Ukr.Biochem.J. 2013; Volume 85, Issue 1, Jan-Feb, pp. 22-32

doi: http://dx.doi.org/10.15407/ubj85.01.022

Non-peptide furin inhibitors based on amidinohydrazones of diarylaldehydes

27.07.2015   Uncategorized   No comments

V. K. Kibirev1, T. V. Osadchuk2, O. P. Kozachenko2,
O. B. Vadzyuk1, V. S. Brovarets2

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
e-mail: kinet@biochem.kiev.ua;
2Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kyiv

A series of novel non-peptidic furin inhibitors containing amidinohydrazone moieties has been synthesized under interaction of dialdehydes, the derivatives of ethylene diethylvanillin ethers, with aminoguanidine bicarbonate. Two aryl cycles were bridged by 1,2-ethylene-, 1,4-buthylene- or 1,4-dimethylenebenzene-group. The compounds have been found to inhibit furin. The antifurin activity was shown to grow with the increase of the length and/or hydrophobicity of the bridge. The most potent compound, containing in the bridge the lypophylic benzene cycle was found to inhibit the activity of furin with Ki = 0.51 µM.

Keywords: , ,

References:

  1. Nakayama K. Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J. 1997 Nov 1;327(Pt 3):625-35. Review. PubMed, PubMedCentral
  2. Thomas G. Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol. 2002 Oct;3(10):753-66. Review. PubMed, PubMedCentral, CrossRef
  3. Bergeron F, Leduc R, Day R. Subtilase-like pro-protein convertases: from molecular specificity to therapeutic applications. J Mol Endocrinol. 2000 Feb;24(1):1-22. Review. PubMed, CrossRef
  4. Kibirev VK, Osadchuk TV, Radavskiĭ IuL. Furin and its biological role. Ukr Biokhim Zhurn. 2007 Nov-Dec;79(6):5-18. Review. Russian. PubMed
  5. Hosaka M, Nagahama M, Kim WS, Watanabe T, Hatsuzawa K, Ikemizu J, Murakami K, Nakayama K. Arg-X-Lys/Arg-Arg motif as a signal for precursor cleavage catalyzed by furin within the constitutive secretory pathway. J Biol Chem. 1991 Jul 5;266(19):12127-30. PubMed
  6. Stawowy P, Meyborg H, Stibenz D, Borges Pereira Stawowy N, Roser M, Thanabalasingam U, Veinot JP, Chrétien M, Seidah NG, Fleck E, Graf K. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Circulation. 2005 May 31;111(21):2820-7. PubMed, CrossRef
  7. Lahlil R, Calvo F, Khatib AM. The potential anti-tumorigenic and anti-metastatic side of the proprotein convertases inhibitors. Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):83-91. Review. PubMed, CrossRef
  8. Benjannet S, Elagoz A, Wickham L, Mamarbachi M, Munzer JS, Basak A, Lazure C, Cromlish JA, Sisodia S, Checler F, Chrétien M, Seidah NG. Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production. J Biol Chem. 2001 Apr 6;276(14):10879-87. PubMed, CrossRef
  9. Croissandeau G, Basak A, Seidah NG, Chrétien M, Mbikay M. Proprotein convertases are important mediators of the adipocyte differentiation of mouse 3T3-L1 cells. J Cell Sci. 2002 Mar 15;115(Pt 6):1203-11. PubMed
  10. Zhong M, Munzer JS, Basak A, Benjannet S, Mowla SJ, Decroly E, Chrétien M, Seidah NG. The prosegments of furin and PC7 as potent inhibitors of proprotein convertases. In vitro and ex vivo assessment of their efficacy and selectivity. J Biol Chem. 1999 Nov 26;274(48):33913-20. PubMed, CrossRef
  11. Peterlin-Mašič L., Kikelj D. Arginine mimetics. Tetrahedron. 2001;57(33):7073-7105.  CrossRef
