Funct. Mater. 2024; 31 (2): 260-268.

doi:https://doi.org/10.15407/fm31.02.260

Synthesis and modification of 7-aroyl derivatives of 4,7-dihydro-[1,2,4]triazolo-[1,5-a]-pyrimidine as potent inhibitors of sirtuin-2

K. I. Marchenko, A. V. Kyrychenko, N. M. Kolos

V.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv, 61022, Ukraine

Abstract: 

Sirtuin-2 (SIRT2) is a member of the human sirtuin class that regulates various biological processes and is considered a novel biomarker for numerous types of cancer. Depending on the type of tumor, SIRT2 knockout leads to a controversial role in tumorigenesis. However, pharmacological inhibition of SIRT2 with small molecules leads exclusively to inhibition of the growth of many cancer cells, thus opening the way to the therapy of oncological diseases. In this work, we synthesized 7-aroyltriazolo[1,5-a]pyrimidine derivatives (some of which showed good inhibitory activity) and modified the active functional groups of the bicyclic structure. The effect of functionalization of the nitrogen atom and the influence of the oxidation and reduction of the dihydropyrimidine fragment on the inhibitory activity of the studied derivatives against sirtuin-2 was analyzed by molecular docking calculations.

Keywords: 
sirtuin-2, inhibitor, organic synthesis, triazolo[1,5-a]pyrimidine, molecular docking.

Full text in PDF

References: 

1. A. Chalkiadaki, L. Guarente. Nat. Rev. Cancer 15, 608-624 (2015). https://doi.org/10.1038/nrc3985.

2. S.-I. Imai, L. Guarente. Trends Cell Biol. 24, 464-471 (2014). https://doi.org/10.1016/j.tcb.2014.04.002.

3. R. Machado de Oliveira, J. Sarkander, A. G. Kazantsev, T. F. Outeiro. Front. Pharmacol. 3, 82 (2012). https://doi.org/10.3389/fphar.2012.00082.

4. S. Chowdhury, S. Sripathy, A. A. Webster, A. Park, U. Lao, J. H. Hsu, T. Loe, A. Bedalov, J. A. Simon. Molecules 25, 455 (2020). https://doi.org/10.3390/molecules25030455.

5. L. M. McGlynn, S. Zino, A. I. MacDonald, J. Curle, J. E. Reilly, Z. M. A. Mohammed, D. C. McMillan, E. Mallon, A. P. Payne, J. Edwards, P. G. Shiels. Eur. J. Cancer 50, 290-301 (2014). https://doi.org/10.1016/j.ejca.2013.10.005.

6. H.-S. Kim, A. Vassilopoulos, R.-H. Wang, T. Lahusen, Z. Xiao, X. Xu, C. Li, Timothy D. Veenstra, B. Li, H. Yu, J. Ji, Xin W. Wang, S.-H. Park, Yong I. Cha, D. Gius, C.-X. Deng. Cancer Cell 20, 487-499 (2011). https://doi.org/10.1016/j.ccr.2011.09.004.

7. C.-A. J. Ong, J. Shapiro, K. S. Nason, J. M. Davison, X. Liu, C. Ross-Innes, M. O’Donovan, W. N. M. Dinjens, K. Biermann, N. Shannon, S. Worster, L. K. E. Schulz, J. D. Luketich, B. P. L. Wijnhoven, R. H. Hardwick, R. C. Fitzgerald. J. Clinic. Oncol. 31, 1576-1582 (2013). https://doi.org/10.1200/JCO.2012.45.9636.

8. P. Y. Liu, N. Xu, A. Malyukova, C. J. Scarlett, Y. T. Sun, X. D. Zhang, D. Ling, S. P. Su, C. Nelson, D. K. Chang, J. Koach, A. E. Tee, M. Haber, M. D. Norris, C. Toon, I. Rooman, C. Xue, B. B. Cheung, S. Kumar, G. M. Marshall, A. V. Biankin, T. Liu. Cell Death Different. 20, 503-514 (2013).https://doi.org/10.1038/cdd.2012.147.

9. A. Deng, Q. Ning, L. Zhou, Y. Liang. Sci. Rep. 6, 27694 (2016). https://doi.org/10.1038/srep27694.

10. G. Hoffmann, F. Breitenbücher, M. Schuler, A. E. Ehrenhofer-Murray. J. Biol. Chem. 289, 5208-5216 (2014). doi:10.1074/jbc.M113.487736.

