Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility

Bioorg Med Chem Lett. 2013 Feb 1;23(3):669-72. doi: 10.1016/j.bmcl.2012.11.114. Epub 2012 Dec 5.

Abstract

We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.

MeSH terms

  • Adenine / administration & dosage
  • Adenine / analogs & derivatives*
  • Adenine / chemical synthesis
  • Adenine / chemistry
  • Adenine / pharmacology
  • Administration, Intravenous
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • HEK293 Cells
  • Humans
  • Mice
  • Molecular Structure
  • Solubility
  • Toll-Like Receptor 7 / agonists*
  • Water / chemistry*

Substances

  • Antineoplastic Agents
  • DSR-6434
  • Toll-Like Receptor 7
  • Water
  • 8-hydroxyadenine
  • Adenine