  12. Tomczuk B, Lu T, Soll RM, Fedde C, Wang A, Murphy L, Crysler C, Dasgupta M, Eisennagel S, Spurlino J, Bone R. Oxyguanidines: application to non-peptidic phenyl-based thrombin inhibitors. Bioorg Med Chem Lett. 2003 Apr 17;13(8):1495-8. PubMed, CrossRef
  13. Fugère M, Day R. Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition. Trends Pharmacol Sci. 2005 Jun;26(6):294-301. Review. PubMed, CrossRef
  14. Basak A. Inhibitors of proprotein convertases. J Mol Med (Berl). 2005 Nov;83(11):844-55. Review. PubMed, CrossRef
  15. Kibirev VK, Osadchuk TV. Structure and properties of proprotein convertase inhibitors. Ukr Biokhim Zhurn. 2012 Mar-Apr;84(2):5-29. Review. Russian. PubMed
  16. Fugère M, Day R. Inhibitors of the subtilase-like pro-protein convertases (SPCs). Curr Pharm Des. 2002;8(7):549-62. Review. PubMed, CrossRef
  17. Becker GL, Sielaff F, Than ME, Lindberg I, Routhier S, Day R, Lu Y, Garten W, Steinmetzer T. Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J Med Chem. 2010 Feb 11;53(3):1067-75. PubMed, PubMedCentral, CrossRef
  18. Becker GL, Lu Y, Hardes K, Strehlow B, Levesque C, Lindberg I, Sandvig K, Bakowsky U, Day R, Garten W, Steinmetzer T. Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J Biol Chem. 2012 Jun 22;287(26):21992-2003. PubMed, PubMedCentral, CrossRef
  19. Soll RM, Lu T, Tomczuk B, Illig CR, Fedde C, Eisennagel S, Bone R, Murphy L, Spurlino J, Salemme FR. Amidinohydrazones as guanidine bioisosteres: application to a new class of potent, selective and orally bioavailable, non-amide-based small-molecule thrombin inhibitors. Bioorg Med Chem Lett. 2000 Jan 3;10(1):1-4. PubMed, CrossRef
  20. US Patent 3878201. 1,5-Bis substituted-1,4-pentadien-3-one substituted amidino hydrazone salts and method of preparing the same. Tomcufcik A. S. 1975.
  21. Messeder JC, Tinoco LW, Figueroa-Villar JD, Souza EM, Santa Rita R, De Castro SL. Aromatic guanyl hydrazones: Synthesis, structural studies and in vitro activity against Trypanosoma cruzi. Bioorg Med Chem Lett. 1995;5(24):3079-3084. CrossRef
  22. Stanek J, Caravatti G, Capraro HG, Furet P, Mett H, Schneider P, Regenass U. S-adenosylmethionine decarboxylase inhibitors: new aryl and heteroaryl analogues of methylglyoxal bis(guanylhydrazone). J Med Chem. 1993 Jan 8;36(1):46-54. PubMed, CrossRef
  23. Sevillano LG, Melero CP, Caballero E, Tomé F, Lelièvre LG, Geering K, Crambert G, Carrón R, Medarde M, San Feliciano A. Inotropic activity of hydroindene amidinohydrazones. J Med Chem. 2002 Jan 3;45(1):127-36. PubMed, CrossRef
  24. Komiyama T, Coppola JM, Larsen MJ, van Dort ME, Ross BD, Day R, Rehemtulla A, Fuller RS. Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J Biol Chem. 2009 Jun 5;284(23):15729-38. PubMed, PubMedCentral, CrossRef
  25. Sielaff F, Than ME, Bevec D, Lindberg I, Steinmetzer T. New furin inhibitors based on weakly basic amidinohydrazones. Bioorg Med Chem Lett. 2011;21(2):836-840. Bioorg Med Chem Lett. 2011 Jan 15;21(2):836-40. PubMed, CrossRef
  26. Henrich S, Cameron A, Bourenkov GP, Kiefersauer R, Huber R, Lindberg I, Bode W, Than ME. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol. 2003 Jul;10(7):520-6. PubMed, CrossRef
  27. US Patent 2649436. Phenol ether resins.  Bock L. H., Carlson L. J. 1953.
  28. Dixon M. The determination of enzyme inhibitor constants. Biochem J. 1953 Aug;55(1):170-1. PubMed, PubMedCentral
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