11. H. Cui, Z. Kamal, T. Ai, Y. Xu, S. S. More, D. J. Wilson, L. Chen. J. Med. Chem. 57, 8340-8357 (2014). https://doi.org/10.1021/jm500777s.

12. A. B. Penteado, H. Hassanie, R. A. Gomes, F. d. Silva Emery, G. H. Goulart Trossini. Future Med. Chem. 15, 291-311 (2023). https://doi.org/10.4155/fmc-2022-0253.

13. W. Yang, W. Chen, H. Su, R. Li, C. Song, Z. Wang, L. Yang. RSC Adv. 10, 37382-37390 (2020). https://doi.org/10.1039/D0RA06316A.

14. S. Sundriyal, S. Moniot, Z. Mahmud, S. Yao, P. Di Fruscia, C. R. Reynolds, D. T. Dexter, M. J. E. Sternberg, E. W. F. Lam, C. Steegborn, M. J. Fuchter. J. Med. Chem. 60, 1928-1945 (2017). https://doi.org/10.1021/acs.jmedchem.6b01690.

15. N. A. Spiegelman, I. R. Price, H. Jing, M. Wang, M. Yang, J. Cao, J. Y. Hong, X. Zhang, P. Aramsangtienchai, S. Sadhukhan, H. Lin. ChemMedChem 13, 1890-1894 (2018). https://doi.org/10.1002/cmdc.201800391.

16. A. L. Nielsen, N. Rajabi, N. Kudo, K. Lundø, C. Moreno-Yruela, M. Bæk, M. Fontenas, A. Lucidi, A. S. Madsen, M. Yoshida, C. A. Olsen. RSC Chem. Biol. 2, 612-626 (2021). https://doi.org/10.1039/D0CB00036A.

17. E. Roshdy, M. Mustafa, A. E.-R. Shaltout, M. O. Radwan, M. A. A. Ibrahim, M. E. Soliman, M. Fujita, M. Otsuka, T. F. S. Ali. Eur. J. Med. Chem. 224, 113709 (2021). https://doi.org/10.1016/j.ejmech.2021.113709.

18. N. V. Chechina, N. N. Kolos, I. V. Omelchenko, V. I. Musatov. Chem. Heterocyc. Comp. 54, 58-62 (2018). https://doi.org/10.1007/s10593-018-2230-1.

19. T. Rumpf, M. Schiedel, B. Karaman, C. Roessler, B. J. North, A. Lehotzky, J. Oláh, K. I. Ladwein, K. Schmidtkunz, M. Gajer, M. Pannek, C. Steegborn, D. A. Sinclair, S. Gerhardt, J. Ovádi, M. Schutkowski, W. Sippl, O. Einsle, M. Jung. Nat. Commun. 6, 6263 (2015). https://doi.org/10.1038/ncomms7263.

20. O. Trott, A. J. Olson. J. Comput. Chem. 31, 455-461 (2010). https://doi.org/10.1002/jcc.21334.

21. D. S. Goodsell, M. F. Sanner, A. J. Olson, S. Forli. Prot. Sci. 30, 31-43 (2021). https://doi.org/10.1002/pro.3934.

22. W. Humphrey, A. Dalke, K. Schulten. J. Mol. Graphics 14, 33-38 (1996). https://doi.org/10.1016/0263-7855(96)00018-5.

23. M. A. A. Ibrahim, K. A. A. Abdeljawaad, E. Roshdy, D. E. M. Mohamed, T. F. S. Ali, G. A. Gabr, L. A. Jaragh-Alhadad, G. A. H. Mekhemer, A. M. Shawky, P. A. Sidhom, A. H. M. Abdelrahman. Sci. Rep. 13, 2146 (2023). https://doi.org/10.1038/s41598-023-28226-7.

24. G. Eren, A. Bruno, S. Guntekin-Ergun, R. Cetin-Atalay, F. Ozgencil, Y. Ozkan, M. Gozelle, S. G. Kaya, G. Costantino. J. Mol. Graph. Model. 89, 60-73 (2019). https://doi.org/10.1016/j.jmgm.2019.02.014.

25. S. Huang, C. Song, X. Wang, G. Zhang, Y. Wang, X. Jiang, Q. Sun, L. Huang, R. Xiang, Y. Hu, L. Li, S. Yang. J. Chem. Inform. Model. 57, 669-679 (2017). https://doi.org/10.1021/acs.jcim.6b00714.

Current number: