Boron clusters in medicinal chemistry

Probably the most famous application of BC in medicine is the Boron Neutron Capture Therapy (BNCT). This radio-therapeutic method is based on tumor-specific delivery of a drug with a high 10B nucleus content followed by a bombardment of the cells containing this drug with low-energy neutrons. Neutron bombardment results in the formation of an excited 11B* nucleus which splits into high-energy 7Li nucleus and α-particles eventually leading to the destruction of cells containing boron drugs. High drug specificity is extremely desirable to avoid damage to surrounding healthy cells.

A simplified BNCT scheme.

In recent years, BC compounds are appearing more frequently in sophisticated drug designs which are reflected in multiple reviews dedicated to this problem.[1] Their unique inorganic origin is a great alternative to fight the biodegradability of organic drugs while maintaining key properties like tunable hydrophobicity, 3D-orthogonal functionality, and solubility. Mostly, the neutral carboranes are used as replacements for benzene or other planar aromatic moieties of complex organic drugs, inevitably leading to a complete change of drug profile. BC also exhibit low to moderate cytotoxicity in several assays, good stability within the host organism, and excellent bioavailability.[1d, 2]

Earlier works from our group were focused on BC as pharmacophores. They have shown that carefully designed metallacarboranes can effectively block the binding cleft within the HIV protease.[3] The described high binding specificity and selectivity are caused by the unconventional binding mode known as the dihydrogen bond.[4]

Therefore, the focus of our group was directed toward the inhibition of Carbonic Anhydrase IX (CAIX), the tumor-associated enzyme responsible for reversible hydration of carbon dioxide to bicarbonate and a proton. C-substituted alkyl sulfamide derivatives of CoSAN proved themselves as ideal candidates mainly thanks to their optimal space-filling properties, hydrophobicity values, and dihydrogen bonding. The best results achieved were in low nanomolar to sub-nanomolar values with high selectivity towards CAIX. Mouse studies revealed tumor size was reduced similarly to the clinically tested organic candidate U-104 (best compound reduced tumor to 67% compared to the vehicle-treated mice, versus 87% reduction by U-104). Furthermore, we described a detailed study on the pharmacokinetics of these compounds showing that BC are highly convenient drug candidates.[2d, 5]

Structures of carbon-connected methyl (A) and ethyl sulfamide (B) bound to the CAIX active site. J. Med. Chem. 2019, 62, 9560.

The antiparasitic activity of various carborane and metallacarborane naphtalimide derivatives was also presented. In this work tested compounds show excellent activity of these species against soil-transmitted helminths compared to the commonly administrated drug Mebendazole (LC50 of the best derivative is 0.148 μg/μL versus 0.440 μg/μL of Mebendazole).[6]

Refences

[1]      a) Scholz, M., E. Hey-Hawkins, Chem. Rev. 2011, 111, 7035; b) Stockmann, P., M. Gozzi, R. Kuhnert, M. B. Sarosi, E. Hey-Hawkins, Chem. Soc. Rev. 2019, 48, 3497; c) Leśnikowski, Z. J., J. Med. Chem. 2016, 59, 7738; d) Issa, F., M. Kassiou, L. M. Rendina, Chem. Rev. 2011, 111, 5701; e) Chen, Y., F. Du, L. Tang, J. Xu, Y. Zhao, X. Wu, M. Li, J. Shen, Q. Wen, C. H. Cho, Z. Xiao, Mol. Ther. Oncolytics 2022, 24, 400.

[2]      a) Różycka, D., Z. J. Leśnikowski, A. B. Olejniczak, J. Organomet. Chem. 2019, 881, 19; b) Vaňková, E., K. Lokočová, O. Maťátková, I. Křížová, J. Masák, B. Grüner, P. Kaule, J. Čermák, V. Šícha, J. Organomet. Chem. 2019, 899; c) Zheng, Y., W. Liu, Y. Chen, H. Jiang, H. Yan, I. Kosenko, L. Chekulaeva, I. Sivaev, V. Bregadze, X. Wang, Organometallics 2017, 36, 3484; d) Grüner, B., J. Brynda, V. Das, V. Šícha, J. Štěpánková, J. Nekvinda, J. Holub, K. Pospíšilová, M. Fábry, P. Pachl, V. Král, M. Kugler, V. Mašek, M. Medvědíková, S. Matějková, A. Nová, B. Lišková, S. Gurská, P. Džubák, M. Hajdúch, P. Řezáčová, J. Med. Chem. 2019, 62, 9560.

[3]      a) Cígler, P., M. Kožíšek, P. Řezáčová, J. Brynda, Z. Otwinowski, J. Pokorná, J. Plešek, B. Grüner, L. Dolečková-Marešová, M. Máša, J. Sedláček, J. Bodem, H.-G. Kräusslich, V. Král, J. Konvalinka, Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 15394; b) Kožíšek, M., P. Cígler, M. Lepšík, J. Fanfrlík, P. n. Řezáčová, J. Brynda, J. Pokorná, J. r. Plešek, B. Grüner, K. Grantz Šašková, J. Med. Chem. 2008, 51, 4839.

[4]      Fanfrlík, J., M. Lepšík, D. Horinek, Z. Havlas, P. Hobza, ChemPhysChem 2006, 7, 1100.

[5]      a) Dvořanová, J., M. Kugler, J. Holub, V. Šícha, V. Das, J. Nekvinda, S. El Anwar, M. Havránek, K. Pospíšilová, M. Fábry, V. Král, M. Medvědíková, S. Matějková, B. Lišková, S. Gurská, P. Džubák, J. Brynda, M. Hajdúch, B. Grüner, P. Řezáčová, Eur. J. Med. Chem. 2020, 200, 112460; b) Grüner, B., M. Kugler, S. El Anwar, J. Holub, J. Nekvinda, D. Bavol, Z. Růžičková, K. Pospíšilová, M. Fábry, V. Král, J. Brynda, P. Řezáčová, ChemPlusChem 2021, 86, 352; c) Nekvinda, J., M. Kugler, J. Holub, S. El Anwar, J. Brynda, K. Pospíšilová, Z. Růžičková, P. Řezáčová, B. Grüner, Chem. Eur. J. 2020, 26, 16541; d) Brynda, J., P. Mader, V. Šícha, M. Fábry, K. Poncová, M. Bakardiev, B. Grüner, P. Cígler, P. Řezáčová, Angew. Chem. Int. Ed. Engl. 2013, 52, 13760.

[6]        Bogucka-Kocka, A., P. Kolodziej, A. Makuch-Kocka, D. Różycka, S. Rykowski, J. Nekvinda, B. Grüner, A. B. Olejniczak, Chem Commun. 2022, 58, 2528.