Synthesis and Activity of Putative Small-Molecule Inhibitors of the F-Box Protein SKP2*
Andrew E. Shouksmith A , Laura E. Evans B , Deborah A. Tweddle B , Duncan C. Miller A , Elaine Willmore B , David R. Newell B D , Bernard T. Golding A D and Roger J. Griffin CA Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
B Northern Institute for Cancer Research, Paul O’Gorman Building, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
C Deceased. Formerly of Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
D Corresponding authors. Email: herbie.newell@ncl.ac.uk; bernard.golding@ncl.ac.uk
Australian Journal of Chemistry 68(4) 660-679 https://doi.org/10.1071/CH14586
Submitted: 24 September 2014 Accepted: 8 November 2014 Published: 5 February 2015
Abstract
The tetrahydropyran 4-(((3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline was reported to disrupt the SCFSKP2 E3 ligase complex. Efficient syntheses of this tetrahydropyran derivative and analogues, including the des-dimethyl derivative 4-(((3-(tetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline, are described. The enantiomers of the des-dimethyl compound were obtained using Evans’ chiral auxiliaries. Structure–activity relationships for these tetrahydropyrans and analogues have been determined by measurement of growth-inhibitory activities in HeLa cells, which indicated a non-specific mechanism of action that correlates with inhibitor lipophilicity. However, preliminary data with (R)- and (S)-4-(((3-(tetrahydro-2H-pyran-4-yl)-4-phenylbutyl)amino)methyl)-N,N-dimethylaniline showed enantioselective inhibition of the degradation of p27 in a cell-based assay that acts as a reporter of SKP2 activity.
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