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).

Institute of Inorganic Chemistry of the Czech Academy of Sciences Hlavní Husinec 1001 25068 Řež Czech Republic

Institute of Molecular and Translational Medicine Hněvotínská 1333 5 77900 Olomouc Czech Republic

Institute of Molecular Genetics of the Czech Academy of Sciences Vídeňská 1083 14220 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Flemingovo nám 2 16610 Prague Czech Republic

See more in PubMed

N. S. Hosmane, J. A. Maguire, Y. Zhu, M. Takagaki, Boron and Gadolinium Neutron Capture Therapy for Cancer Treatment, 1st ed., World Scientific, New, 2012;

M. F. Hawthorne, M. W. Lee, J. Neuro-Oncol. 2003, 62, 33-45;

N. Protti, A. Deagostino, P. Boggio, D. Alberti, S. G. Crich, New Boronated Compounds for an Imaging-Guided Personalized Neutron Capture Therapy, Wiley, Chichester, 2018.

M. F. Hawthorne, A. Maderna, Chem. Rev. 1999, 99, 3421-3434.

S. J. Baker, C. Z. Ding, T. Akama, Y.-K. Zhang, V. Hernandez, Y. Xia, Future Med. Chem. 2009, 1, 1275-1288;

W. Yang, X. Gao, B. Wang, Med. Res. Rev. 2003, 23, 346-368;

Y. H. Zhu, X. L. Lin, H. M. Xie, J. L. Li, N. S. Hosmane, Y. J. Zhang, Curr. Med. Chem. 2019, 26, 5019-5035.

C. J. Van der Schyf, W. J. Geldenhuys, Neurotherapeutics 2009, 6, 175-186;

R. N. Grimes, Carboranes, 3rd ed., Academic Press, London, 2016;

D. Gabel, Pure Appl. Chem. 2015, 87, 173-179;

J. F. Valliant, K. J. Guenther, A. S. King, P. Morel, P. Schaffer, O. O. Sogbein, K. A. Stephenson, Coord. Chem. Rev. 2002, 232, 173-230;

F. Issa, M. Kassiou, M. Rendina, Chem. Rev. 2011, 111, 5701-5722;

Z. J. Leśnikowski, J. Med. Chem. 2016, 59, 7738-7758;

M. Scholz, E. Hey-Hawkins, Chem. Rev. 2011, 111, 7035-7062;

J. Kahlert, C. J. D. Austin, M. Kassiou, L. M. Rendina, Austr. J. Chem. 2013, 66, 1118-1123.

T. M. Goszczynski, K. Fink, K. Kowalski, Z. J. Lesnikowski, J. Boratynski, Sci. Rep. 2017, 7, 12.

Z. J. Lesnikowski, Collect. Czech. Chem. Commun. 2007, 72, 1646-1658;

P. Stockmann, M. Gozzi, R. Kuhnert, M. B. Sarosi, E. Hey-Hawkins, Chem. Soc. Rev. 2019, 48, 3497-3512.

J. Casanova, J. Am. Chem. Soc. 1999, 121, 6522-6522;

R. E. Williams, Chem. Rev. 1992, 92, 177-207.

J. Fanfrlík, M. Lepšík, D. Horinek, Z. Havlas, P. Hobza, ChemPhysChem 2006, 7, 1100-1105.

J. Fanfrlik, D. Hnyk, M. Lepsik, P. Hobza, Phys. Chem. Chem. Phys. 2007, 9, 2085-2093.

J. Fanfrlik, A. Pecina, J. Řezáč, R. Sedlák, D. Hnyk, M. Lepšík, P. Hobza, Phys. Chem. Chem. Phys. 2017, 19, 18194-18200;

R. Sedlak, J. Fanfrlik, A. Pecina, D. Hnyk, P. Hobza, M. Lepsik, Boron: The Fifth Element, Vol. 20 (Eds.: D. Hnyk, M. L. McKee), Springer, Dordrecht, 2015, pp. 219-239.

