Synthesis of dichloroacetamides and study of their anti-tumor activity

Keywords: dichloroacetamides, physical and chemical properties, antitumor activity

Abstract

Dichloroacetic acid and its derivatives exhibit the properties of metabolic cytoprotectors and apoptosis inducers. Nowadays evaluation of these derivatives is being conducted regarding the induction of immunogenic cell death. Therefore, the search for new derivatives of dichloroacetic acid as potential antitumor agents has a certain perspective and may be successful for the molecular design of «drug-like» structures.

The aim of the work was the development of synthetic approaches to the obtaining of dichloroacetic acid amides and the primary screening of the antitumor activity of the synthesized compounds.

Synthetic studies were conducted using reagents from the companies «Merck» (Darmstadt, Germany) and «Sigma-Aldrich» (Missouri, USA). 1H NMR spectra were measured on a Varian VXR-400 instrument, and LC-MS spectra on an Agilent 1100 Series LCMS instrument. The anticancer activity of the synthesized compounds was studied according to the international scientific program of the US National Cancer Institute – DTP (Developmental Therapeutic Program).

Amides were synthesized based on acylation reactions of the corresponding substituted ethylamines and aminobenzoic acids with methyldichloroacetate and dichloroacetyl chloride. The use of two methods of acylation of amines allows obtaining the target compounds with sufficient purity and satisfactory yields (44–98%). The structure and purity of the synthesized compounds were confirmed by the methods of elemental analysis, LCMS spectrometry and 1H NMR spectroscopy.

It was shown that dichloroacetyl chloride and methyl dichloroacetate are effective acylating agents, which was confirmed by the synthesis of a series of amides based on substituted ethylamines and aromatic amino acids. Moderate antitumor activity of dichloroacetamides was established on some melanoma, leukemia, and renal cancer cell lines. The highest activity was observed for 4-(2,2-dichloroacetylamino)-2-hydroxybenzoic acid, against which the mitotic activity of the LOX IMV melanoma line was 45.83%. Preliminary data on the antitumor activity indicate certain prospects for the search for anticancer agents in the group of dichloroarylacetamides in comparison with alkyl amides.

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Published
2022-08-29
How to Cite
Havryshchuk, L. M., Horishny, V. Y., & Lesyk, R. B. (2022). Synthesis of dichloroacetamides and study of their anti-tumor activity. Farmatsevtychnyi Zhurnal, (4), 42-49. https://doi.org/10.32352/0367-3057.4.22.05
Section
Synthesis and analysis of biologically active compounds