- Benzimidazole derivatives as potent and isoform selective tumor-associated carbonic anhydrase IX/XII inhibitors
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We describe the synthesis of a series of 2-arylbenzimidazole derivatives bearing sulfonamide functionality (4a–d, 7a–c and 10) as well as hydroxamic acid (15a–b), carboxylic acid (16a–b), carboxamide (17a–b) and boronic acid (22a–b and 26) functionalities, which act as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. The newly synthesized benzimidazole derivatives were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IX, and XII), and especially the sulfonamide-containing benzimidazoles demonstrated intriguing inhibitory activity against tumor associated CA IX and XII with KI values in the range of 5.2–29.3 nM and 9.9–41.7 nM, respectively. Notably, compound 4c was the most potent and selective CA IX (KI = 6.6 nM) and XII (KI = 9.9 nM) inhibitor with a significant selectivity ratio over cytosolic CA I and II isoforms in the range of 3.4–25.2. In addition, compounds having hydroxamic acid (15a-b) or carboxylic acid (16a-b) functionalities resulted in greater selectivity ratios for CA IX/XII over CAI/II in the range of 4.1–121.5 although with KI values in lower micromolar potency (KIs = 0.36–0.85 μM for CA IX/XII).
- ?al??kan, Burcu,Banoglu, Erden,Gür Maz, Tu??e,Nocentini, Alessio,Supuran, Claudiu T.,Uslu, Azize Gizem
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supporting information
(2020/01/08)
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- Preparation method of 2-nitrochlorobenzene-4-sulfamide
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The invention provides a preparation method of 2-nitrochlorobenzene-4-sulfamide. The preparation method comprises the following steps of adding 2-nitrochlorobenzene-4-sulfonyl chloride and ammonia salt into water, and using Turkey red oil as a wetting agent; adding inorganic alkaline for controlling the pH (potential of hydrogen) value of the system to be 7 to 9, and performing ammonolysis reaction at the temperature of 30 to 60 DEG C, so as to obtain the corresponding product, namely the 2-nitrochlorobenzene-4-sulfamide. The preparation method has the advantages that the ammonia water is replaced with the ammonia salt, so that the adverse effect due to volatilizing of the ammonia water is avoided, the pollution to environment is low, and the hazard to the health of human body can be effectively avoided; all raw materials are added by one step, so that the waste of time and labor in the batch adding process is reduced, the reaction conditions are improved, the reaction can be performedat lower pH value, the decomposing of the 2-nitrochlorobenzene-4-sulfamide is reduced, the production of byproduct is reduced, and the yield rate is increased by 10% or above; because the reaction temperature is higher, the adding of ice is not required, so that the energy consumption is decreased.
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Paragraph 0022-0031
(2019/03/28)
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- PROCESS FOR THE PREPARATION OF VENETOCLAX
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The present disclosure provides novel synthetic process for the preparation of venetoclax. The disclosed processes involve the use of novel intermediates. Processes for the preparation of these intermediates are also disclosed as well as methods for the preparation of particularly useful salts thereof.
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Page/Page column 30; 31
(2018/03/06)
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- Amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide
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An amplified synthesis method of 3-nitro-4-halogeno-benzenesulfonamide is disclosed. According to the method, 4-halogeno-benzenesulfonyl chloride which is used as a raw material undergoes nitration to prepare 3-nitro-4-halogeno-benzenesulfonyl chloride; and after aminolysis, 3-nitro-4-halogeno-benzenesulfonamide is prepared. By the synthesis method provided by the invention, the synthesis route by the adoption of chlorosulfonic acid is changed, and production safety is remarkably raised. The reaction condition is milder and is easy for production control. Thus, mass production of the compound is easier to implement and realize.
