Stereoselective Synthesis and Evaluation of C6″-Substituted 5a-Carbasugar Analogues of SL0101 as Inhibitors of RSK1/2

Abstract

A convergent synthesis of 5a-carbasugar analogues of the n-Pr-variant of SL0101 is described. The analogues were synthesized in an effort to find compounds with potent in vivo efficacy in the inhibition of p90 ribosomal s6 kinase (RSK1/2). The synthesis derived the desired C-4 L-rhamnose stereochemistry from quinic acid and used a highly selective cuprate addition, NaBH reduction, Mitsunobu inversion, and alkene dihydroxylation to install the remaining stereochemistry. A Pd-catalyzed cyclitolization stereoselectively installed the aglycon at the anomeric position. The analogues were evaluated as RSK1/2 inhibitors and found to have 3- to 6-fold improved activity.

RSK2 Maintains Adult Estrogen Homeostasis by Inhibiting ERK1/2-Mediated Degradation of Estrogen Receptor Alpha

“…Reduced ERα protein levels in the RSK2-KO could be the result of decreased RSK2 kinase activity or the loss of the RSK2 protein. To distinguish between these mechanisms, RSK2 activity was inhibited in vivo by the specific RSK1/2 inhibitor C5′′ -n -propyl cyclitol SL0101 (C5′′) ( Ludwik et al, 2016 ; Li et al, 2017 ). ERα protein levels were reduced by the RSK1/2 inhibitor ( Figure 4E ).…”

Gram-scale carbasugar synthesis via intramolecular seleno-Michael/aldol reaction

“…The 6S-hydroxyshikimic ester (6S)-5 has been transformed to non-natural valienamine derivative (11) with known protocol in 27% yield over 3 steps. 16,24 Exposure of 10 to chlorosulfonyl isocyanate in DCM afforded the desired product (11) in 51% yield.…”

“…5,6 For example, synthetic nucleotide analogues containing thiosugar or carbasugars have been reported to be glycosyltransferase inhibitors. [7][8][9] The mechanism of glycosidase inhibition has been studied and several carba-analogues, such as Sergliozin-A 10 or SL0101, 11 have been introduced (Fig. 1).…”

Identifying requirements for RSK2 specific inhibitors

“…As expected, based on the interaction mechanism a detailed analysis of the specificity of the SL0101 derivative, C5”- n -propyl cyclitol SL0101 ( 1b ), demonstrated that 1b primarily targeted RSK1/2 in a screen of 247 kinases, containing representatives from all kinase families 11 . Furthermore, ( 1b ) was ineffective at inhibiting proliferation in a cell-based assay when its targets, RSK1/2, were silenced 26 . These data predict that SL0101-based derivatives will have limited off target effects and therefore, we have continued to evaluate and develop SL0101-based analogues.…”