Synthesis and evaluation of N-acylamino acids derivatives of triazenes. Activation by tyrosinase in human melanoma cell lines

Eur J Med Chem. 2013:70:1-9. doi: 10.1016/j.ejmech.2013.09.040. Epub 2013 Oct 2.

Abstract

In this research work we report the synthesis of a new series of triazene prodrugs designed for Melanocyte-Directed Enzyme Prodrug Therapy (MDEPT). These compounds are derived from the N-acyltyrosine amino acid - a good enzyme substrate for the tyrosinase enzyme, which is significantly overexpressed in melanoma cells. We analysed their chemical stability and plasma enzymatic hydrolysis, and we also evaluated the release of the antitumoral drug in the presence of the tyrosinase. Subsequently, we performed the evaluation of the prodrug cytotoxicity in melanoma cell lines with different levels of tyrosinase activity. Prodrug 5c showed the highest cytotoxicity against melanoma cell lines, and this effect correlated well with the tyrosinase activity suggesting that prodrug cytotoxicity is tyrosinase-dependent.

Keywords: Melanoma cells; Prodrugs; Triazenes; Tyrosinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Melanoma / enzymology
  • Molecular Structure
  • Monophenol Monooxygenase / metabolism*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / metabolism*
  • Prodrugs / pharmacology
  • Structure-Activity Relationship
  • Triazenes / chemical synthesis*
  • Triazenes / chemistry*
  • Triazenes / metabolism
  • Triazenes / pharmacology*

Substances

  • Amino Acids
  • Antineoplastic Agents
  • Prodrugs
  • Triazenes
  • Monophenol Monooxygenase