Chemical Papers

, Volume 72, Issue 12, pp 2979–2985 | Cite as

Synthesis of glycolysis inhibitor (E)-3-(pyridin-3-yl)-1-(pyridin-4-yl)prop-2-en-1-one (3PO) and its inhibition of HUVEC proliferation alone or in a combination with the multi-kinase inhibitor sunitinib

  • Miroslav Murár
  • Jana Horvathová
  • Roman Moravčík
  • Gabriela Addová
  • Michal Zeman
  • Andrej BoháčEmail author
Original Paper


While a treatment of tumours by anti-angiogenic kinase inhibitors has limited efficacy and is associated with resistance and side effects, also other key biological pathways should be targeted to fight cancer more effectively. Active endothelial and cancer cells acquire energy predominantly via a glycolysis (Warburg effect) in contrast to most of other somatic cells preferring an oxidative phosphorylation. Proliferation of endothelial and cancer cells may be suppressed by a glycolysis inhibitor (E)-3-(pyridin-3-yl)-1-(pyridin-4-yl)prop-2-en-1-one (3PO) that synthesis is not sufficiently described in the literature. Moreover, a synergistic effect of inhibitors with different mechanisms of action may provide further advantages in cancer treatment. A combined effect of 3PO with inhibitor of angiogenesis sunitinib l-malate (SU) was not yet investigated on HUVEC cells. We have developed a novel and efficient method for a synthesis of a glycolysis inhibitor 3PO. The activity of 3PO on HUVECs proliferation was investigated and its IC50 = 10.7 μM determined. By combination of 3PO (10 μM) with sunitinib l-malate (0.1 μM) a significant synergistic effect on HUVECs proliferation was observed. Based on the structure, chemical reactivity and biological results, we proposed that 3PO could be a multi-target inhibitor.


Synthesis 3PO Sunitinib Inhibitor PFKFB3 Glycolysis Kinases HUVEC 



VEGA1/0670/18 and 1/0557/15; Biomagi, Ltd. (novel synthesis of 3PO, proposals: mechanism of Et2NH, multi-target 3PO properties). This publication is partially also the result of the project implementation: Comenius University in Bratislava Science Park supported by the Research and Development Operational Programme funded by the ERDF. Grant number: ITMS 26240220086.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

11696_2018_548_MOESM1_ESM.docx (724 kb)
Supplementary material 1 (DOCX 724 kb)


