Cancer Biology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232, United States.
Departments of Pathology, Microbiology & Immunology , Nashville, Tennessee 37232, United States.
Org Lett. 2017 May 5;19(9):2410-2413. doi: 10.1021/acs.orglett.7b00945. Epub 2017 Apr 25.
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.
描述了 SL0101 的 n-Pr 变体的 5a-碳环糖类似物的收敛合成。这些类似物是为了寻找具有强效体内功效的化合物而合成的，能够抑制 p90 核糖体 S6 激酶（RSK1/2）。合成从奎宁酸获得所需的 C-4 L-鼠李糖立体化学，并使用高选择性的铜酸盐加成、NaBH 还原、Mitsunobu 反转和烯烃双羟化反应来安装其余的立体化学。Pd 催化的环糖醇化选择性地在糖苷位置安装糖苷配基。对类似物进行了 RSK1/2 抑制剂评估，发现其活性提高了 3 至 6 倍。
