Table 2: Anti-tumor agents for targeting hypoxia-induced CA IX for therapy and diagnosis.

The expression of carbonic anhydrase (CA) IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors

Municipal administration structure, competence and activity practice

This final paper examines one of the local authorities – municipal administration – structure, discovers the competence of the municipal administration, the competence of the head of the municipal administration (the director of municipal administration), also the competence of the structural, structural territorial subdivisions - wardens (branches) and also examines the activity practice of the municipal administration highlighting the problematical sides of it. Moreover, it is examined the legal status of the director of the municipal administration, also the legal status of civil servants and employees working under employment contracts who organize the municipal administration. The activity practice is examined invoking the activity reports of Šiauliai district municipal administration and also invoking the jurisprudence of the Supreme Administrative Court of Lithuania. Also in this final paper it is pursued to reveal the potencial influence of the reforms of the self government institute upon the legal regulation of the municipal administration. Finally, this final paper draws inferences from the analysis of the legal rules and the activity of Šiauliai district municipal administration and lays the suggestions of the improvement of the legal regulation of the municipal administration and of the activity efficiency of Šiauliai district municipal administration

Intrinsic Thermodynamics and Structure Correlation of Benzenesulfonamides with a Pyrimidine Moiety Binding to Carbonic Anhydrases I, II, VII, XII, and XIII

<div><p>The early stage of drug discovery is often based on selecting the highest affinity lead compound. To this end the structural and energetic characterization of the binding reaction is important. The binding energetics can be resolved into enthalpic and entropic contributions to the binding Gibbs free energy. Most compound binding reactions are coupled to the absorption or release of protons by the protein or the compound. A distinction between the observed and intrinsic parameters of the binding energetics requires the dissection of the protonation/deprotonation processes. Since only the intrinsic parameters can be correlated with molecular structural perturbations associated with complex formation, it is these parameters that are required for rational drug design. Carbonic anhydrase (CA) isoforms are important therapeutic targets to treat a range of disorders including glaucoma, obesity, epilepsy, and cancer. For effective treatment isoform-specific inhibitors are needed. In this work we investigated the binding and protonation energetics of sixteen [(2-pyrimidinylthio)acetyl]benzenesulfonamide CA inhibitors using isothermal titration calorimetry and fluorescent thermal shift assay. The compounds were built by combining four sulfonamide headgroups with four tailgroups yielding 16 compounds. Their intrinsic binding thermodynamics showed the limitations of the functional group energetic additivity approach used in fragment-based drug design, especially at the level of enthalpies and entropies of binding. Combined with high resolution crystal structural data correlations were drawn between the chemical functional groups on selected inhibitors and intrinsic thermodynamic parameters of CA-inhibitor complex formation.</p></div