We have previously identified carboranes and metallacarboranes modified by sulfamido or sulfonamido goup as a promising class of specific inhibitors of Carbonic Anhydrase IX (CA IX)1.
Here we report on recent advances in the molecular design of carborane and metallacarborane inhibitors targeting CA IX isoenzyme. This enzyme, which is associated with solid hypoxic tumors, belongs to newly identified targets for cancer therapy and diagnostics.
The scope of currently available site-directed modifications on various boron cages is overviewed, with an emphasis on the progress in the synthesis of carboranes and metallacarboranes substituted by sulfamide, sulfonamide and other similar groups, i.e. functions known to bind tightly to the zinc atom in the active site of CA-IX. The new generations of polyhedral inhibitors of CA-IX, based on the careful selection of boron cages and optimized substitutions, exhibit significantly enhanced in vitro activities with corresponding Ki values in the range of tenths of pM to several nM. The structure-activity relationship (SAR) observed within a small library of ca. 60 substituted carboranes and metallacarboranes is discussed.
These results are complemented by synchrotron structures of enzyme-inhibitor complexes and by a short overview of pharmacologically relevant factors such as plasma protein binding, cell membrane penetration, and basic results from toxicology and pharmacokinetic studies (mouse model) performed on a panel of the selected inhibitors of CA IX enzymes. Due to promising inhibitory properties, these compounds are thus primarily considered as candidates for drugs applicable in cancer treatment.
Supported by Czech Science Foundation, Project No. 15-05677S and in part by Technology Agency of the Czech Republic, Project No. TE01020028 (pharmacology and in vivo testing). Also support from institutional research projects RVO 68378050, 61388963, and 61388980 by the Academy of Sciences of the Czech Republic is appreciated.