Synthesis of a novel tricyclic 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system and CXCR4 antagonists with potent activity against HIV-1

Bioorg Med Chem Lett. 2010 Apr 1;20(7):2186-90. doi: 10.1016/j.bmcl.2010.02.030. Epub 2010 Feb 12.

Abstract

Stereorandom and diastereoselective syntheses of a novel 1,2,3,4,4a,5,6,10b-octahydro-1,10-phenanthroline ring system are described. Derivatives of all four diastereomers were prepared and isolated in >98% ee. The pure enantiomers were compared in order to determine the preferred absolute and relative configuration required for optimal anti-HIV activity. Anti-HIV potency and pharmacokinetic properties of the newly synthesized tricyclic octahydrophenanthroline inhibitors are presented and comparisons are made to previously reported bicyclic (8S)-N-methyl-5,6,7,8-tetrahydro-8-quinolinamine analogs.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Cell Line
  • Dogs
  • HIV Infections / drug therapy*
  • HIV-1 / drug effects*
  • Humans
  • Models, Molecular
  • Phenanthrolines / chemical synthesis
  • Phenanthrolines / chemistry*
  • Phenanthrolines / pharmacokinetics
  • Phenanthrolines / pharmacology*
  • Rats
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism

Substances

  • Anti-HIV Agents
  • Phenanthrolines
  • Receptors, CXCR4
  • 1,10-phenanthroline