K. Hermansson, M. Wójcik, S. Sjöberg, Inorg. Chem. 1999, 38, 6039-6048.

K. Yamamoto, Y. Endo, Bioorg. Med. Chem. Lett. 2001, 11, 2389-2392.

M. A. Fox, W. R. Gill, P. L. Herbertson, J. A. H. MacBride, K. Wade, H. M. Colquhoun, Polyhedron 1996, 15, 565-571.

R. N. Grimes, Coord. Chem. Rev. 2000, 200, 773-811;

B. P. Dash, R. Satapathy, B. R. Swain, C. S. Mahanta, B. B. Jena, N. S. Hosmane, J. Organomet. Chem. 2017, 849-850, 170-194;

I. B. Sivaev, V. I. Bregadze, Collect. Czech. Chem. Commun. 1999, 64, 783-805.

J. Rak, R. Kaplánek, V. Král, Bioorg. Med. Chem. Lett. 2010, 20, 1045-1048.

O. Leukart, M. Caviezel, A. Eberle, E. Escher, A. Tun-Kyi, R. Schwyzer, Helv. Chim. Acta 1976, 59, 2184-2187.

W. Fischli, O. Leukart, R. Schwyzer, Helv. Chim. Acta 1977, 60, 959-963.

J.-L. Fauchère, O. Leukart, A. Eberle, R. Schwyzer, Helv. Chim. Acta 1979, 62, 1385-1395;

E. Escher, G. Guillemette, O. Leukart, D. Regoli, Eur. J. Pharmacol. 1980, 66, 267-272;

R. J. Nachman, P. E. A. Teal, P. A. Radel, G. M. Holman, R. L. Abernathy, Peptides 1996, 17, 747-752.

Y. Endo, T. Iijima, Y. Yamakoshi, H. Fukasawa, C. Miyaura, M. Inada, A. Kubo, A. Itai, Chem. Biol. 2001, 8, 341-355.

T. Iijima, Y. Endo, M. Tsuji, E. Kawachi, H. Kagechika, K. Shudo, Chem. Pharm. Bull. 1999, 47, 398-404;

T. Goto, K. Ohta, T. Suzuki, S. Ohta, Y. Endo, Bioorg. Med. Chem. 2005, 13, 6414-6424.

M. Tsuji, Y. Koiso, H. Takahashi, Y. Hashimoto, Y. Endo, Biol. Pharm. Bull. 2000, 23, 513-516.

B. T. S. Thirumamagal, X. B. Zhao, A. K. Bandyopadhyaya, S. Naranyanasamy, J. Johnsamuel, R. Tiwari, D. W. Golightly, V. Patel, B. T. Jehning, M. V. Backer, R. F. Barth, R. J. Lee, J. M. Backer, W. Tjarks, Bioconjugate Chem. 2006, 17, 1141-1150.

P. Cígler, M. Kožíšek, P. Řezáčová, J. Brynda, Z. Otwinowski, J. Pokorná, J. Plešek, B. Grűner, L. Dolečková-Marešová, M. Máša, J. Sedláček, J. Bodem, H. G. Krausslich, V. Král, J. Konvalinka, Proc. Natl. Acad. Sci. USA 2005, 102, 15394-15399.

I. Fuentes, T. Garcia-Mendiola, S. Sato, M. Pita, H. Nakamura, E. Lorenzo, F. Teixidor, F. Marques, C. Viñas, Chem. Eur. J. 2018, 24, 17239-17254;

