Carborane-based carbonic anhydrase inhibitors.
Jiří Brynda1, Pavel Mader, Václav Šícha
1Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i. Vídeňská 1083, 142 20 Prague 4 (Czech Republic); Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. Flemingovo nám. 2, 16610 Prague 6 (Czech Republic).
Angewandte Chemie (International Ed. in English)
|December 6, 2013
Summary
New carborane compounds effectively inhibit cancer-associated carbonic anhydrases (CAs). These inhibitors show high selectivity for the cancer-specific isozyme IX, aiding in targeted cancer therapy development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Structural Biology
Background:
- Human carbonic anhydrases (CAs) are crucial diagnostic and therapeutic targets.
- CA inhibitors are actively researched for various medical applications.
Purpose of the Study:
- To investigate carborane cages as active-site-directed inhibitors of carbonic anhydrases.
- To develop selective inhibitors targeting the cancer-specific isozyme IX.
Main Methods:
- Synthesis and characterization of novel carborane derivatives.
- Evaluation of inhibitory activity against human carbonic anhydrase isozymes.
- X-ray crystallography to determine binding modes within the enzyme active site.
Main Results:
- Various carborane cages demonstrated active-site-directed inhibition of CAs.
- Substitution with sulfamide and other groups yielded compounds with high selectivity for CA IX.
- Crystal structures revealed detailed interactions of carboranes in the CA active site.
Conclusions:
- Carborane-based compounds are promising candidates for selective CA IX inhibition.
- Structure-based design approaches can be applied to optimize these inhibitors.
- These findings support the development of targeted therapies for cancers expressing CA IX.
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