Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy

Eur J Med Chem. 2018 Jan 1:143:334-347. doi: 10.1016/j.ejmech.2017.11.074. Epub 2017 Dec 1.

Abstract

Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex-fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13+ cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer.

Keywords: Anticancer; CD13 inhibitor; Conjugate; Liver cancer; Pharmacokinetic.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Fluorouracil / chemistry
  • Fluorouracil / pharmacology*
  • Humans
  • Leucine / analogs & derivatives*
  • Leucine / chemistry
  • Leucine / pharmacology
  • Mice
  • Mice, Inbred Strains
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / pathology
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Leucine
  • ubenimex
  • Fluorouracil