Preparation of 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives and their activity against DOT1L

Bioorg Med Chem Lett. 2017 Nov 15;27(22):4960-4963. doi: 10.1016/j.bmcl.2017.10.019. Epub 2017 Oct 10.

Abstract

From a readily available 5-C-Me ribofuranoside, we have realized a reliable route to valuable 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives at gram scale with confirmed stereochemistry. These adenosine derivatives are useful starting materials for the preparation of 5'-deoxy-5'-amino-5'-C-methyl adenosine derivatives with higher complexity. From one of the new adenosine derivatives, some 5'-deoxy-5'-amino-5'-C-methyl adenosine DOT1L inhibitors were prepared in several steps. Data from DOT1L assay indicated that additional 5'-C-Me group improved the enzyme inhibitory activity.

Keywords: 5′-Deoxy-5′-amino-5′-C-methyl adenosine derivative; DOT1L inhibitor; N-glycosylation; Nucleoside synthesis; Structure activity relationship.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / metabolism
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Inhibitory Concentration 50
  • Methyltransferases / antagonists & inhibitors*
  • Methyltransferases / metabolism
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Nucleosides
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Adenosine