P. Farras, E. J. Juarez-Perez, M. Lepšík, R. Luque, R. Núñez, F. Teixidor, Chem. Soc. Rev. 2012, 41, 3445-3463.

W. S. Sly, P. Y. Hu, Annu. Rev. Biochem. 1995, 64, 375-401;

C. T. Supuran, A. Scozzafava, Bioorg. Med. Chem. 2007, 15, 4336-4350;

T. S. Claudiu, Curr. Top. Med. Chem. 2007, 7, 825-833.

S. Hamidi, M. Avoli, Neuropharmacology 2015, 95, 377-387;

E. Ruusuvuori, K. Kaila, Subcell. Biochem. 2014, 75, 271-290;

R. L. Arechederra, A. Waheed, W. S. Sly, C. T. Supuran, S. D. Minteer, Bioorg. Med. Chem. 2013, 21, 1544-1548.

C. B. Mishra, M. Tiwari, C. T. Supuran, Med. Res. Rev. 2020, 40, 2485-2565.

C. T. Supuran, Curr. Pharm. Des. 2008, 14, 601-602;

E. Masini, F. Carta, A. Scozzafava, C. T. Supuran, Expert Opin. Ther. Pat. 2013, 23, 705-716;

A. Scozzafava, C. T. Supuran, F. Carta, Expert Opin. Ther. Pat. 2013, 23, 725-735;

F. Carta, C. T. Supuran, Expert Opin. Ther. Pat. 2013, 23, 681-691;

M. Aggarwal, B. Kondeti, R. McKenna, Expert Opin. Ther. Pat. 2013, 23, 717-724.

M. de Martino, I. Lucca, A. Mbeutcha, H. G. Wiener, A. Haitel, M. Susani, S. F. Shariat, T. Klatte, Eur. Urol. 2015, 68, 552-554;

L. Capkova, L. Koubkova, R. Kodet, Neoplasma 2014, 61, 161-169;

M. Kobayashi, T. Matsumoto, S. Ryuge, K. Yanagita, R. Nagashio, Y. Kawakami, N. Goshima, S.-X. Jiang, M. Saegusa, A. Iyoda, Y. Satoh, N. Masuda, Y. Sato, PLoS One 2012, 7, e33952-e33952;

M.-H. Chien, T.-H. Ying, Y.-H. Hsieh, C.-H. Lin, C.-H. Shih, L.-H. Wei, S.-F. Yang, Oral Oncol. 2012, 48, 417-423.

J. Kopecka, I. Campia, A. Jacobs, A. P. Frei, D. Ghigo, B. Wollscheid, C. Riganti, Oncotarget 2015, 6, 6776-6793;

T. Dorai, I. S. Sawczuk, J. Pastorek, P. H. Wiernik, J. P. Dutcher, Eur. J. Cancer 2005, 41, 2935-2947;

J.-S. Yang, C.-W. Lin, C.-Y. Chuang, S.-C. Su, S.-H. Lin, S.-F. Yang, Tumor Biol. 2015, 36, 9517-9524.

M. A. Pinard, B. Mahon, R. McKenna, BioMed Res. Int. 2015, 2015, 453543.

A. Bhatt, B. P. Mahon, V. W. D. Cruzeiro, B. Cornelio, M. Laronze-Cochard, M. Ceruso, J. Sapi, G. A. Rance, A. N. Khlobystov, A. Fontana, A. Roitberg, C. T. Supuran, R. McKenna, ChemBioChem 2017, 18, 213-222.

V. Alterio, A. Di Fiore, K. D′Ambrosio, C. T. Supuran, G. De Simone, Chem. Rev. 2012, 112, 4421-4468.

S. Pastorekova, S. Parkkila, J. Pastorek, C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2004, 19, 199-229;

C. T. Supuran, Future Med. Chem. 2011, 3, 1165-1180.

C. T. Supuran, J. Enzyme Inhib. Med. Chem. 2012, 27, 759-772;

C. T. Supuran, Bioorg. Med. Chem. Lett. 2010, 20, 3467-3474.

V. Alterio, R. M. Vitale, S. M. Monti, C. Pedone, A. Scozzafava, A. Cecchi, G. De Simone, C. T. Supuran, J. Am. Chem. Soc. 2006, 128, 8329-8335;

S. Biswas, M. Aggarwal, Ö. Güzel, A. Scozzafava, R. McKenna, C. T. Supuran, Bioorg. Med. Chem. 2011, 19, 3732-3738;

F. Carta, V. Garaj, A. Maresca, J. Wagner, B. S. Avvaru, A. H. Robbins, A. Scozzafava, R. McKenna, C. T. Supuran, Bioorg. Med. Chem. 2011, 19, 3105-3119.

J. Brynda, P. Mader, V. Šícha, M. Fábry, K. Poncová, M. Bakardiev, B. Grüner, P. Cígler, P. Řezáčová, Angew. Chem. Int. Ed. 2013, 52, 13760;

Angew. Chem. 2013, 125, 14005-13763.

