Synthesis, <i>in silico</i> and <i>in vitro</i> Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents
Yevheniia Velihina, Thomas Scattolin, Denys Bondar, С. Г. Пильо, Nataliya Obernikhina, Olesksiy Kachkovskyi, Ivan Semenyuta, Isabella Caligiuri, Flavio Rizzolio, В. С. Броварец, Yevgen Karpichev, Steven P. Nolan
Abstract
Abstract New potential bioactive oxazolopyrimidines have been synthesized using two main approaches: the pyrimidine ring annulation on a functionalized oxazole and the benzoyl bromide trimerization followed by rearrangement and formation of the oxazolo[5,4‐ d ]pyrimidine scaffold. The docking analyzes have shown that 7‐piperazine substituted oxazolo[4,5‐ d ]pyrimidines 8a – 8c could be potential VEGFR2 inhibitors with high free energy of ligand–protein complex formation (Δ G : −10.1, −9.6, −9.8 kcal/mol, respectively). In vitro antitumor assays confirmed theoretical predictions that oxazolo[4,5‐ d ]pyrimidines 8a – 8c containing positively charged piperazine moiety should demonstrate significantly higher cytotoxic effects. 4‐[5‐(4‐Chlorophenyl)‐2‐phenyl[1,3]oxazolo[4,5‐ d ]pyrimidin‐7‐yl]piperazin‐1‐ium trifluoroacetate ( 8c ) exhibited a slightly higher antiproliferative effect ( IC 50 =0.21 μ m ) than doxorubicin ( IC 50 =0.36 μ m ) on MDA‐MB‐231 cell line and has relatively good results on OVCAR‐3 ( IC 50 =1.7 μ m ) and HCT‐116 ( IC 50 =0.24 μ m ) cells.