 3720
(2011/11/06)
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- COMPOUNDS USEFUL AS CARBONIC ANHYDRASE MODULATORS AND USES THEREOF
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Compounds are disclosed that have formula (I'): wherein A, W, Cy1, Cy2, L1, L2, R1 and R2 are as defined herein. The compounds and pharmaceutical compositions thereof are useful as probes and imaging agents for identifying hypoxic tumors, and treatment of a variety of conditions such as cancers involving hypoxic tumors, in mammals including humans, including by way of non-limiting example, and others.
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Page/Page column 59
(2010/12/31)
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- SMALL MOLECULE INHIBITORS OF THE PLECKSTRIN HOMOLOGY DOMAIN AND METHODS FOR USING SAME
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Pleckstrin homology domain binding compounds, pharmaceutical compositions including such compounds, and methods for their use are described herein.
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Page/Page column 96
(2009/12/02)
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- Carbonic anhydrase inhibitors. Novel sulfanilamide/acetazolamide derivatives obtained by the tail approach and their interaction with the cytosolic isozymes I and II, and the tumor-associated isozyme IX
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A series of sulfonamides has been obtained by reacting sulfanilamide or 5-amino-1,3,4-thiadiazole-2-sulfonamide with ω-chloroalkanoyl chlorides, followed by replacement of the ω-chlorine atom with secondary amines. Tails incorporating heterocyclic amines belonging to the morpholine, piperidine and piperazine ring systems have been attached to these sulfonamides, by means of an alkanoyl-carboxamido linker containing from two to five carbon atoms. The new derivatives prepared in this way were tested as inhibitors of three carbonic anhydrase (CA, EC 4.2.1.1) isozymes, the cytosolic isozymes CA I and II, and the catalytic domain of the transmembrane, tumor-associated isozyme CA IX. Several low nanomolar CA I and CA II inhibitors were detected both in the aromatic and heterocyclic sulfonamide series, whereas the best hCA IX inhibitors (inhibition constants in the range of 22-35 nM) all belonged to the acetazolamide-like derivatives.
- Turkmen, Hasan,Durgun, Mustafa,Yilmaztekin, Serpil,Emul, Mahmut,Innocenti, Alessio,Vullo, Daniela,Scozzafava, Andrea,Supuran, Claudiu T.
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p. 367 - 372
(2007/10/03)
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- NEW AMIDE DERIVATIVES OF 2,2,3,3-TETRAMETHYLCYCLOPROPANE CARBOXYLIC ACID
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The invention relates to new 2,2,3,3-tetramethylcyclopropane carboxamide derivative compounds, pharmaceutical compositions thereof and uses thereof for treating psychotic disorders, neurodegenerative diseases, epilepsy and pain.
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- Carbonic anhydrase inhibitors. Part 36*. Inhibition of isozymes I and II with Schiff bases derived from chalkones and aromatic/heterocyclic sulfonamides
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A series of 27 Schiff bases was prepared by reaction of chalkones with sulfanilamide and 5-amino-1,3,4-thiadiazole-2-sulfonamide. The new compounds were characterized by analysis and standard physico-chemical methods. They possess good inhibitory properties towards isozymes I and II of carbonic anhydrase. Structure-activity effects in this series of inhibitors are also discussed.
- Supuran,Popescu,Ilisiu,Costandache,Banciu
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p. 439 - 447
(2007/10/03)
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- Topically active ocular thiadiazole sulfonamide carbonic anhydrase inhibitors
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The present invention is directed to a compound of the formula: STR1 or pharmaceutically acceptable salts thereof which are useful in the treatment of glaucoma and in the assessment of corneal function.
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- Treatment of chronic inflammatory joint disease with arylsulfonamides
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A method of treating chronic inflammatory joint disease with arylsulfonamides of the formula: wherein R1 and R2 are selected from hydrogen, lower alkyl, lower alkenyl, cycloalkyl, phenyl, loweralkylphenyl, 2 or 3 pyrrolidinyl, 2 or 3-(N-loweralkylpyrrolidinyl, or R1 and R2 taken together may form pyrrolidinyl or piperidinyl heterocyclic amino radicals and Z is an aryl group selected from substituted or unsubstituted tetrazole, 1,3,4-thiadiazole, 1,2,4-triazole, benzothiazole, benzimidazole, imidazole, pyridyl, 4,6-dimethyl pyrimidine, benzene or naphthalene is disclosed.
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- Topically active ocular gem-diacylthiadiazole sulfonamide carbonic anhydrase inhibitors
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This invention relates to compounds of the following formula useful as a carbonic anhydrase inhibitor: A compound of the formula: STR1 and pharmaceutically acceptable salts thereof wherein X is NR12 ; R1 is STR2 R2 is STR3 R3 is hydrogen or lower alkyl; R is hydrogen or lower alkyl; each R4 and R5 are independently hydrogen or lower alkyl; each R7 and R8 are independently hydrogen or lower alkyl; R6 is OR10 or NR10 R11 ; R9 is OR13 OR NR11 R13 ; R10, R11 R12, and R13 are independently hydrogen or lower alkyl; and n and m are independently 0-6.
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