Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, FI-00014 University of Helsinki, Finland.
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, FI-90014 University of Oulu, Finland.
Bioorg Med Chem. 2018 May 1;26(8):1588-1597. doi: 10.1016/j.bmc.2018.02.006. Epub 2018 Feb 13.
The human O-acetyl-ADP-ribose deacetylase MDO1 is a mono-ADP-ribosylhydrolase involved in the reversal of post-translational modifications. Until now MDO1 has been poorly characterized, partly since no ligand is known besides adenosine nucleotides. Here, we synthesized thirteen compounds retaining the adenosine moiety and bearing bioisosteric replacements of the phosphate at the ribose 5'-oxygen. These compounds are composed of either a squaryldiamide or an amide group as the bioisosteric replacement and/or as a linker. To these groups a variety of substituents were attached such as phenyl, benzyl, pyridyl, carboxyl, hydroxy and tetrazolyl. Biochemical evaluation showed that two compounds, one from both series, inhibited ADP-ribosyl hydrolysis mediated by MDO1 in high concentrations.
人源 O-乙酰-ADP-核糖脱乙酰酶 MDO1 是一种单 ADP-核糖基水解酶，参与翻译后修饰的逆转。到目前为止，MDO1 的特征描述较差，部分原因是除了腺苷核苷酸之外，还不知道其他配体。在这里，我们合成了十三种化合物，保留了腺苷部分，并在核糖 5'-氧上用生物等排体取代了磷酸。这些化合物由 squaryldiamide 或酰胺基团作为生物等排体取代基和/或作为连接子组成。这些基团连接了各种取代基，如苯基、苄基、吡啶基、羧基、羟基和四唑基。生化评估表明，两种化合物，一种来自两个系列，在高浓度下抑制了 MDO1 介导的 ADP-核糖基水解。
