Design, Synthesis, and in vitro Antiproliferative Activity of 4,5,6-Trisubstituted 2-Aminopyrimidines as Potential TGF-β Inhibitors

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Abstract

The TGF-β signaling cascade is a regulator of cellular processes such as growth, division, differentiation, migration, invasion and apoptosis. Due to the deep involvement of this signaling pathway in the processes of carcinogenesis, participants in the cascade are promising oncology targets. Based on literature data, we have proposed a new structural class of TGF-β receptor inhibitors based on 2-aminopyrimidines. Two universal approaches to their synthesis have been proposed; the key transformation is the three-component Biginelli condensation aimed at the formation of a pyrimidine fragment. Using the developed synthetic approaches, 16 new compounds were obtained, for which antiproliferative activity in vitro was established against a number of tumor cell lines.

About the authors

A. A Sachkova

Lobachevsky State University of Nizhny Novgorod

Nizhny Novgorod, Russia

Yu. D Rysina

Lobachevsky State University of Nizhny Novgorod

Nizhny Novgorod, Russia

E. V Svirshchevskaya

M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry RAS

Moscow, Russia

I. D Grishin

Lobachevsky State University of Nizhny Novgorod

Nizhny Novgorod, Russia

A. Yu Fedorov

Lobachevsky State University of Nizhny Novgorod

Email: afedorovNN@yandex.ru
Nizhny Novgorod, Russia

E. S Shchegravina

Lobachevsky State University of Nizhny Novgorod

Email: sc.katarina@yandex.ru
Nizhny Novgorod, Russia

References

  1. Massagué J. Nat. Rev. Mol. Cell Biol. 2012, 13 (10), 616. doi: 10.1038/nrm3434
  2. Burt D.W., Law A.S. Prog. Growth Factor Res. 1994, 5 (1), 99. doi: 10.1016/0955-2235(94)90020-5
  3. Hachim M.Y., Hachim I.Y., Dai M., Ali S., Lebrun J.-J. Tumor Biol. 2018, 40 (1). doi: 10.1177/1010428317748254
  4. Hanson I., Pitman K.E., Edin N.F.J. Int. J. Mol. Sci. 2023, 24 (8), 7614. doi: 10.3390/ijms24087614
  5. Birrer M.J., Fujiwara K., Oaknin A., Randall L., Ojalvo L.S., Valencia C., Ray-Coquard I. Front. Oncol. 2022, 12, 814169. doi: 10.3389/fonc.2022.814169
  6. Kim B.-G., Malek E., Choi S.H., Ignatz-Hoover J.J., Driscoll J.J. J. Hematol. Oncol. 2021, 14 (1), 55. doi: 10.1186/s13045-021-01053-x
  7. Ciardiello D., Elez E., Tabernero J., Seoane J. Ann. Oncol. 2020, 31 (10), 1336. doi: 10.1016/j.annonc.2020.07.009
  8. van den Bulk J., de Miranda N.F.C.C., ten Dijke P. Clin. Sci. 2021, 135 (1), 35. doi: 10.1042/CS20201236
  9. Welsh B.T., Faucette R., Bilic S., Martin C.J., Schürpf T., Chen D., Nicholls S., Lansita J., Kalra A. Int. J. Toxicol. 2021, 40 (3), 226. doi: 10.1177/1091581821998945
  10. Martin C.J., Datta A., Littlefield C., Kalra A., Chapron C., Wawersik S., Dagbay K.B., Brueckner C.T., Nikiforov A., Danehy F.T. Sci. Transl. Med. 2020, 12 (536), eaay8456. doi: 10.1126/scitranslmed.aay8456
  11. Datta A., Capili A., Schurpf T., Martin C., Dagbay K.B., Chapron C., Wawersik S., Littlefield C., Carven G.J., Buckler A., Lin S., Jackson J.W., Cooper A., Avery A., Salotto M., Stein C. EU Patent Appl. EP3677278A1, 2020.
