Synthesis of novel feruloyl dipeptides with proapoptotic potential against different cancer cell lines
Graphical abstract
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 (2–5) 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 2–5
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.
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