Ynamide Click chemistry in development of triazole VEGFR2 TK modulators

Abstract

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 a b s t r a c t 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 T1eT7 were proposed by oxazole (AAZ from PDB: 1Y6A)/1,2,3-triazole isosteric replacement, molecular modelling and docking. In order to enable synthesis of T1eT7 we developed a methodology for preparation of ynamide 22. Compound 22 was used for all Click chemistry reactions leading to triazoles T1eT3 and T6eT7. 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 T1eT7 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 T1eT3, T6 and T7 to an oxazole AAZ inhibitor binding site in VEGFR2 TK (PDB: 1Y6A or 1Y6B). Moreover T1eT3 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.

An investigation on the second-order nonlinear optical response of cationic bipyridine or phenanthroline iridium(iii) complexes bearing cyclometallated 2-phenylpyridines with a triphenylamine substituent

“…5-Nitro-1,10-phenthroline and 4,4'-ditert-butyl-2,2'-bipyridine are commercial. The 2-phenylpyridines substituted with a triphenylamine (TPA) L1-L3 (Chart S1 in ESI †) were prepared through cross-coupling reactions using the appropriate bromosubstituted 2-phenylpyridines namely 2-(4bromophenyl)pyridine, 42 2-(3-bromophenyl)pyridine), 43 and (4-(diphenylamino)phenyl)boronic acid, which were prepared Please do not adjust margins Please do not adjust margins according to the literature. Likewise, the pro-ligand L1 44 and the 4-bromo-2-phenylpyridine 45 precursor were synthesised according to published procedures.…”

Synthesis and Biological Evaluation of Small Molecules as Potential Anticancer Multitarget Agents

“…Our goal in this study was the development of small molecules bearing a 1,2,3-triazole central ring that could target both PD-L1 and VEGFR-2 in tumor cells. For 1,2,3-triazole ring-containing structures that have been shown to be active on VEGFR2 inhibition, see References [13][14][15][16][17][18][19]. We were also interested in checking the effect of these molecules on c-Myc.…”