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ACS Med Chem Lett. 2014 Nov 26;6(1):95-9. doi: 10.1021/ml5004525. eCollection 2015 Jan 8.

Synthesis and Structure-Activity Relationship Study of 5a-Carbasugar Analogues of SL0101.

Author information

1
Department of Chemistry and Chemical Biology, Northeastern University , Boston, Massachusetts 02115, United States.
2
Departments of Pathology, Microbiology, and Immunology, and Cancer Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.
3
Department of Chemistry, West Virginia University , Morgantown, West Virginia 26506, United States.
4
Departments of Pathology, Microbiology, and Immunology, and Cancer Biology, Vanderbilt University , Nashville, Tennessee 37232, United States ; Departments of Pathology, Microbiology, and Immunology, and Cancer Biology, Vanderbilt University , Nashville, Tennessee 37232, United States.

Abstract

The Ser/Thr protein kinase, RSK, is associated with oncogenesis, and therefore, there are ongoing efforts to develop RSK inhibitors that are suitable for use in vivo. SL0101 is a natural product that demonstrates selectivity for RSK inhibition. However, SL0101 has a short biological half-life in vivo. To address this issue we designed a set of eight cyclitol analogues, which should be resistant to acid catalyzed anomeric bond hydrolysis. The analogues were synthesized and evaluated for their ability to selectively inhibit RSK in vitro and in cell-based assays. All the analogues were prepared using a stereodivergent palladium-catalyzed glycosylation/cyclitolization for installing the aglycon. The l-cyclitol analogues were found to inhibit RSK2 in in vitro kinase activity with a similar efficacy to that of SL0101, however, the analogues were not specific for RSK in cell-based assays. In contrast, the d-isomers showed no RSK inhibitory activity in in vitro kinase assay.

KEYWORDS:

RSK inhibition; SL0101; Ser/Thr protein kinase; cyclitol; de novo synthesis

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