Ynamide Click chemistry in development of triazole VEGFR2 TK modulators.

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Vojtickova M., Dobias J., Hanquet G., Addova G., Cetin-Atalay R., Yildirim D. C., ...More

European journal of medicinal chemistry, vol.103, pp.105-22, 2015 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 103
  • Publication Date: 2015
  • Doi Number: 10.1016/j.ejmech.2015.08.012
  • Journal Name: European journal of medicinal chemistry
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.105-22
  • Keywords: Oxazole/1,2,3-triazole isosteric replacement, Ynamide, CuACC Click chemistry, VEGFR2 tyrosine kinase inhibition, Cytotoxic activity in Huh-7 and Mahlavu, hepatocellular carcinoma cell lines, PI3K/Akt pathway, N-FUNCTIONALIZED 1-ALKYNYLAMIDES, TYROSINE KINASE INHIBITORS, ARYL HALIDES, CHEMOSELECTIVE REACTIVITY, CATALYZED CYCLOADDITION, ALKYNYLIODONIUM SALTS, HIGHLY EFFICIENT, DISCOVERY, DESIGN, CANCER
  • Middle East Technical University Affiliated: Yes


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 Ti T7 in VEGFR2 TIC were similar to the one known for the oxazole inhibitor AAZ (PDB: 1Y6A). Unfortunately the VEGFR2 inhibition by triazoles e.g. T3 and Ti 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 17 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1-T3 and 16 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. (C) 2015 Elsevier Masson SAS. All rights reserved.