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

J Med Chem. 2019 Nov 14;62(21):9560-9575. doi: 10.1021/acs.jmedchem.9b00945. Epub 2019 Oct 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Animals
  • Biological Transport / drug effects
  • Boranes / chemistry*
  • Boranes / pharmacology*
  • Carbonic Anhydrase IX / chemistry
  • Carbonic Anhydrase IX / metabolism*
  • Carbonic Anhydrase Inhibitors / chemistry*
  • Carbonic Anhydrase Inhibitors / pharmacology*
  • Catalytic Domain
  • Cell Line, Tumor
  • Doxorubicin / metabolism
  • Drug Design
  • Drug Synergism
  • Humans
  • Mice
  • Models, Molecular
  • Xenograft Model Antitumor Assays


  • Amides
  • Boranes
  • Carbonic Anhydrase Inhibitors
  • Doxorubicin
  • Carbonic Anhydrase IX