Ukr.Biochem.J. 2019; Volume 91, Issue 4, Jul-Aug, pp. 5-16


1,3-Oxazol-4-ylphosphonium salts as new non-peptide inhibitors of furin

T. V. Osadchuk1, V. K. Kibirev1,2, O. V. Shybyryn1, A. V. Semyroz1,
Ye. S. Velihina1, Е. R. Abdurakhmanova1, V. S. Brovarets1

1V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry,
National Academy of Sciences of Ukraine, Kyiv;
2Palladin Institute of Biochemistry, National Academy
of Sciences of Ukraine, Kyiv

Received: 22 February 2019; Accepted: 17 May 2019

A series of novel triphenylphosphonium derivatives of 1,3-oxazole containing at C2 and C5-positions electron withdrawing or electron-donating groups were synthesized and characterized by 1H, 31P NMR and IR spectroscopy, element analysis and chromato-mass spectrometry. These compounds were found to be a new class of non-peptide inhibitors of furin. Depending on the chemical structure, they inactivated enzyme at micromolar level by mechanism of competitive, non-competitive or mixed inhibition. Evaluation of the synthesized derivatives as furin inhibitors showed that among the triphenylphosphonium salts studied by us, oxazole 12 containing 2,4-dichlorophenyl- in the C2-position and MeS-group at C5 is the most active (Ki = 1.57 μM) competitive inhibitor of furin. Our results provided evidence that chemical modification of 1,3-oxazole-4-yl-triphenylphosphonium salts may be useful for developing new more potent and selective inhibitors of furin.

