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Metallocene-based inhibitors of cancer-associated carbonic anhydrase enzymes IX and XII.

Abstract
In this study, 20 metallocene-based compounds comprising extensive structural diversity were synthesized and evaluated as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. These compounds proved moderate to good CA inhibitors in vitro, with several compounds displaying selectivity for cancer-associated isozymes CA IX and CA XII compared to off-target CA I and CA II. Compound 6 was the most potent ferrocene-based inhibitor with K(i)s of 5.9 and 6.8 nM at CA IX and XII, respectively. A selection of key drug-like parameters comprising Log P, Log D, solubility, and in vitro metabolic stability and permeability were measured for two of the ferrocene-based compounds, regioisomers 1 and 5. Compounds 1 and 5 were found to have characteristics consistent with lipophilic compounds, however, our findings show that the lipophilicity of the ferrocene moiety is not well modeled by replacement with either a naphthyl or a phenyl moiety in software prediction tools.
AuthorsAdam J Salmon, Michael L Williams, Quoc K Wu, Julia Morizzi, Daniel Gregg, Susan A Charman, Daniela Vullo, Claudiu T Supuran, Sally-Ann Poulsen
JournalJournal of medicinal chemistry (J Med Chem) Vol. 55 Issue 11 Pg. 5506-17 (Jun 14 2012) ISSN: 1520-4804 [Electronic] United States
PMID22540953 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antigens, Neoplasm
  • Antineoplastic Agents
  • Carbonic Anhydrase Inhibitors
  • Coordination Complexes
  • Cyclopentanes
  • Ferrous Compounds
  • Metallocenes
  • Triazoles
  • Ruthenium
  • CA9 protein, human
  • Carbonic Anhydrase IX
  • Carbonic Anhydrases
  • carbonic anhydrase XII
  • ferrocene
Topics
  • Antigens, Neoplasm (metabolism)
  • Antineoplastic Agents (chemical synthesis, chemistry, metabolism)
  • Caco-2 Cells
  • Carbonic Anhydrase IX
  • Carbonic Anhydrase Inhibitors (chemical synthesis, chemistry, metabolism)
  • Carbonic Anhydrases (metabolism)
  • Coordination Complexes (chemical synthesis, chemistry, metabolism)
  • Cyclopentanes (chemical synthesis, chemistry, metabolism)
  • Ferrous Compounds (chemical synthesis, chemistry, metabolism)
  • Humans
  • Metallocenes
  • Microsomes, Liver (metabolism)
  • Permeability
  • Ruthenium
  • Solubility
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazoles (chemical synthesis, chemistry, metabolism)

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