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Paragraph 0019; 0021
(2017/08/29)
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- Discovery of a potent inhibitor of the antiapoptotic protein Bcl-X L from NMR and parallel synthesis
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The antiapoptotic proteins Bcl-xL and Bcl-2 play key roles in the maintenance of normal cellular homeostasis. However, their overexpression can lead to oncogenic transformation and is responsible for drug resistance in certain types of cancer. This makes Bcl-xL, and Bcl-2 attractive targets for the development of potential anticancer agents, Here we describe the structure-based discovery of a potent Bcl-xL inhibitor directed at a hydrophobic groove on the surface of the protein. This groove represents the binding site for BH3 peptides from proapoptotic Bcl-2 family members such as Bak and Bad. Application of NMR-based screening yielded an initial biaryl acid with an affinity (Kd) of ~300 μM for the protein. Following the classical "SAR by NMR" approach, a second-site ligand was identified that bound proximal to the first-site ligand in the hydrophobic groove. From NMR-based structural studies and parallel synthesis, a potent ligand was obtained, which binds to Bcl-xL with an inhibition constant (K i) of 36 ± 2 nM.
- Petros, Andrew M.,Dinges, Jurgen,Augeri, David J.,Baumeister, Steven A.,Betebenner, David A.,Bures, Mark G.,Elmore, Steven W.,Hajduk, Philip J.,Joseph, Mary K.,Landis, Shelley K.,Nettesheim, David G.,Rosenberg, Saul H.,Shen, Wang,Thomas, Sheela,Wang, Xilu,Zanze, Irini,Zhang, Haichao,Fesik, Stephen W.
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p. 656 - 663
(2007/10/03)
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- NEW BENZOTHIAZOLESULFONAMIDES
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The present invention relates to new compounds of formula I, (I) wherein R1to R4 are as defined as in formula I, or salts, solvates or solvated salts thereof, processes for their preparation and to new intermediates used in the preparation thereof, pharmaceutical formulations containing said compounds and to the use of said compounds in therapy.
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Page/Page column 19
(2008/06/13)
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- Antileishmanial dinitroaniline sulfonamides with activity against parasite tubulin.
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Novel dinitroaniline sulfonamides based on the herbicide oryzalin 3 were synthesized and evaluated for activity against the parasitic protozoan Leishmania donovani and against leishmanial tubulin, the putative antiparasitic target of oryzalin. A subset of these compounds possess more activity against both Leishmania and the target protein in vitro. Compound 20 displays improved potency against leishmanial tubulin and is 13.4-fold more active against L. donovani axenic amastigotes than oryzalin.
- Bhattacharya, Gautam,Salem, Manar M,Werbovetz, Karl A
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p. 2395 - 2398
(2007/10/03)
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- N-acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula are BCL-Xl inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-Xl inhibiting compositions and methods of promoting apoptosis in a mammal.
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- N-Acylsulfonamide apoptosis promoters
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N-Benzoyl arylsulfonamides having the formula Are BCL-X1 inhibitors and are useful for promoting apoptosis. Also disclosed are BCL-X1 inhibiting compositions and methods of promoting apoptosis in a mammal.
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- Monoazo dyes, process for their preparation, and the use thereof
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The invention relates to monoazo dyes of the formula STR1 wherein K is the radical of a coupling component of the benzene, naphthalene or heterocyclic series, and R is hydrogen, halogen, carboxy, a C1 -C6 alkyl, C1 -C6 alkoxy, C2 -C6 alkanoylamino, C1 -C6 alkylsulfonylamino, C1 -C6 alkylsulfonyl, phenyl(C1 -C4)alkylsulfonyl or naphthyl(C1 -C4)alkylsulfonyl or benzoyl radical, which radicals may be further substituted, or is a STR2 group, wherein each of R1 and R2 independently of the other is hydrogen or a C1 -C6 alkyl, C5 -C7 cycloalkyl, phenyl or naphthyl radical, which radicals may be further substituted, and wherein X is hydrogen, halogen or a C1 -C6 alkyl, C1 -C6 alkoxy, C2 -C6 alkanoylamino or C1 -C6 alkylsulfonylamino radical, which radicals may be further substituted. These dyes give dyeings of good light- and wetfastness properties on polyamide material.
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