Keywords: , , , ,


  1. Molloy SS, Bresnahan PA, Leppla SH, Klimpel KR, Thomas G. Human furin is a calcium-dependent serine endoprotease that recognizes the sequence Arg-X-X-Arg and efficiently cleaves anthrax toxin protective antigen. J Biol Chem. 1992 Aug 15;267(23):16396-402. PubMed
  2. 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
  3. 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. PubMed, PubMedCentral, CrossRef
  4. Artenstein AW, Opal SM. Proprotein convertases in health and disease. N Engl J Med. 2011 Dec 29;365(26):2507-18. PubMed, CrossRef
  5. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov. 2012 May;11(5):367-83. PubMed, CrossRef
  6. Couture F, Kwiatkowska A, Dory YL, Day R. Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat. 2015 Apr;25(4):379-96. PubMed, CrossRef
  7. Basak A. Inhibitors of proprotein convertases. J Mol Med (Berl). 2005 Nov;83(11):844-55. PubMed, CrossRef
  8. De UC, Mishra P, Pal PR, Dinda B, Basak A. Non-peptide inhibitors of proprotein convertase subtilisin kexins (PCSKs): An overall review of existing and new data. (ed. M.Khatib). Colloquium Series on Protein Activation and Cancer.  2012;1(3):1-76. CrossRef
  9. Kibirev VK, Osadchuk TV, Kozachenko OP, Kholodovych V, Fedoryak D, Brovarets VS. Synthesis, biological evaluation and docking of novel bisamidinohydrazones as non-peptide inhibitors of furin. Ukr Biochem J. 2015 Jan-Feb;87(1):55-63. PubMed, CrossRef
  10. Osadchuk TV, Shybyryn OV, Kibirev VK. Chemical structure and properties of low-molecular furin inhibitors. Ukr Biochem J. 2016 Nov-Dec;88(6):5-25. PubMed, CrossRef
  11. Kibirev VK, Osadchuk TV, Vadziuk OB, Shablykin OV, Kozachenko AP, Chumachenko SA, Popil’nichenko SV, Brovarets VS. Study on derivatives of 5-amino-4-acylamino-1H-pyrazole as inhibitors of furin. Ukr Biokhim Zhurn. 2011 Jan-Feb;83(1):30-7. (In Russian). PubMed
  12. Zhang HZ, Zhao ZL, Zhou CH. Recent advance in oxazole-based medicinal chemistry. Eur J Med Chem. 2018 Jan 20;144:444-492. PubMed, CrossRef
  13. Jin Z. Muscarine, imidazole, oxazole and thiazole alkaloids. Nat Prod Rep. 2016 Oct 26;33(11):1268-1317. PubMed, CrossRef
  14. Joshi S, Bisht AS, Juyal D. Systematic scientific study of 1,3-oxazole derivatives as a useful lead for pharmaceuticals: A review. The Pharma Innov J. 2017;6(1): 109-117.
  15. Ghani A, Hussain EA, Sadiq Z, Naz N. Advanced synthetic and pharmacological aspects of 1,3-oxazoles and benzoxazoles. Indian J Chem. 2016;55B(7): 833-853.
  16. Kachaeva MV, Pilyo SG, Zhirnov VV, Brovarets VS. Synthesis, characterization, and in vitro anticancer evaluation of 2-substituted 5-arylsulfonyl-1,3-oxazole-4-carbonitriles. Med Chem Res. 2019;28(1):71-80.  CrossRef
  17. Maekawa T, Sakai N, Tawada H, Murase K, Hazama M, Sugiyama Y, Momose Y. Synthesis and biological activity of novel 5-(omega-aryloxyalkyl)oxazole derivatives as brain-derived neurotrophic factor inducers. Chem Pharm Bull (Tokyo). 2003 May;51(5):565-73. PubMed, CrossRef
  18. Zhou H, Cheng JQ, Wang ZS, Chen FH, Liu XH. Oxazole: A Promising Building Block for the Development of Potent Antitumor Agents. Curr Top Med Chem. 2016;16(30):3582-3589. PubMed, CrossRef
  19. Kachaeva MV, Pilyo SG, Demydchuk BA, Prokopenko VM, Zhirnov VV, Brovarets VS. 4-Cyano-1,3-oxazole-5-sulfonamides as novel promising anticancer lead compounds. Int J Curr Res. 2018;10(5):69410-69425.
  20. Semenyuta I, Kovalishyn V, Tanchuk V, Pilyo S, Zyabrev V, Blagodatnyy V, Trokhimenko O, Brovarets V, Metelytsia L. 1,3-Oxazole derivatives as potential anticancer agents: Computer modeling and experimental study. Comput Biol Chem. 2016 Dec;65:8-15. PubMed, CrossRef
  21. Semenyuta IV, Kovalishyn VV, Pilyo SG, Blagodatnyy VN, Trokhimenko EP, Brovarets VS, Metelitsa LA. Application of QSAR models to the search for tubulin inhibitors in a series of derivatives of 1,3-oxazole. Rep Nat Acad Sci Ukraine. 2014;(12):152-157. (In Russian). CrossRef
  22. Song MX, Rao BQ, Cheng BB, Yi Wu, Zeng H, Luo Y, Deng XQ. Design, synthesis and evaluation of the antidepressant and anticonvulsant activities of thiazole-containing benzo[d]oxazoles. CNS Neurol Disord Drug Targets. 2017;16(2):187-198.  CrossRef
  23. Tomi IHR, Tomma JH, Al-Daraji AHR, Al-Dujaili AH. Synthesis, characterization and comparative study the microbial activity of some heterocyclic compounds containing oxazole and benzothiazole moieties. J Saudi Chem Soc. 2015;19(4):392-398. CrossRef
  24. Swellmeen L. 1,3-Oxazole derivatives: A review of biological activities as antipathogenic. Der Pharma Chemica. 2016;8(13):269-286.
  25. Sadek B, Fahelelbom KM. Synthesis, characterization, and antimicrobial evaluation of oxadiazole congeners. Molecules. 2011 May 25;16(6):4339-47. PubMed, PubMedCentral, CrossRef
