Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity

J Med Chem. 2006 May 4;49(9):2731-4. doi: 10.1021/jm058288w.

Abstract

In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 degrees C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antimalarials / administration & dosage
  • Antimalarials / pharmacology*
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Artemisinins / chemistry*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Dimerization
  • Heterocyclic Compounds / administration & dosage
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Molecular Structure
  • Plasmodium falciparum / drug effects*
  • Sesquiterpenes / chemistry*

Substances

  • Antimalarials
  • Antineoplastic Agents
  • Artemisinins
  • Heterocyclic Compounds
  • Sesquiterpenes
  • artemisinin