Synthesis and Activity of Putative Small-Molecule Inhibitors of the F-Box Protein SKP2

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.

Alkyl Halides as Both Hydride and Alkyl Sources in Catalytic Regioselective Reductive Olefin Hydroalkylation

“…The first application that demonstrates utility of our Markovnikovselective reductive hydroalkylation protocol involves the synthesis of a family of therapeutic compounds 9 for the treatment of metabolic disorders 61 (Fig. 4a) In a second instance, chemoselective reduction of the 8-aminoquinaldine amide in 6ag to aldehyde 10 followed by reductive amination with benzylamine 11 and N-Boc protection delivered 12, a precursor for the synthesis of an anti-cancer compound 62 , in 51% overall yield.…”

“…The entire sequence is more concise compared to a previous report. 62 The preparation of 14 highlights yet another compelling example of the versatility of the branched hydroalkylation products. Facile conversion of 6ah to its redox-active ester derivative 13 (70% overall yield) set the stage for a catalytic decarboxylative cross-coupling 52 with 1-(benzyloxy)-3-iodobenzene to furnish 14, which has been further elaborated to another anti-cancer agent.…”

Alkyl Halides as Both Hydride and Alkyl Sources in Catalytic Regioselective Reductive Olefin Hydroalkylation

“…4a) The entire sequence is more concise compared to a previous report. 64 The preparation of 16 highlights yet another compelling example of the versatility of the branched hydroalkylation products. Facile conversion of 9ai to its redox-active ester derivative 15 (70% overall yield) set the stage for a catalytic decarboxylative cross-coupling 53 with 1-(benzyloxy)-3-iodobenzene to furnish 16, which has been further elaborated to another anti-cancer agent 3.…”

“…. Chemoselective removal of the amide directing group in 9y (recovered 8-aminoquinaldine in 95% yield) afforded acid 11, a key intermediate employed in the preparation of 1, in 83% yield.In a second instance, chemoselective reduction of the 8-aminoquinaldine amide in 9ah to aldehyde 12 followed by reductive amination with benzylamine 13 and N-Boc protection delivered 14, a precursor for the synthesis of an anti-cancer compound 264 , in 51% overall yield.…”

Sir John Cornforth Memorial Issue

“…[22] Bernard Golding and co-workers at Newcastle University, UK, report the synthesis and activity of putative small-molecule inhibitors of the Fbox protein SKP2. [23] Margaret Brimble and collaborators at The University of Auckland report the synthesis of novel water-soluble triazole-containing phosphonate polymers. [24] This writer with co-workers Carsten Plüg and Hussein Kanaani report a versatile synthesis of ketenes by flash vacuum pyrolysis of N-(2-pyridyl)amides.…”