Inhibitors of CA IX Enzyme Based on Polyhedral Boron Compounds

Abstract

This review describes recent progress in the design and development of inhibitors of human carbonic anhydrase IX (CA IX) based on space‐filling carborane and cobalt bis(dicarbollide) clusters. CA IX enzyme is known to play a crucial role in cancer cell proliferation and metastases. The new class of potent and selective CA IX inhibitors combines the structural motif of a bulky inorganic cluster with an alkylsulfamido or alkylsulfonamido anchor group for Zn2+ ion in the enzyme active site. Detailed structure‐activity relationship (SAR) studies of a large series containing 50 compounds uncovered structural features of the cluster‐containing inhibitors that are important for efficient and selective inhibition of CA IX activity. Preclinical evaluation of selected compounds revealed low toxicity, favorable pharmacokinetics and ability to reduce tumor growth. Cluster‐containing inhibitors of CA IX can thus be considered as promising candidates for drug development and/or for combination therapy in boron neutron capture therapy (BNCT).

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…CAIX is an enzyme expressed on the surface of hypoxic tumor cells. 206 , 207 , 208 , 209 This enzyme promoted the survival of tumor cells and could be a target for anticancer therapy. 206 , 207 In this context, biscarborane-containing CAIX inhibitors ( 43 ) were designed and synthesized by the Grüner group ( Figure 6 F).…”

“… 206 , 207 , 208 , 209 This enzyme promoted the survival of tumor cells and could be a target for anticancer therapy. 206 , 207 In this context, biscarborane-containing CAIX inhibitors ( 43 ) were designed and synthesized by the Grüner group ( Figure 6 F). 206 , 210 These cobalt bis(dicarbollide) ions acted as highly potent and specific CAIX inhibitors both in vitro and in vivo .…”

Synthesis of Boronated Amidines by Addition of Amines to Nitrilium Derivative of Cobalt Bis(Dicarbollide)

“…Cobalt bis(dicarbollide) [3,3 -Co(1,2-C 2 B 9 H 11 ) 2 ] − is the most available and the most stable of metallacarboranes [1][2][3][4], which attracts considerable attention of researchers due to possibility of its use in a variety of fields, from the development of new materials [5][6][7][8][9][10][11][12] to medicine [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]. Therefore, the development of new convenient methods for the functionalization of cobalt bis(dicarbollide) cobalt is an important task [3,4].…”

Structurally rigidified cobalt bis(dicarbollide) derivatives, a chiral platform for labelling of biomolecules and new materials

“…8–13 Its behaviour in aqueous systems has been denoted as a superchaotropic ion 10,13 or “nonstealth” amphiphile. 14–16 The cobalta bis(dicarbollide) ion easily penetrates into cells and cell tissues 12,17–19 and its modified derivatives have been shown to function in DNA labelling 20 and as unconventional structural blocks 7,21 in drug design for specific inhibitors of HIV-Protease, 8 cancer-associated Carbonic Anhydrase (CAIX), 12,22 antimicrobial and/or cytotoxic agents 23–25 and modulators of interactions between biomolecules. 26…”

“…This effect is manifested in, for example, complicated discrimination of enantiomers that do not contain a rotational restriction group, by HPLC using cyclodextrin chiral stationary phases (CSPs), 29 splitting the electrode signals into several peaks in electrochemistry, 30 or by the presence of two observed orientations of the auxiliary substituent in the X-ray structures of CAIX–inhibitor complexes. 22 For some stereo-sensitive applications, the presence of one single conformer (rotamer) might be advantageous. This can be easily achieved by means of an intramolecular bridge between two dicarbollide parts.…”