  26. Kachaeva MV, Pilyo SG, Kornienko AM, Prokopenko VM, Zhirnov VV, Prichard MN, Keith KA, Yang G,  Wang HK, Banerjee NS, Chow LT, Broker TR, Brovarets VS. In vitro activity of novel 1,3-oxazole derivatives against of human papillomavirus. Ibnosina J Med Biomed Sci. 2017;9(4):111–118. CrossRef
  27. Kovalishyn V, Kopernyk I, Chumachenko S, Shablykin O, Kondratyuk  K, Pil’o S, Prokopenko V, Brovarets V, Metelytsia L. QSAR Studies, Design, Synthesis and Antimicrobial Evaluation of Azole Derivatives. Comput Biol Bioinform. 2014;2(2):25-32.  CrossRef
  28. Kopernik IM, Blagodatnyj VM, Petrenko OV, Kalashnikova LE, Prokopenko VV, Kondratyuk KM, Lukashuk OI, Golovchenko OV, Chumachenko SA, Shablykin OV, Metelitsa LO, Brovarets VS. Study in vitro for antimicrobic activity of new oxazole derivatives and products of its transformations. Ukrainica Bioorg Acta. 2011;9(2): 57-68. (In Ukrainian).
  29. Kumar A, Ahmad P, Maurya RA, Singh AB, Srivastava AK. Novel 2-aryl-naphtho[1,2-d]oxazole derivatives as potential PTP-1B inhibitors showing antihyperglycemic activities. Eur J Med Chem. 2009 Jan;44(1):109-16.  PubMed, CrossRef
  30. Selva M, Perosa A, Noѐ M. Phosphonium salts and P-ylides. Organophosphorus Chem. 2016;45:132-169.   CrossRef
  31. Trnka J, Elkalaf M, Anděl M. Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. PLoS One. 2015 Apr 30;10(4):e0121837.  PubMed, PubMedCentral, CrossRef
  32. Zielonka J, Joseph J, Sikora A, Hardy M, Ouari O, Vasquez-Vivar J, Cheng G, Lopez M, Kalyanaraman B. Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic application. Chem Rev. 2017;117(15):10043-10120. CrossRef
  33. Trush MM, Kovalishyn V, Ocheretniuk AD, Kalashnikova LE, Prokopenko VM, Holovchenko OV, Kobzar OL, Brovarets VS, Metelytsia LO. New 1,3-oxazolylphosphonium salts as potential biocides: QSAR study, synthesis, antibacterial activity and toxicity evaluation. Lett Drug Design Disc. 2018;15(12):1259-1267. CrossRef
  34. Xue Y, Pan Y, Xiao H, Zhao Y.  Novel quaternary phosphonium-type cationic polyacrylamide and elucidation of dual-functional antibacterial/antiviral activity. RSC Adv. 2014;4(87):46887-46895.  CrossRef
  35. Trush MM, Kovalishyn VV, Blagodatnyi VM, Brovarets VS, Pilyo SG, Prokopenko VM, Hodyna DM, Metelytsia LO. QSAR studies and antimicrobial potential of 1,3-thiazolylphosphonium salts. Ukr Biochem J. 2016 Jul-Aug;88(4):57-65.  PubMed, CrossRef
  36. Cheng G, Zielonka J, Ouari O, Lopez M, McAllister D, Boyle K, Barrios CS, Weber JJ, Johnson BD, Hardy M, Dwinell MB, Kalyanaraman B. Mitochondria-Targeted Analogues of Metformin Exhibit Enhanced Antiproliferative and Radiosensitizing Effects in Pancreatic Cancer Cells. Cancer Res. 2016 Jul 1;76(13):3904-15. PubMed, PubMedCentral, CrossRef
  37. Jameson VJ, Cochemé HM, Logan A, Hanton LR, Smith RA, Murphy MP. Synthesis of triphenylphosphonium vitamin E derivatives as mitochondria-targeted antioxidants. Tetrahedron. 2015 Nov 4;71(44):8444-8453. PubMed, PubMedCentral, CrossRef
  38. Millard M, Pathania D, Shabaik Y, Taheri L, Deng J, Neamati N. Preclinical evaluation of novel triphenylphosphonium salts with broad-spectrum activity. PLoS One. 2010 Oct 4;5(10). pii: e13131. PubMed, PubMedCentral, CrossRef
  39. Brovarets V, Holovchenko O, Naumenko A, Vydzhak R, Abdurakhmanova E, Prostota Ya, Kachkovsky O. Electronic and spectral properties of phosphonium ylides-betaines, derivatives of 2 oxazoline-5-one with conjugated and non-conjugated substituents. Eur Chem Bull. 2017;6(9):380-392. CrossRef
  40. Klimova VA. Basic Micromethodes for the Analysis of Organic Compounds. M.: Khimya, 1975. 224 p. (In Russian).
  41. Brovarets VS, Lobanov ОP, Drach BS. Syntheses of 2,5-substituted azoles from (2,2-dichloro-1-acylaminovinyl)triphenylphosphonium chlorides. J Gen Chem. USSR (Engl. Transl.). 1984;15(11):1819-1823. CrossRef
  42. Golovchenko AV, Brovarets VS, Drach BS. A convenient procedure for introducing arylsulfanyl and heterylsulfanyl groups into the 5 position of the oxazole ring. Russ J Gen Chem. 2004;74(9):1414-1417.  CrossRef
  43. Brovarets VS, Lobanov ОP, Kisilenko AA, Kalinin VN, Drach BS.  Conversions of substituted phosphinomethylenes containing 2‐alkyl‐(aryl)‐4,5‐dihydro‐5‐thioxo‐4‐oxazolylidene fragments. J Gen Chem. USSR (Engl. Transl.). 1987;18(6):1323-1332. CrossRef
  44. Brovarets VS, Vydzhak RN, Pil’o SG, Zyuz’ KV, Drach BS. Synthesis and transformations of 4-phosphorylated 2-alkyl(aryl)-5-hydrazinooxazoles. Russ J Gen Chem. 2001;71(11):1726-1728. CrossRef
  45. Brovarets VS, Lobanov ОP, Drach BS. Synthesis of 4-phosphorylated oxazoles and thiazoles. J Gen Chem. USSR (Engl. Transl.). 1983;53(3):574-577. CrossRef

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