Synthesis of novel feruloyl dipeptides with proapoptotic potential against different cancer cell lines

Bioorg Chem. 2020 Apr;97:103678. doi: 10.1016/j.bioorg.2020.103678. Epub 2020 Feb 21.

Abstract

In this study, a series of novel N-feruloyl dipeptides (10-17) have been synthesized through the coupling of N-feruloyl amino acids (6-9) with glycine/alanine methyl ester hydrochloride. Structures of the peptides were assigned using 1D and 2D NMR and HRESIMS. According to initial in vitro cytotoxic screening against the cervix carcinoma cell line KB-3-1, aromatic dipeptides (12, 13, 16, 17) were the most potent ones among all tested feruloyl dipeptides. Accordingly, these peptides were further intensively investigated as potential anticancer agents against a panel of ten cancer cell lines from different tissue origin. Based on that, compound 17 showed the strongest cytotoxic efficiency towards the whole panel of tested cell lines with IC50 values from 2.1 to 7.9 μM. By contrast, the dipeptides 12, 13 and 16 showed moderate to weak cytotoxicity (IC50 16.1-28.3 or >30, 5.7-21.9 and 3.9-21.2 or ≥30 μM, respectively). Mechanistically, compound 17 induced a strong dissipation of the mitochondrial transmembrane potential and an early activation of caspase 3/7 in the triple-negative MDA-MB-231 breast cancer cell line. In an in vivo model, compound 17 inhibited growth, proliferation and induced apoptosis in MDA-MB-231 xenografted onto the chick chorioallantoic membrane. All the synthesized compounds were also tested against a set of pathogenic bacterial strains, displaying no potential activity.

Keywords: CAM xenografts; Caspase-3/7; Feruloyl-dipeptides; In vitro cytotoxicity; Mitochondrial potential; Triple negative breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chick Embryo
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry*
  • Dipeptides / pharmacology*
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Female
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism

Substances

  • Antineoplastic Agents
  • Dipeptides