  12. Morris J.C., Tan A.R., Olencki T.E., Shapiro G.I., Dezube B.J., Reiss M., Hsu F.J., Berzofsky J.A., Lawrence D.P. PLoS One 2014, 9 (3), e90353. doi: 10.1371/journal.pone.0090353
  13. Schurpf T., Carven G.J., Datta A., Long K. Int. Patent Appl. Pub. WO2017156500A1, 2017.
  14. Jaschinski F., Rothhammer T., Jachimczak P., Seitz C., Schneider A., Schlingensiepen K.-H. Curr. Pharm. Biotechnol. 2011, 12 (12), 2203. doi: 10.2174/138920111798808266
  15. Ghisoli M., Barve M., Schneider R., Mennel R., Lenarsky C., Wallraven G., Pappen B.O., LaNoue J., Kumar P., Nemunaitis D. Mol. Ther. 2015, 23 (6), 1103. doi: 10.1038/mt.2015.43
  16. Giaccone G., Bazhenova L.A., Nemunaitis J., Tan M., Juhász E., Ramlau R., van den Heuvel M.M., Lal R., Kloecker G., Eaton K.D. Eur. J. Cancer 2015, 51 (16), 2321. doi: 10.1016/j.ejca.2015.07.035
  17. Barve M., Aaron P., Manning L., Bognar E., Wallraven G., Horvath S., Stanbery L., Nemunaitis J. Clin. Med. Insights Oncol. 2022, 16. doi: 10.1177/11795549221110501
  18. Kovacs R.J., Maldonado G., Azaro A., Fernández M.S., Romero F.L., Sepulveda-Sánchez J.M., Corretti M., Carducci M., Dolan M., Gueorguieva I. Cardiovasc. Toxicol. 2015, 15 (4), 309. doi: 10.1007/s12012-014-9297-4
  19. Kim T.W., Lee K.W., Ahn J.B., Lee J., Ryu J., Oh B., Ock C.-Y., Hwang S., Hahm K.B., Kim S.-J. J. Clin. Oncol. 2021, 39 (15 Suppl.), 3573. doi: 10.1200/JCO.2021.39.15_suppl.3573
  20. Jung M., Lee C.-K., Kim H.S., Ock C.-Y., Bum B.J., Lee J., Kang D.W., Hwang S., Kim S.-J., Chung H.C. J. Clin. Oncol. 2020, 38 (15 Suppl.), e16505. doi: 10.1200/JCO.2020.38.15_suppl.e16505
  21. Jung M., Lee C.-K., Kim H.S., Ock C.-Y., Bae J.B., Lee J.K., Kang D.W., Hwang S., Hahm K.B., Kim S.-J. Ann. Oncol. 2020, 31, S912. doi: 10.1016/j.annonc.2020.08.1959
  22. Malek E., Rana P.S., Swamydas M., Daunov M., Miyagi M., Murphy E., Ignatz-Hoover J.J., Metheny L., Seong Jin K., Driscoll J.J. Res. Square 2023, preprint. doi: 10.21203/rs-3.rs3112163/v1
  23. Hong E., Barczak W., Park S., Heo J.S., Ooshima A., Munro S., Hong C.P., Park J., An H., Park J.O. Cell Death Dis. 2023, 14 (2), 93. doi: 10.1038/s41419-023-05630-5
  24. Selfridge J.E., Bajor D.L., Mohamed A., Chakrabarti S., Reese J., Lazarus H.M., Dowlati A., Mahipal A., Wald D. J. Clin. Oncol. 2023, 41 (4 Suppl.), TPS273. doi: 10.1200/JCO.2023.41.4_suppl.TPS273
  25. Gellibert F., Woolven J., Fouchet M.-H., Mathews N., Goodland H., Lovegrove V., Laroze A., Nguyen V.-L., Sautet S., Wang R. J. Med. Chem. 2004, 47 (18), 4494. doi: 10.1021/jm0400247
  26. Jin C.H., Krishnaiah M., Sreenu D., Subrahmanyam V.B., Rao K.S., Lee H.J., Park S.-J., Park H.-J., Lee K., Sheen Y.Y. J. Med. Chem. 2014, 57(10), 4213. doi: 10.1021/jm500115w
  27. Huse M., Chen Y.-G., Massagué J., Kuriyan J. Cell 1999, 96(3), 425. doi: 10.1016/S0092-8674(00)80555-3
  28. Sawyer J.S., Beight D.W., Britt K.S., Anderson B.D., Campbell R.M., Goodson T., Herron D.K., Li H.-Y., McMillen W.T., Mort N., Parsons S., Smith E.C.R., Wagner J.R., Yan L., Zhang F., Yingling J.M. Bioorg. Med. Chem. Lett. 2004, 14(13), 3581. doi: 10.1016/j.bmcl.2004.04.007
  29. Guo Z., Song X., Zhao L.-M., Piao M.G., Quan J., Piao H.-R., Jin C.H. Bioorg. Med. Chem. Lett. 2019, 29 (16), 2070. doi: 10.1016/j.bmcl.2019.07.015
