Metallacarborane Sulfamides: Unconventional, Specific, and Highly Selective Inhibitors of Carbonic Anhydrase IX

Carbonic
anhydrase IX (CAIX) is a transmembrane enzyme that regulates
pH in hypoxic tumors and promotes tumor cell survival. Its expression
is associated with the occurrence of metastases and poor prognosis.
Here, we present nine derivatives of the cobalt bis­(dicarbollide)(1−)
anion substituted at the boron or carbon sites by alkysulfamide group(s)
as highly specific and selective inhibitors of CAIX. Interactions
of these compounds with the active site of CAIX were explored on the
atomic level using protein crystallography. Two selected derivatives
display subnanomolar or picomolar inhibition constants and high selectivity
for the tumor-specific CAIX over cytosolic isoform CAII. Both derivatives
had a time-dependent effect on the growth of multicellular spheroids
of HT-29 and HCT116 colorectal cancer cells, facilitated penetration
and/or accumulation of doxorubicin into spheroids, and displayed low
toxicity and showed promising pharmacokinetics and a significant inhibitory
effect on tumor growth in syngenic breast 4T1 and colorectal HT-29
cancer xenotransplants.