Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery

Org Lett. 2014 Nov 7;16(21):5776-9. doi: 10.1021/ol5028392. Epub 2014 Oct 21.

Abstract

Ferrous iron-promoted reduction of a hindered peroxide bond underlies the antimalarial action of the 1,2,4-trioxane artemisinin and the 1,2,4-trioxolane arterolane. In appropriately designed systems, a 1,2,4-trioxolane ring can serve as a trigger to realize ferrous iron-dependent and parasite-selective drug delivery, both in vitro and in vivo. A stereocontrolled, expeditious (three steps), and efficient (67-71% overall yield) synthesis of 1,2,4-trioxolanes possessing the requisite 3″ substitution pattern that enables ferrous iron-dependent drug delivery is reported. The key synthetic step involves a diastereoselective Griesbaum co-ozonolysis reaction to afford primarily products with a trans relationship between the 3″ substituent and the peroxide bridge, as confirmed by X-ray structural analysis of a 3″-substituted 4-nitrobenzoate analogue.

Publication types

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

MeSH terms

  • Antimalarials / chemical synthesis*
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Artemisinins / chemical synthesis*
  • Artemisinins / chemistry
  • Artemisinins / pharmacology*
  • Crystallography, X-Ray
  • Drug Delivery Systems
  • Ferrous Compounds / chemistry*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Humans
  • Iron / chemistry
  • Molecular Structure
  • Nitrobenzoates / chemistry*
  • Plasmodium falciparum / drug effects*

Substances

  • 1,2,4-trioxane
  • Antimalarials
  • Artemisinins
  • Ferrous Compounds
  • Heterocyclic Compounds
  • Nitrobenzoates
  • Iron