  1. Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307. CrossRefPubMedPubMedCentralGoogle Scholar
  2. Clem BF, O’Neal J, Tapolsky G, Clem AL, Imbert-Fernandez Y, Kerr DA 2nd, Klarer AC, Redman R, Miller DM, Trent JO, Telang S, Chesney J (2013) Targeting 6-phosphofructo-2-kinase (PFKFB3) as a therapeutic strategy against cancer. Mol Cancer Ther 12:1461–1470. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Conradi L-C, Brajic A, Cantelmo AR, Bouché A, Kalucka J, Pircher A, Brüning U, Teuwen L-A, Vinckier S, Ghesquière B, Dewerchin M, Carmeliet P (2017) Tumor vessel disintegration by maximum tolerable PFKFB3 blockade. Angiogenesis 20:599–613. CrossRefPubMedGoogle Scholar
  4. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW, Cantelmo AR, Quaegebeur A, Ghesquière B, Cauwenberghs S, Eelen G (2013) Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:651–663. CrossRefPubMedGoogle Scholar
  5. Durinda J, Szucs L, Krasnec L, Heger J, Springer V, Kolena J, Keleti J (1966) Chemistry and biological properties of azachalcones. Acta Facultatis Pharmaceuticae Bohemoslovenicae 12:89–129 (Chem. Abstr. 1968 68: 114494y) Google Scholar
  6. Durinda J, Kolena J, Szücs L, Krasnec L, Heger J (1967) Study of adrenal cortex inhibitors of the amphenone group. I. Azachalcones Ceskoslovenska farmacie 16:14–15 (PMID: 6044302) PubMedGoogle Scholar
  7. Eurocord-Slovakia Accessed 30 May 2018
  8. FDA (U.S. Food and Drug Administration). Accessed 30 May 2018
  9. Ferrara N, Hillan KJ, Gerber H-P, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discovery 3:391–400. CrossRefPubMedGoogle Scholar
  10. Jeong B-S, Choi H, Kwak Y-S, Lee E-S (2011) Synthesis of 2,4,6-Tripyridyl pyridines, and evaluation of their antitumor cytotoxicity, topoisomerase i and ii inhibitory activity, and structure-activity relationship. Bull Korean Chem Soc 32:3566–3570. CrossRefGoogle Scholar
  11. Kerbel R, Folkman J (2002) Clinical translation of angiogenesis inhibitors. Nat Rev Cancer 2:727–739. CrossRefPubMedGoogle Scholar
  12. Lintnerová L, García-Caballero M, Gregáň F, Melicherčík M, Quesada AR, Dobiaš J, Lác J, Sališsová M, Boháč A (2014) A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex—medicinal chemistry consequences of a TKs analysis. Eur J Med Chem 72:146–159. CrossRefPubMedGoogle Scholar
  13. Liptaj T, Mlynarik V, Remko M, Durinda J, Heger J (1981) 13C-NMR spectra of azachalcones. Collect Czech Chem Commun 46:1486–1491. CrossRefGoogle Scholar
  14. Moravčík R, Stebelová K, Boháč A, Zeman M (2016) Inhibition of VEGF mediated post receptor signalling pathways by recently developed tyrosine kinase inhibitor in comparison with sunitinib. Gen Physiol Biophys 35:511–514. CrossRefPubMedGoogle Scholar
  15. Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, Hess Ch, Christofori G (2016) Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep 15:1161–1174. CrossRefPubMedPubMedCentralGoogle Scholar
  16. Pla AF, Brossa A, Bernardini M, Genova T, Grolez G, Villers A, Leroy X, Prevarskaya N, Gkika D, Bussolati B (2014) Differential sensitivity of prostate tumor derived endothelial cells to sorafenib and sunitinib. BMC Cancer 14:939. CrossRefGoogle Scholar
  17. Reaxys DB (2018) Accessed 30 May 2018
  18. Schoors S, De Bock K, Cantelmo AR, Georgiadou M, Ghesquière B, Cauwenberghs S, Kuchnio A, Wong BW, Quaegebeur A, Goveia J (2014) Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metab 19:37–48. CrossRefPubMedGoogle Scholar
  19. SciFinder DB (2018) Accessed 30 May 2018
  20. Shaheen RM, Tseng WW, Davis DW, Liu W, Reinmuth N, Vellagas R, Wieczorek AA, Ogura Y, McConkey DJ, Drazan KE (2001) Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Can Res 61:1464–1468 PMID: 11245452 Google Scholar
  21. Tejpar S, Prenen H, Mazzone M (2012) Overcoming resistance to antiangiogenic therapies. Oncologist 17:1039–1050. CrossRefPubMedPubMedCentralGoogle Scholar
  22. WSS Inc. US (2018) Spectral data were obtained from Wiley Subscription Services, Inc. (US)Google Scholar
  23. Vatsadze SZ, Nuriev VN, Leshcheva IF, Zyk NV (2004) New aspects of the aldol condensation of acetylpyridines with aromatic aldehydes. Russ Chem Bull 53:911–915. CrossRefGoogle Scholar
  24. Zecchin A, Kalucka J, Dubois C, Carmeliet P (2017) How Endothelial Cells Adapt Their Metabolism to Form Vessels in Tumors. Front Immunol 8:1750. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Institute of Chemistry, Slovak Academy of Sciences 2018

Authors and Affiliations

  1. 1.Department of Organic Chemistry, Faculty of Natural SciencesComenius University in BratislavaBratislavaSlovakia
  2. 2.Department of Animal Physiology and Ethology, Faculty of Natural SciencesComenius University in BratislavaBratislavaSlovakia
  3. 3.Institute of Chemistry, Faculty of Natural SciencesComenius University in BratislavaBratislavaSlovakia
  4. 4.Biomagi, Ltd.BratislavaSlovakia

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