T. N. Bhat, P. Bourne, Z. K. Feng, G. Gilliland, S. Jain, V. Ravichandran, B. Schneider, K. Schneider, N. Thanki, H. Weissig, J. Westbrook, H. M. Berman, Nucleic Acids Res. 2001, 29, 214-218.

P. Mader, J. Brynda, R. Gitto, S. Agnello, P. Pachl, C. T. Supuran, A. Chimirri, P. Řezáčová, J. Med. Chem. 2011, 54, 2522-2526.

B. Grüner, J. Brynda, V. Das, V. Šícha, J. Štepánková, J. Nekvinda, J. Holub, K. Pospíšilová, M. Fábry, P. Pachl, V. Král, M. Kugler, V. Mašek, M. Medvedíková, S. Matějková, A. Nová, B. Lišková, S. Gurská, P. Džubák, M. Hajdůch, P. Řezáčová, J. Med. Chem. 2019, 62, 9560-9575;

J. Dvořanová, M. Kugler, J. Holub, V. Šícha, V. Das, J. Nekvinda, S. El Anwar, M. Havránek, K. Pospíšilová, M. Fábry, V. Král, M. Medvedíková, S. Matějková, B. Liškova, S. Gurská, P. Džubák, J. Brynda, M. Hajdůch, B. Grüner, P. Rezáčová, Eur. J. Med. Chem. 2020, 200, 112460;

B. Grüner, M. Kugler, S. El Anwar, J. Holub, J. Nekvinda, D. Bavol, Z. Růžičková, K. Pospíšilová, M. Fábry, V. Král, J. Brynda, P. Řezáčová, ChemPlusChem 2020, 85, 351-363;

M. Kugler, J. Holub, J. Brynda, K. Pospíšilová, S. E. Anwar, D. Bavol, M. Havránek, V. Král, M. Fábry, B. Grüner, P. Rezáčová, J. Enzyme Inhib. Med. Chem. 2020, 35, 1800-1810;

J. Nekvinda, M. Kugler, J. Holub, S. El Anwar, J. Brynda, K. Pospíšilová, Z. Růžičková, P. Řezáčová, B. Grüner, Chem. Eur. J. 2020, 69, 16541-16553.

F. Carta, C. T. Supuran, A. Scozzafava, Future Med. Chem. 2014, 6, 1149-1165;

A. Bonardi, A. Nocentini, S. Bua, J. Combs, C. Lomelino, J. Andring, L. Lucarini, S. Sgambellone, E. Masini, R. McKenna, P. Gratteri, C. T. Supuran, J. Med. Chem. 2020, 63, 7422-7444.

J. G. Wilson, A. K. M. Anisuzzaman, F. Alam, A. H. Soloway, Inorg. Chem. 1992, 31, 955-1958.

J. D. Lee, Y. J. Lee, H. J. Jeong, J. S. Lee, C. H. Lee, J. Ko, S. O. Kang, Organometallics 2003, 22, 445-449;

S. L. Woodhouse, L. M. Rendina, Dalton Trans. 2004, 2004, 3669-3677.

A. S. Batsanov, A. E. Goeta, J. A. K. Howard, A. K. Hughes, J. M. Malget, J. Chem. Soc. Dalton Trans. 2001, 1820-1826.

V. N. Kalinin, E. G. Rys, A. A. Tyutyunov, A. Z. Starikova, A. A. Korlyukov, V. A. Ol′shevskaya, D. D. Sung, A. B. Ponomaryov, P. V. Petrovskii, E. Hey-Hawkins, Dalton Trans. 2005, 903-908;

L. N. Goswami, T. J. Olds, T. G. Monk, Q. L. Johnson, J. P. Dilger, M. A. Shanawaz, S. S. Jalisatgi, M. F. Hawthorne, G. R. Kracke, ChemMedChem 2019, 14, 1108-1114.

V. A. Ol′shevskaya, Y. V. Dutikova, A. A. Tyutyunov, E. G. Kononova, P. V. Petrovskii, D. D. Sung, V. N. Kalinin, Synlett 2010, 1265-1267.

