Ynamide Click chemistry in development of triazole VEGFR2 TK modulators.
Structure novelty, chemical stability and synthetic feasibility attracted us to design 1,2,3-triazole compounds as potential inhibitors of VEGFR2 tyrosine kinase. Novel triazoles T1-T7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1-T7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1-T3 and T6-T7. Among the obtained products, T1, T3 and T7 specifically bind VEGFR2 TK and modulate its activity by concentration dependent manner. Moreover predicted binding poses of T1-T7 in VEGFR2 TK were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and T7 is lower than that determined for their oxazole bioisosters T3-ox and AAZ, resp. Different electronic properties of 1,2,3-triazole/oxazole heterocyclic rings were proposed to be the main reason for the diminished affinity of T1-T3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1-T3 and T6 were screened on cytotoxic activity against two human hepatocellular carcinoma cell lines. Selective cytotoxic activity of T2 against aggressive Mahlavu cells has been discovered indicating possible affinity of T2 to Mahlavu constitutionally active PI3K/Akt pathway.
Université de Strasbourg, Ecole européenne de Chimie, Polymères et Matériaux (ECPM) Laboratoire de Synthèse et Catalyse (UMR CNRS 7509), 25, rue Becquerel, F-67087 Strasbourg, France; Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, 842 15 Bratislava, Slovakia. Electronic address: vojtickova.margareta@gmail.com.
Margaréta
M
Vojtičková
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, 842 15 Bratislava, Slovakia. Electronic address: jur.dobias@gmail.com.
Juraj
J
Dobiaš
Université de Strasbourg, Ecole européenne de Chimie, Polymères et Matériaux (ECPM) Laboratoire de Synthèse et Catalyse (UMR CNRS 7509), 25, rue Becquerel, F-67087 Strasbourg, France. Electronic address: ghanquet@unistra.fr.
Gilles
G
Hanquet
Institute of Chemistry, Mlynská dolina, 842 15 Bratislava, Slovakia. Electronic address: addova@fns.uniba.sk.
Gabriela
G
Addová
Cancer Systems Biology Laboratory, Graduate School of Informatics, METU, 06800 Ankara, Turkey. Electronic address: rengul@bilkent.edu.tr.
Rengul
R
Cetin-Atalay
Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
Deniz Cansen
DC
Yildirim
Comenius University in Bratislava, Faculty of Natural Sciences, Department of Organic Chemistry, Mlynská dolina, 842 15 Bratislava, Slovakia; Biomagi, Ltd., Mamateyova 26, 851 04 Bratislava, Slovakia(1). Electronic address: andrej.bohac@fns.uniba.sk.
Andrej
A
Boháč
D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057930:Click Chemistry; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000480:Alkynes; D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D014230:Triazoles; D040301:Vascular Endothelial Growth Factor Receptor-2
CuACC Click chemistry; Cytotoxic activity in Huh-7 and Mahlavu hepatocellular carcinoma cell lines; Oxazole/1,2,3-triazole isosteric replacement; PI3K/Akt pathway; VEGFR2 tyrosine kinase inhibition; Ynamide