Abstract
Article describes the synthesis of fifteen β-hydroxy-β-arylalkanoic acids byReformatsky reaction using the 1-ethoxyethyl-2-bromoalkanoates, aromatic or cycloalkylketones or aromatic aldehydes. The short survey of previously reported synthetic proceduresfor title compounds, is given. The majority of obtained compounds exert antiproliferativeactivity in vitro toward human: HeLa, Fem-X cells, K562, and LS174 cells, having IC50values from 62.20 to 205 μM. The most active compound is 3-OH-2,2-di-Me-3-(4-biphenylyl)-butanoic acid, having the IC50 value 62.20 μM toward HeLa cells. Sevenexamined compounds did not affect proliferation of healthy human blood peripheralmononuclear cells (PBMC and PBMC PHA), IC50 > 300 μM. The preliminary QSARresults show that estimated lipophilicity of compounds influences their antiproliferativeactivity in the first place. The ability of dehydration, and the spatial arrangement ofhydrophobic portion, HBD and HBA in molecules are has almost equal importance aslipophilicity.
Highlights
Cyclooxygenases (COX) or prostaglandin endoperoxide synthases (PGHS) are the key enzymes in the synthesis of prostaglandins from their precursor, arachidonic acid.Arachidonic acid is cleaved from cell membrane phospholipids by phospholipase A2
Article describes the synthesis of fifteen β-hydroxy-β-arylalkanoic acids by Reformatsky reaction using the 1-ethoxyethyl-2-bromoalkanoates, aromatic or cycloalkyl ketones or aromatic aldehydes
The preliminary QSAR results show that estimated lipophilicity of compounds influences their antiproliferative activity in the first place
Summary
Cyclooxygenases (COX) or prostaglandin endoperoxide synthases (PGHS) are the key enzymes in the synthesis of prostaglandins from their precursor, arachidonic acid. Our compounds belong to the class of aryl- and cycloalkylpropanoic acids, structurally similar with commercially available NSAID-s Their antiproliferative activity toward malignant cell lines was evaluated in this work. Another method for direct synthesis β-hydroxy acids can be used when α-bromo acid is not accessible, and utilizes the dianion of carboxylic acids obtained by the reaction between acids and extremely strong bases as Lidiisopropylamide, instead of Reformatsky reagent [13] In this reaction carboxylic proton and αhydrogen are both substituted by lithium. Accessible α-bromo ester-acetals, obtained by the action of aliphatic vinyl ethers on αbromo acids, can be used in the Reformatsky reaction for direct preparation of β-hydroxy acids [16,17]. All compounds were characterized by their melting points, MS, IR, 1H, and 13C NMR spectra, and by elemental analysis, as well
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