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.
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.
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.
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.
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.
A red-shifted photochromic sulfonylurea for the remote control of pancreatic beta cell function
Broichhagen,Frank,Johnston,Mitchell,?mid,Marchetti,Bugliani,Rutter,Trauner,Hodson
, p. 6018 - 6021 (2015)
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.
Infrared and raman spectra of 5-amino-1,3,4-thiadiazole-2-sulfonamide (Hats). Experimental data and quantum chemistry calculations
Camí,Chufán,Pedregosa,Varetti
, p. 119 - 127 (2001)
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.
Synthesis and properties of two new membrane-impermeant high-molecular-weight carbonic anhydrase inhibitors
Conroy, Curtis W.,Wynns, George C.,Maren, Thomas H.
, p. 262 - 272 (1996)
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.
Synthesis, molecular docking analysis and biological evaluations of saccharide-modified thiadiazole sulfonamide derivatives
Zhang, Zuo-Peng,Zhong, Ye,Han, Zhen-Bin,Zhou, Lin,Su, Hua-Sheng,Wang, Jian,Liu, Yang,Cheng, Mao-Sheng
, (2021/05/26)
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.
RADIOACTIVE IMIDAZOTHIADIAZOLE DERIVATIVE COMPOUND
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Paragraph 0085-0087; 0112; 0113, (2021/10/22)
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.