TY - JOUR
T1 - Synthesis, in silico and in vitro Evaluation of Novel Oxazolopyrimidines as Promising Anticancer Agents
AU - Velihina, Yevheniia
AU - Scattolin, Thomas
AU - Bondar, Denys
AU - Pil'o, Stepan
AU - Obernikhina, Nataliya
AU - Kachkovskyi, Olesksiy
AU - Semenyuta, Ivan
AU - Caligiuri, Isabella
AU - Rizzolio, Flavio
AU - Brovarets, Volodymyr
AU - Karpichev, Yevgen
AU - Nolan, Steven P.
N1 - Funding Information:
Authors thank for assistance with NMR studies. Support from COST Action CA15106: ‘C−H Activation in Organic Synthesis’ (CHAOS) is gratefully acknowledged. . thanks the European Regional Development Fund (Dora Plus Programme) for financial support. . acknowledges the financial support from the BOF fund (starting and senior grants). Indrek Reile Ye. V S. P. N
Publisher Copyright:
© 2020 Wiley-VHCA AG, Zurich, Switzerland
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/12
Y1 - 2020/12
N2 - 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 (ΔG: −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 (IC50=0.21 μm) than doxorubicin (IC50=0.36 μm) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC50=1.7 μm) and HCT-116 (IC50=0.24 μm) cells.
AB - 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 (ΔG: −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 (IC50=0.21 μm) than doxorubicin (IC50=0.36 μm) on MDA-MB-231 cell line and has relatively good results on OVCAR-3 (IC50=1.7 μm) and HCT-116 (IC50=0.24 μm) cells.
KW - antitumor agents
KW - donor-acceptor systems
KW - molecular docking
KW - oxazolopyrimidines
KW - Suzuki-Miyaura reaction
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U2 - 10.1002/hlca.202000169
DO - 10.1002/hlca.202000169
M3 - Article
AN - SCOPUS:85096762058
VL - 103
JO - Helvetica Chimica Acta
JF - Helvetica Chimica Acta
SN - 0018-019X
IS - 12
M1 - e2000169
ER -