Methotrexate γ-hydroxamate derivatives as potential dual target antitumor drugs

M. Amélia Santos, Eva A. Enyedy, Elisa Nuti, Armando Rossello, Natalia I. Krupenko, Sergey A. Krupenko

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A series of new aminopteroyl-based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs. These compounds were designed to target two families of enzymes, matrix metalloproteinases (MMP) and a folate enzyme, dihydrofolate reductase (DHFR). These enzymes are the components of two unrelated cellular pathways and they are often over-expressed in metastasizing tumors. In addition to the synthesis and full structural characterization of the hybrid molecules, we describe their inhibitory activities against a series of MMPs (MMP-2, MMP-7, MMP-9, MMP-14) and DHFR, as well as their antiproliferative activity in three cancer cell lines. The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and DHFR in the micromolar and nanomolar range, respectively. Furthermore, they showed strong antiproliferative activity against A549 cells (non-small cell lung carcinoma), and PPC-1 and Tsu-Pr1 prostate cancer cell lines. Therefore, based on the present results, these bi-functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development.

Original languageEnglish
Pages (from-to)1266-1274
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number3
DOIs
Publication statusPublished - Feb 1 2007

Keywords

  • Antifolates
  • DHFR inhibitors
  • Dual drugs
  • MMP inhibitors
  • Methotrexate-hydroxamate derivatives

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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