Synthesis and antitumor activity evaluations of albumin-binding prodrugs of CC-1065 analog

Bioorg Med Chem. 2008 Jul 1;16(13):6552-9. doi: 10.1016/j.bmc.2008.05.025. Epub 2008 May 15.

Abstract

An albumin-binding prodrug of the extremely potent CC-1065 analog, (+)-FDI-CBI, has been synthesized. This analog, (+)-FDI-CBIM, formed an albumin conjugate when added to human albumin in vitro. A greater amount (>3-fold) of the prodrug can be administered to animals compared to the free drug. The prodrug had significantly improved antitumor efficacy compared to the free drug in animal models using syngeneic animal tumors and human ovarian xenografted tumor cells. Antitumor drug delivery by in situ formation of drug-albumin conjugate is a promising strategy to improve antitumor efficacy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents / toxicity*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Disease Models, Animal
  • Duocarmycins
  • Female
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / therapeutic use
  • Indoles / toxicity*
  • Mice
  • Molecular Structure
  • Neoplasm Transplantation
  • Neoplasms / drug therapy
  • Prodrugs / chemical synthesis*
  • Prodrugs / chemistry
  • Prodrugs / therapeutic use
  • Prodrugs / toxicity*
  • Serum Albumin / chemistry*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Duocarmycins
  • Indoles
  • Prodrugs
  • Serum Albumin
  • CC 1065