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
- 28 Downloads
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.
KeywordsSynthesis 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.
- 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. https://doi.org/10.1158/1535-7163 CrossRefGoogle Scholar
- 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. https://doi.org/10.1007/s10456-017-9573-6 CrossRefGoogle Scholar
- 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
- 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) Google Scholar
- Eurocord-Slovakia http://eurocord.sk/. Accessed 30 May 2018
- FDA (U.S. Food and Drug Administration). https://www.fda.gov. Accessed 30 May 2018
- 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. https://doi.org/10.5012/bkcs.2011.32.10.3566 CrossRefGoogle Scholar
- 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. https://doi.org/10.1016/j.ejmech.2013.11.023 CrossRefGoogle Scholar
- Reaxys DB (2018) https://www.reaxys.com. Accessed 30 May 2018
- 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. https://doi.org/10.1016/j.cmet.2013.11.008 CrossRefGoogle Scholar
- SciFinder DB (2018) https://scifinder.cas.org. Accessed 30 May 2018
- 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
- WSS Inc. US (2018) Spectral data were obtained from Wiley Subscription Services, Inc. (US)Google Scholar
- 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. https://doi.org/10.1023/b:rucb.0000037863.85554.35 CrossRefGoogle Scholar