scholarly journals Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

2021 ◽  
Vol 23 (1) ◽  
pp. 130
Author(s):  
Audrius Zakšauskas ◽  
Edita Čapkauskaitė ◽  
Vaida Paketurytė-Latvė ◽  
Alexey Smirnov ◽  
Janis Leitans ◽  
...  

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

2004 ◽  
Vol 14 (2) ◽  
pp. 337-341 ◽  
Author(s):  
Francesco Abbate ◽  
Anita Coetzee ◽  
Angela Casini ◽  
Samuele Ciattini ◽  
Andrea Scozzafava ◽  
...  

Biochemistry ◽  
2006 ◽  
Vol 45 (37) ◽  
pp. 11052-11060 ◽  
Author(s):  
Sara E. Cnudde ◽  
Mary Prorok ◽  
Francis J. Castellino ◽  
James H. Geiger

Author(s):  
Zhuolun Shen ◽  
Yufei Xiang ◽  
Sandra Vegara ◽  
Apeng Chen ◽  
Zhengyun Xiao ◽  
...  

AbstractTherapeutic and diagnostic efficacies of numerous small biomolecules and chemical compounds are hampered by the short half-lives. Here we report the development of a repertoire of diverse, high-affinity albumin-nanobodies (NbHSA) to facilitate drug delivery. By integrating biophysics, and hybrid structural biology, we have systematically characterized the NbHSA for albumin binding, mapped the epitopes, and resolved the architecture of a tetrameric Nb-albumin complex. We employed quantitative proteomics for accurate, multiplex Nb pharmacokinetic analysis. Using a humanized albumin mouse model, we found that the NbHSA has outstanding pharmacokinetics; the most stable NbHSA has a 771-fold T1/2 improvement compared with a control Nb. Interestingly, the pharmacokinetics of NbHSA is related to their biophysical and structural properties. To demonstrate the utility of NbHSA, we developed a highly stable NbHSA-hIL-2 cytokine conjugate “Duraleukin” and confirmed its improved anticancer properties than hIL-2 alone. We envision that this high-quality Nb resource will advance research into novel biotherapeutics.


Author(s):  
Judith A. Murphy ◽  
Anthony Paparo ◽  
Richard Sparks

Fingernail clams (Muscu1ium transversum) are dominant bottom-dwelling animals in some waters of the midwest U.S. These organisms are key links in food chains leading from nutrients in water and mud to fish and ducks which are utilized by man. In the mid-1950’s, fingernail clams disappeared from a 100-mile section of the Illinois R., a tributary of the Mississippi R. Some factor(s) in the river and/or sediment currently prevent clams from recolonizing areas where they were formerly abundant. Recently, clams developed shell deformities and died without reproducing. The greatest mortality and highest incidence of shell deformities appeared in test chambers containing the highest proportion of river water to well water. The molluscan shell consists of CaCO3, and the tissue concerned in its secretion is the mantle. The source of the carbonate is probably from metabolic CO2 and the maintenance of ionized Ca concentration in the mantle is controlled by carbonic anhydrase. The Ca is stored in extracellular concentric spherical granules(0.6-5.5μm) which represent a large amount of inertCa in the mantle. The purpose of this investigation was to examine the role of raw river water and well water on shell formation in the fingernail clam.


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