期刊
BIOORGANIC CHEMISTRY
卷 99, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.103777
关键词
Heme oxygenase-1; HO-1 inhibitors; Docking studies; Racemic approach; Imidazole; Enantiomers resolution
资金
- Research Funding for University (Piano per la Ricerca) [57722172107]
- Ministry of Health [02769.N.VLY]
- PON RI funds [CUP: E66C18001320007, AIM1872330]
Heme oxygenase-1 (HO-1) has been recognized as extensively involved in the development and aggravation of cancer, cell propagation and at in the mechanism of chemoresistance development. Low micromolar HO-1 inhibitors selective towards HO-2 has been recently reported, wherein the azole core and the hydrophobic residues are linked through a phenylethanolic spacer bearing a chiral center. Since less information are known about the stereoselective requirements for HO-1 inhibition, here we report the enantiomeric resolution of 1-(biphenyl-3yl)-2-(1H-imidazol-1-yl)ethanol (1) and 1-[4-[(4-bromobenzyl)oxy]phenyl]-2-(1H-imidazol-1-yl)ethanol (2), two among the most potent and selective HO-1 inhibitors known thus far when tested as racemates. The absolute configuration was established for 1 by a combination of experimental and in silico derived electronic circular dichroism spectra, while docking approaches were useful in the case of compound 2. Biological evaluation of pure enantiomers highlighted higher HO-1 inhibitory activity of (R)-enantiomers. Docking studies demonstrated the importance of hydrogen bond interaction, more pronounced for the (R)-enantiomers, with a consensus water molecule within the binding pocket. The present study demonstrates that differences in three-dimensional structure amongst compounds 1 and 2 enantiomers affect significantly the selectivity of these HO-1 inhibitors.
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