Synthesis and antiaggregative acti vity of αIIbβ3-receptor antagonist based on 2-(4-piperazine- 1-yl)-3H-quinazoline-4-one

Authors

  • S.A. Andronati A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa
  • A.Yu. Kornylov A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa
  • P.G. Polishchuk Institute of Molecular and Translational Medicine, Palacký University and University Hospital in Olomouc, Czech Republic
  • A.A. Krysko A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa
  • O.L. Krysko A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa
  • T.A. Kabanova A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa
  • S.E. Sambursky A.V. Bogatsky Physico-Chemical Institute of the NAS of Ukraine, Odesa

DOI:

https://doi.org/10.15407/dopovidi2019.09.060

Keywords:

6-bromo-3H-quinazoline-4-one, C–C cross-coupling, fibrinogen receptor antagonist, palladium-catalysis, peptide bond formation, platelet aggregation, αIIbβ3

Abstract

A new derivative of 2-(4-piperazin-1-yl)-quinazolin-4-one is synthesized, the compound has structure similar to small-molecule αIIbβ3-receptor antagonist based on 7-(piperazin-1-yl)-[1,3,4]thiadiazolo[3,2-a]pirimidin-5- one (RUC-2). To obtain the target compound, two alternative methods are used. The compound is an antagonist of the αIIbβ3-receptor, which binds to the closed form of the protein. The antiaggregative activity of the compound is studied on platelet-rich plasma (PRP) in an in vitro test. The molecular mechanism of antiplatelet action is measured as the inhibition of the fluorescein isothiocyanate-labeled fibrinogen (FITC-Fg) binding to activated human platelets by the tested compound. Docking studies of the synthesized compound revealed that ligand–protein interactions mainly correspond to the complex RUC-2–αIIbβ3. The target compound has high antiaggregative activity and can be recommended for the further study as a promising antithrombotic agent.

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References

Coller, B. S. (1995). Blockade of platelet GP IIb/IIIa receptors as an antithrombotic strategy. Circulation, 92, Iss. 9, pp. 2373-2380. doi: https://doi.org/10.1161/01.CIR.92.9.2373

Andronati, S. A., Karaseva, T. L. & Krysko, A. A. (2004). Peptidomimetics — antagonists of the fibrinogen receptors: molecular design, structures, properties and therapeutic applications. Curr. Med. Chem., 11, Iss. 9, pp. 1183-1211. doi: https://doi.org/10.2174/0929867043365314

Bougie, D. W., Rasmussen, M., Zhu, J. & Aster, R. H. (2012) Antibodies causing thrombocytopenia in pa- tients treated with RGD-mimetic platelet inhibitors recognize ligand-specific conformers of αIIb/β3 integrin. Blood., 119, Iss. 26, pp. 6317-6325. doi: https://doi.org/10.1182/blood-2012-01-406322

Blue, R., Murcia, M., Karan, C., Jirouškova, M. & Coller, B. S. (2008). Application of high-throughput screening to identify a novel αIIβ-specific small- molecule inhibitor of αIIbB3 -mediated platelet interaction with fibrinogen. Blood, 111, Iss. 3, pp. 1248-1257. doi: https://doi.org/10.1182/blood-2007-08-105544

Zhu, J., Choi, W-S., McCoy, J. G., Negri, A., Zhu, J., Naini, S., Li J., Shen, M., Huang, W., Bougie, D., Ras- mussen, M., Aster, R., Thomas, C. J., Filizola, M., Springer, T. A. & Coller, B. S. (2012). Structure-guided 2+ design of a high-affinity platelet integrin αIIbB3 receptor antagonist that disrupts Mg binding to the MIDAS. Sci. Transl. Med., 4, Iss. 125, 125ra32. doi: https://doi.org/10.1126/scitranslmed.3003576

Polishchuk, P. G., Samoylenko, G. V, Khristova, T. M., Krysko, O. L., Kabanova, T. A., Kabanov, V. M., Korny- lov, A. Yu., Klimchuk, O., Langer, T., Andronati, S. A., Kuz’min, V. E., Krysko, A. A. & Varnek, A. (2015). Design, virtual screening, and synthesis of antagonists of αIIbB3 as antiplatelet agents. J. Med. Chem., 58, Iss. 19, pp. 7681-7694. doi: https://doi.org/10.1021/acs.jmedchem.5b00865

Pokhodylo, N. T., Shyyla, O. Y., Matiychuk, V. S. & Obushak, M. D. (2015). New convenient strategy for annulation of pyrimidines to thiophenes or furans via the one-pot multistep cascade reaction of 1H-tetrazo- les with aliphatic amines. ACS Comb. Sci., 17, Iss. 7, pp. 399-403. doi: https://doi.org/10.1021/co5001376

Born, G. V. R. (1962). Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature, 194, pp. 927-929. doi: https://doi.org/10.1038/194927b0

Xia, Z., Wong, T., Liu, Q., Kasirer-Friede, A., Brown, E. & Frojmovic, M. M. (1996). Optimally functional flourescein isothiocyanate-labelled fibrinogen for quantitative studies of binding to activated platelets and platelet aggregation. Br. J. Haematol., 93, Iss. 1, pp. 204-214. https://doi.org/10.1046/j.1365-2141. 1996.445980.x

Hoffer, L. & Horvath, D. (2013). S4MPLE — Sampler for multiple protein-ligand entities: simultaneous docking of several entities. J. Chem. Inf. Model., 53, Iss. 1, pp. 88-102. doi: https://doi.org/10.1021/ci300495r

RCSB PDB. Retrieved from: http://www.rcsb.org/pdb/

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Published

24.04.2024

How to Cite

Andronati, S., Kornylov, A., Polishchuk, P., Krysko, A., Krysko, O., Kabanova, T., & Sambursky, S. (2024). Synthesis and antiaggregative acti vity of αIIbβ3-receptor antagonist based on 2-(4-piperazine- 1-yl)-3H-quinazoline-4-one . Reports of the National Academy of Sciences of Ukraine, (9), 60–67. https://doi.org/10.15407/dopovidi2019.09.060

Issue

No. 9 (2019): Reports of the National Academy of Sciences of Ukraine

Section

Chemistry

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