| Abstract [eng] |
The dissertation compared two groups of synthesized benzenesulfonamide inhibitors bearing bulky substituents at the 4,5- and 2,5- positions. In both groups, inhibitors exhibiting exceptionally high subnanomolar affinity toward individual CA isozymes were identified. The synthesized compounds enabled the determination of crystal structures of inhibitor–CA complexes. This facilitated understanding of structure–biological activity relationships and provided an overall positive advance in the research, particularly in the search for inhibitors of the cancer-associated carbonic anhydrase IX isozyme. The regioselectivity of nucleophilic substitution reactions of 2,4-dihalo-5-sulfamoylbenzoates bearing identical halogens was investigated, and a new synthetic approach for 2,5-disubstituted-4-halobenzenesulfonamides was developed. It was determined that, within the group of 2,5-disubstituted benzenesulfonamide inhibitors, substituents at the 2-position have a particularly strong influence on inhibitor properties. 2-Amino and 2-sulfanyl substituents exhibited high affinity and selectivity toward the CA IX isozyme. In contrast, 2-sulfonyl substituents resulted in a pronounced decrease in affinity toward all CA isozymes. It was also demonstrated that 2-substituted benzenesulfonamides may represent promising and superior CA IX inhibitors compared to previously used drugs of similar structure. |