  30. Jin C.H., Krishnaiah M., Sreenu D., Subrahmanyam V.B., Park H.-J., Park S.-J., Sheen Y.Y., Kim D.-K. Bioorg. Med. Chem. 2014, 22 (9), 2724. doi: 10.1016/j.bmc.2014.03.022
  31. Liu Y.Y., Guo Z., Wang J.Y., Wang H.M., Da Qi J., Ma J., Piao H.-R., Jin C.H., Jin X. Eur. J. Med. Chem. 2021, 216, 113311. doi: 10.1016/j.ejmech.2021.113311
  32. Patel H.M., Sing B., Bhardwaj V., Palkar M., Shaikh M.S., Rane R., Alwan W.S., Gadad A.K., Noolvi M.N., Karpoormath R. Eur. J. Med. Chem. 2015, 93, 599. doi: 10.1016/j.ejmech.2014.09.002
  33. Zhao L.-M., Guo F.Y., Wang H.M., Dou T., Da Qi J., Xu W.B., Piao L., Jin X., Chen F.-E., Piao H.-R. Med. Chem. (Los Angeles) 2022, 18 (4), 509. doi: 10.2174/1573406417666210628144849
  34. Sabat M., Wang H., Scorah N., Lawson J.D., Atienza J., Kamran R., Hixon M.S., Dougan D.R. Bioorg. Med. Chem. Lett. 2017, 27 (9), 1955. doi: 10.1016/j.bmcl.2017.03.026
  35. Kharbanda A., Tran P., Zhang L., Leung Y.-K., Li H., Frett B. Eur. J. Med. Chem. 2021, 225, 113763. doi: 10.1016/j.ejmech.2021.113763
  36. Li W., Liu X., Muhammad S., Shi J., Meng Y., Wang J. Comput. Biol. Chem. 2018, 76, 139. doi: 10.1016/j.compbiolchem.2018.07.002
  37. Guo Y., Wang Z., Zhou H., Pan H., Han W., Deng Y., Zhang Y., Zhang Y., Wang S., Wang J. J. Clin. Oncol. 2023, 41 (16 Suppl.), e15117. doi: 10.1200/JCO.2023.41.16_suppl.e15117
  38. Teicher B.A. Pharmacol. Ther. 2021, 217, 107666. doi: 10.1016/j.pharmthera.2020.107666
  39. Huang S., Pan Y., Zhu Y., Wu A. Org. Lett. 2005, 7 (17), 3797. doi: 10.1021/ol051458e
  40. Donckele E.J., Finke A.D., Ruhlmann L., Boudon C., Trapp N., Diederich F. Org. Lett. 2015, 17 (14), 3506. doi: 10.1021/acs.orglett.5b01598
  41. Muthukrishnan I., Vinoth P., Vivekanand T., Nagarajan S., Maheswari C.U., Menéndez J.C., Sridharan V. J. Org. Chem. 2016, 81 (3), 1116. doi: 10.1021/acs.joc.5b02669
  42. Lu J.-Y., Arndt H.-D. J. Org. Chem. 2007, 72 (11), 4205. doi: 10.1021/jo0703505
  43. Kappe C.O., Stadler A. Org. React. 2004, 63, 2. doi: 10.1002/0471264180.or063.01
  44. Wang D., Hu J., Zhao J., Shen M., Wang Y., Yu P. Tetrahedron 2018, 74(30), 4100. doi: 10.1016/j.tet.2018.06.025
  45. Tolkunov S.V., Dulenko V.I. Chem. Heterocycl. Compd. 1987, 23 (6), 633. doi: 10.1007/BF00486906
  46. Biscoe M.R., Buchwald S.L. Org. Lett. 2009, 11 (8), 1773. doi: 10.1021/ol900295u
  47. Robinson S.J., Petzer J.P., Terre’Blanche G., Petzer A., van der Walt M.M., Bergh J.J., Lourens A.C.U. Eur. J. Med. Chem. 2015, 104, 177. doi: 10.1016/j.ejmech.2015.09.035
  48. Kaschel J., Schneider T.F., Schirmer P., Maaß C., Stalke D., Werz D.B. Eur. J. Org. Chem. 2013, 2013 (21), 4539. doi: 10.1002/ejoc.201300390
  49. Mathi G.R., Kweon B., Moon Y., Jeong Y., Hong S. Angew. Chem., Int. Ed. 2020, 59 (50), 22675. doi: 10.1002/anie.202010597
  50. Kalčic F., Kolman V., Zídek Z., Janeba Z. ChemMedChem 2021, 16 (18), 2802. doi: 10.1002/cmdc.202100263
  51. van Veldhoven J.P.D., Chang L.C.W., von Frijtag Drabbe Künzel J.K., Mulder-Krieger T., Struensee-Link R., Beukers M.W., Brussee J., IJzerman A.P. Bioorg. Med. Chem. 2008, 16 (6), 2741. doi: 10.1016/j.bmc.2008.01.013

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