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Pharmacologically relevant boron cluster compounds

Contact Person: Bohumír Grüner

Scientists from the Department of Synthesis at the Institute of Inorganic Chemistry play a crucial role in a broader interdisciplinary collaboration focused on developing biologically active carboranes and metallacarboranes. Their contributions include the design and synthesis of unconventional biologically active compounds. Biological studies are carried out in cooperation with teams from the Institute of Molecular Genetics of the CAS (IMG CAS), the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB CAS), the Institute of Biophysics of the CAS (IBP CAS) in Brno, the Institute of Macromolecular Chemistry of the CAS (IMC CAS), the Institute of Molecular and Translational Medicine at Palacký University in Olomouc (IMTM), and IKEM Prague.

Design and Synthesis of Pharmacologically Relevant Boron Cluster Compounds

Promising results in the development of specific inhibitors of the enzyme carbonic anhydrase IX (CA-IX) have provided inspiration to continue research in this area, particularly focusing on the use of these compounds in imaging techniques and the identification of additional pharmacological targets for chemical intervention using boron clusters. The presence of CA-IX is associated with the surface of hypoxic tumour cells and is currently recognized as a validated target for cancer diagnosis and treatment.
A series of newly developed chemical methods have enabled the synthesis of substituted derivatives of carboranes and the cobalt bis(dicarbollide) ion with terminal sulfonamide (or similar) groups, which are known to bind strongly to the Zn²⁺ atom in the CA-IX active site. These new inorganic CA-IX inhibitors are currently accessible through three to six synthetic steps and exhibit promising in vitro activity, with Ki values ranging from low nanomolar to picomolar levels (20 pM for the most potent inhibitor to date). The best selectivity factor values for CAIX/CAII currently reach 668 (for metallacarborane) and 1312 (for carborane). Concurrent structural, physicochemical, and theoretical studies of enzyme-inhibitor complexes, conducted in collaboration with IOCB CAS and IMG CAS (Figures 1 and 2), have provided valuable insights into the structure-activity relationships (SAR) [1-8].
Further studies on pharmacologically relevant factors, such as in vitro cytotoxic properties, protein-binding affinity, membrane permeability, in vivo toxicity, pharmacokinetic, and activity studies in mouse xenograft models, conducted in cooperation with IMTM, have confirmed the promising properties of these compounds. Therefore, these inhibitors can be considered suitable candidates for further development into drug formulations and as diagnostic tools for cancer therapy. Additionally, ionic compounds have demonstrated potential for effective transport of cytostatics like Doxorubicin across cell membranes [1, 2, 5].

Figure 1: Structure of the metallacarborane inhibitor CB-31 in the active site of CA-29 (CA-IX mimic) enzyme. Structure determination: J. Brynda, P. Řezáčová, IMG CAS, IOCB CAS.

Figure 2: Overlay of the structure of the metallacarborane inhibitor CB-30 in the CA-29 (CA-IX mimic) active site with the simplest ortho- closo- and nido-carboranes-based inhibitors [1], carrying a zinc binding group. The structures provide insights into the higher activity observed with metallacarboranes due to better interactions with both enzyme pockets and multiple steric contacts near the active site. Structure determination: J. Brynda, P. Řezáčová, IMG CAS, IOCB CAS.

Interdisciplinary and International Collaboration

Given the limited understanding of how polyhedral compounds interact with components of living systems, research in this field is carried out alongside experimental, theoretical, and physicochemical studies of various types of interactions with natural and model systems. This research is conducted in collaboration with IMTM, IMG, IOCB, and IBP. In cooperation with Constructor University in Bremen, Germany, interactions of substituted ionic boron cluster compounds with supramolecular platforms, model and natural cell membranes, and selected cell lines are being studied. Recently, it has been discovered that bulky borate cluster anions can transport impermeable cationic proteins across cell membranes [9,10].
Simultaneously, collaboration with IBP CAS focuses on understanding the redox behaviuor of compounds in aqueous solutions using electrochemical methods and employing selected metallacarborane structural blocks for biomolecule labelling. Current goals include structural modifications to enable easy and specific conjugation with biomacromolecules and fine-tuning the electrochemical window and response of cluster labels [11-13].

References:

  1. B. Grüner, J. Brynda, V. Das, V. Šícha, J. Štěpánková, J. Nekvinda, J. Holub, K. Pospíšilová, M. Fábry, P. Pachl, V. Kral, M. Kugler, V. Mašek, M. Medvědíková, S. Matějková, A. Nová, B. Lišková, S. Gurská, P.  Džubak, M. Hajdůch and P. Řezáčová, J. Med. Chem., 2019, 62, 9560-9575.
  2. 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. Lišková, S. Gurská, P. Džubák, J. Brynda, M. Hajdůch, B. Grüner and P. Řezáčová, European Journal of Medicinal Chemistry, 2020, 200, 13.
  3. J. Nekvinda, M. Kugler, J. Holub, S. El Anwar, J. Brynda, K. Pospíšilová, Z. Růžicková, P. Řezáčová and B. Grüner, Chem.-Eur. J., 2020, 26, 16541-16553.
  4. B. Grüner, M. Kugler, S. El Anwar, J. Holub, J. Nekvinda, D. Bavol, Z. Růžicková, K. Pospíšilová, M. Fábry, V. Král, J. Brynda and P. Řezáčová, ChemPlusChem, 2021, 86, 352-363.
  5. M. Kugler, J. Nekvinda, J. Holub, S. El Anwar, V. Das, V. Šícha, K. Pospíšilová, M. Fábry, V. Král, J. Brynda, V. Kašička, M. Hajdůch, P. Řezáčová and B. Grűner, ChemBioChem, 2021, 22, 2741-2761.
  6. M. Kugler, J. Holub, J. Brynda, K. Pospíšilová, S. El Anwar, D. Bavol, M. Havránek, V. Král, M. Fábry, B. Grüner and P. Řezáčová, J. Enzym. Inhib. Med. Chem., 2020, 35, 1800-1810.
  7. J. Fanfrlík, J. Brynda, M. Kugler, M. Lepšik, K. Pospíšilová, J. Holub, D. Hnyk, J. Nekvinda, B. Grűner and P. Řezáčová, Phys. Chem. Chem. Phys., 2023, 25, 1728-1733.
  8. V. Šolínová, J. Brynda, V. Šícha, J. Holub, B. Grűner and V. Kašička, Electrophoresis, 2021, 42, 910-919.
  9. Y. Chen, A. Barba-Bon, B. Grüner, M. Winterhalter, M. A. Aksoyoglu, S. Pangeni, M. Ashjari, K. Brix, G. Salluce, Y. Folgar-Cameán, J. Montenegro and W. M. Nau, J. Am. Chem. Soc., 2023, 145, 13089-13098.
  10. G. Salluce, Y. Folgar-Cameán, A. Barba-Bon, I. Niksic-Franjic, S. El Anwar, B. Grüner, I. Lostalé-Seijo, W. M. Nau and J. Montenegro, Angew. Chem.-Int. Edit., 2024, 63, 9.
  11. S. El Anwar, L. Pazderová, D. Bavol, M. Bakardjiev, Z. Ružičková, O. Horáček, L. Fojt, R. Kučera and B. Grüner, Chem. Commun., 2022, 58, 2572-2575.
  12. L. Fojt, B. Gruner, J. Holub, L. Havran and M. Fojta, J. Electroanal. Chem., 2022, 910, 8.
  13. L. Fojt, J. Nekvinda, S. El Anwar, B. Grüner, L. Havran and M. Fojta, Electroanalysis, 2020, 32, 1859-1866.