Elsevier

Bioorganic Chemistry

Volume 97, April 2020, 103678
Bioorganic Chemistry

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

https://doi.org/10.1016/j.bioorg.2020.103678Get rights and content

Highlights

  • Novel feruloyl dipeptides were synthesized and their anticancer activity was evaluated.

  • Dipeptides with aromatic amino acid residues (12, 13, 16, 17) were the most potent.

  • Compound 17 induced a strong mitochondrial transmembrane potential dissipation.

  • Compound 17 induced activation of caspase 3/7 in triple-negative MDA-MB-231 cell line.

  • Compound 17 inhibited growth of MDA-MB-231 breast cancer xenografts in vivo.

Abstract

In this study, a series of novel N-feruloyl dipeptides (1017) have been synthesized through the coupling of N-feruloyl amino acids (69) 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.

Introduction

Being the second leading cause of mortality, cancer represents the major public health concern in the United States and many other parts of the world [1]. Particularly, breast, lung, cervical, liver, prostate and pancreatic cancers are the most frequent causes of death worldwide with cancer death rates depending strongly on gross national product (GNP) per capita and health-care expenditures [2].

Breast cancer is the most frequently diagnosed cancer type and the leading cause of cancer-related mortality in females worldwide. The high mortality from breast cancer is consistently due to tumor metastases [2]. Triple-negative breast cancers (TNBC) are among the most aggressive and deadly breast cancer subtypes with a high risk of tumor relapse. TNBC affects more frequently younger premenopausal women and metastasizes to critical visceral organs [3], [4], [5]. Therefore, there is worldwide interest in the design of new approaches in the management and treatment of this life-threatening disease either through exploration of new natural products or synthetic chemistry.

Ferulic acid is a naturally abundant plant’s phenolic compound [6], [7], [8], [9], [10], [11], which, due to its low toxicity even in high doses [12], has recently been approved as an antioxidant in food additives [13], [14]. Additional therapeutic claims of FA encompassing anticarcinogenic [15], antidiabetic [16], hepatoprotective [17], [18], [19], antimicrobial, anti-inflammatory [20], [21], [22], anticholesterolemic [23], neuroprotective [24], UV protective [25] and radioprotective [26] effects motivated us to synthesize new N-feruloyl-dipeptide conjugates as an approach to explore new promising anticancer agents of low side effects and toxicity. Thereby, we have created novel ferulic acid derivatives with increased lipophilicity and membrane penetration, hence, maximizing their bioavailability and therapeutic value.

Section snippets

Chemistry

As illustrated in Scheme 1, the formation of amide linkage between ferulic acid and C-protected amino acids was achieved according to recently reported literature [27] to produce N-feruloyl amino acid methyl esters (25) of colorless solids appearance. Chemical structures of the latter were assigned on the basis of their physicochemical properties and spectroscopic data (NMR, ESI-MS) and comparison with corresponding Refs. [28], [29], [30].

Based on ESI-MS, the molecular weights of compounds 25

Chemistry

Melting points were determined on a BÜCHI Melting Point B-540 apparatus (BÜCHI Germany). NMR spectra (1H NMR, 13C NMR, COSY, HMQC, and HMBC) were measured on Bruker Avance DRX 500 MHz (125 MHz for 13C NMR) spectrometer (Bruker, USA) with tetramethylsilane as internal standard. Chemical shifts were reported relative to residual solvent peaks ([D6] dimethyl sulphoxide (DMSO): 1H: 2.50 ppm, 13C: 39.5 ppm). ESI mass spectra were recorded using an ion trap mass spectrometer equipped with a standard

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors are grateful to the NMR and MS Departments at Bielefeld University for the spectral measurements. We would like to thank Carmela Michalek for the in vitro analysis of KB-3-1 cell line, Marco Wißbrock and Anke Nieß for technical assistance. This research work has been financed by DAAD in the frame of the Research Project ID 57166072 and by the Academic Center for Complementary and Integrative Medicine (AZKIM), State Ministry of Baden-Württemberg for Sciences, Research and Arts.

References (40)

  • R.L. Siegel et al.

    Cancer statistics

    CA Cancer J. Clin.

    (2018)
  • L.A. Torre et al.

    Global cancer statistics

    CA Cancer J. Clin.

    (2012)
  • L. Carey et al.

    Triple-negative breast cancer: disease entity or title of convenience?

    Nat. Rev. Clin. Oncol.

    (2010)
  • E. Lee et al.

    Characteristics of triple-negative breast cancer in patients with a BRCA1 mutation: results from a population-based study of young women

    J. Clin. Oncol.

    (2011)
  • C.R. Santangelo

    Ferulic acid: pharmacological and toxicological aspects

    Food Chem. Toxicol.

    (2014)
  • S. Westfall et al.

    The gut microflora and its metabolites regulate the molecular crosstalk between diabetes and neurodegeneration

    J. Diabetes Metab.

    (2015)
  • K. Yama et al.

    Covalent cross-links in the cell wall

    Plant Physiol.

    (1994)
  • K. Rumbold et al.

    Purification and properties of a feruloyl esterase involved in lignocellulose degradation by Aureobasidium pullulans

    Appl. Environ. Microbiol.

    (2003)
  • A.E. Fazary et al.

    Feruloyl esterases as biotechnological tools: current and future perspectives

    Acta Biochim. Biophys. Sin.

    (2007)
  • S. Ou et al.

    Ferulic acid: pharmaceutical functions, preparation and applications in foods

    J. Sci. Food Agric.

    (2004)
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