Boron Cluster Derivatives as Inhibitors of Important Therapeutical Targets: HIV-1 Protease and Carbonic Anhydrase IX

Jiří Brynda^1,2, Pavel Mader¹, Jana Pokorná², Milan Kožíšek², Petr Cígler², Václav Šícha³, Martin Lepšík², Pavel Hobza², Jan Konvalinka², Bohumír Grüner³, Pavlína Řezáčová^1,2

¹Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic

²Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Gilead Sciences and IOCB Research Center

³Institute of Inorganic Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Husinec-Řež u Prahy, Czech Republic

brynda@img.cas.cz, pavel.mader@gmail.com

Boron cluster derivatives have been previously identified and characterized as a new class of HIV protease inhibitors [1,2]. Structural studies of metallacarboranes in complex with HIV protease as well as novel type of boron cluster derivatives designed on basis of previous structural studies [3,4] and their specific inhibitory effect on human carbonic anhydrase IX (CA IX) will be presented.

CA IX is overexpressed in several hypoxic cancer tissues. The structure and enzyme inhibition effects of boron cluster based inhibitors will be presented. This novel types of selective CA IX inhibitors could play important role in cancer diagnostics and therapy.

Figure 1. Boron cluster derivatives as novel types of inhibitors of HIV protease (left panel) and carborane-sulfamide molecule binding to the active site of hCA II (right panel).

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3. Mader, P. „Structure, function and inhibition of human carbonic anhydrases. Ph.D. Thesis“, Charles University in Prague, 2010.

4. Mader, P.; Brynda, J.; Gitto, R.; Agnello, S.; Pachl, P.; Supuran, C. T.; Chimirri, A.; Rezacova, P. Structural Basis for the Interaction Between Carbonic Anhydrase and 1,2,3,4-tetrahydroisoquinolin-2-ylsulfonamides. Journal of Medicinal Chemistry 54, 2522-2526, 2011.