Carbohydrate-based synthetic approach to control toxicity profiles of folate-drug conjugates

J Org Chem. 2010 Jun 4;75(11):3685-91. doi: 10.1021/jo100448q.

Abstract

To better regulate the biodistribution of the vinblastine-folate conjugate, EC145, a new folate-spacer that incorporates 1-amino-1-deoxy-D-glucitol-gamma-glutamate subunits into a peptidic backbone, was synthesized. Synthesis of Fmoc-3,4;5,6-di-O-isopropylidene-1-amino-1-deoxy-D-glucitol-gamma-glutamate 20, suitable for Fmoc-strategy solid-phase peptide synthesis (SPPS), was achieved in four steps from delta-gluconolactone. Addition of alternating glutamic acid and 20 moieties onto a cysteine-loaded resin, followed by the addition of folate, deprotection, and cleavage, resulted in the isolation of the new folate-spacer: Pte-gammaGlu-(Glu(1-amino-1-deoxy-D-glucitol)-Glu)(2)-Glu(1-amino-1-deoxy-D-glucitol)-Cys-OH (21). The addition of 21 to an appropriately modified desacetylvinblastine hydrazide (DAVLBH) resulted in a conjugate (25) with an improved therapeutic index. Treatment of 25 with DTT in neutral buffer at room temperature demonstrated that free DAVLBH would be released under the reductive environment of the internalized endosome.

MeSH terms

  • Animals
  • Antineoplastic Agents
  • Carbohydrates / chemistry*
  • Drug Design
  • Endosomes / metabolism
  • Folic Acid / analogs & derivatives*
  • Folic Acid / chemical synthesis
  • Folic Acid / chemistry
  • Folic Acid / pharmacokinetics
  • Folic Acid / therapeutic use
  • Folic Acid / toxicity
  • Humans
  • Tissue Distribution
  • Vinblastine / chemistry
  • Vinblastine / therapeutic use
  • Vinca Alkaloids / chemical synthesis*
  • Vinca Alkaloids / pharmacokinetics
  • Vinca Alkaloids / toxicity*

Substances

  • Antineoplastic Agents
  • Carbohydrates
  • EC145
  • Vinca Alkaloids
  • Vinblastine
  • Folic Acid