K. Vyakaranam, S. J. Li, C. Zheng, N. S. Hosmane, Inorg. Chem. Commun. 2001, 4, 180-182.

B. E. Maryanoff, D. F. McComsey, M. J. Costanzo, C. Hochman, V. Smith-Swintosky, R. P. Shank, J. Med. Chem. 2005, 48, 1941-1947.

R. J. Pace, J. Williams, R. L. Williams, J. Chem. Soc. 1961, 2196-&.

A. A. Semioshkin, I. B. Sivaev, V. I. Bregadze, Dalton Trans. 2008, 2008, 977-992.

J. Plešek, B. Grüner, V. Sicha, V. Bohmer, I. Cisařová, Organometallics 2012, 31, 1703-1715.

B. Grüner, P. Švec, V. Šícha, Z. Padělková, Dalton Trans. 2012, 41, 7498-7512;

J. Nekvinda, J. Švehla, I. Císařová, B. Grüner, J. Organomet. Chem. 2015, 798, 112-120.

B. Grüner, V. Šícha, D. Hnyk, M. G. S. Londesborough, I. Cisařová, Inorg. Chem. 2015, 54, 3148-3158.

R. M. Chamberlin, B. L. Scott, M. M. Melo, K. D. Abney, Inorg. Chem. 1997, 36, 809-817.

R. G. Khalifah, J. Biol. Chem. 1971, 246, 2561-2573.

M. A. Pinard, C. D. Boone, B. D. Rife, C. T. Supuran, R. McKenna, Bioorg. Med. Chem. 2013, 21, 7210-7215.

M. Aggarwal, B. Kondeti, R. McKenna, Bioorg. Med. Chem. 2013, 21, 1526-1533.

P. Mader, A. Pecina, P. Cígler, M. Lepšík, V. Šícha, P. Hobza, B. Gruner, J. Fanfrlík, J. Brynda, P. Řezáčová, BioMed Res. Int. 2014, 2014, 9.

C. T. Supuran, Expert Opin. Drug Discovery 2017, 12, 61-88.

V. M. Krishnamurthy, G. K. Kaufman, A. R. Urbach, I. Gitlin, K. L. Gudiksen, D. B. Weibel, G. M. Whitesides, Chem. Rev. 2008, 108, 946-1051.

V. Šolínová, J. Brynda, V. Šícha, J. Holub, B. Grűner, V. Kašička, Electrophoresis 2021, 42, 910-919.

C. L. Lomelino, B. P. Mahon, R. McKenna, F. Carta, C. T. Supuran, Bioorg. Med. Chem. 2016, 24, 976-981.

J. T. Andring, M. Fouch, S. Akocak, A. Angeli, C. T. Supuran, M. A. Ilies, R. McKenna, J. Med. Chem. 2020, 63, 13064-13075.

P. C. McDonald, S. Chia, P. L. Bedard, Q. Chu, M. Lyle, L. R. Tang, M. Singh, Z. H. Zhang, C. T. Supuran, D. J. Renouf, S. Dedhar, Am. J. Clin. Oncol. Cancer Clin. Trials 2020, 43, 484-490;

Y. M. Lou, P. C. McDonald, A. Oloumi, S. Chia, C. Ostlund, A. Ahmadi, A. Kyle, U. A. D. Keller, S. Leung, D. Huntsman, B. Clarke, B. W. Sutherland, D. Waterhouse, M. Bally, C. Roskelley, C. M. Overall, A. Minchinton, F. Pacchiano, F. Carta, A. Scozzafava, N. Touisni, J. Y. Winum, C. T. Supuran, S. Dedhar, Cancer Res. 2011, 71, 3364-3376.

D. Alberti, A. Michelotti, A. Lanfranco, N. Protti, S. Altieri, A. Deagostino, S. G. Crich, Sci. Rep. 2020, 10, 13.

Carbon-Substituted Amines of the Cobalt Bis(dicarbollide) Ion: Stereochemistry and Acid-Base Properties

Chemistry of Carbon-Substituted Derivatives of Cobalt Bis(dicarbollide)(1-) Ion and Recent Progress in Boron Substitution

Electrochemistry of Cobalta Bis(dicarbollide) Ions Substituted at Carbon Atoms with Hydrophilic Alkylhydroxy and Carboxy Groups