Development of 5-fluorouracil-dichloroacetate mutual prodrugs as anticancer agents

• Published in: Bioorganic chemistry 2023-11, Vol.140, p.106784-106784, Article 106784
• Main Authors: Mironiuk-Puchalska, Ewa, Karatsai, Olena, Żuchowska, Agnieszka, Wróblewski, Wojciech, Borys, Filip, Lehka, Lilya, Rędowicz, Maria Jolanta, Koszytkowska-Stawińska, Mariola
• Format: Article
• Language: English
• Subjects: 3D spheroids model; 5-fluorouracil (5-FU) codrugs; anticancer drugs; dichloroacetate (DCA); mutual prodrugs; Organ-on Chip
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106784

[Display omitted] •Designed and synthesis of a new mutual drug of 5-fluorouracil (5-FU)•Analysis of 5-FU release profiles from new derivatives.•Testing the toxicity of new 5-FU derivatives on selected cancer cell lines.•Toxicity analysis of 5-FU derivatives using a microfluidic device simulating human tissue.•Searching for apoptosis factors in in-silico studies. 5-Fluorouracil (5-FU) is one of the most widely applied chemotherapeutic agents with a broad spectrum of activity. However, despite this versatile activity, its use poses many limitations. Herein, novel derivatives of 5-FU and dichloroacetic acid have been designed and synthesized as a new type of codrugs, also known as mutual prodrugs, to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency. The stability of the obtained compounds has been tested at various pH values using different analytical techniques, namely HPLC and potentiometry. The antiproliferative activity of the new 5-FU derivatives was assessed in vitro on SK-MEL-28 and WM793 human melanoma cell lines in 2D culture as well as on A549 human lung carcinoma, MDA-MB-231 breast adenocarcinoma, LL24 normal lung tissue, and HMF normal breast tissue as a multicellular 3D spheroid model cultured in standard (static) conditions and with the use of microfluidic systems, which to a great extent resembles the in vivo environment. In all cases, new mutual prodrugs showed a higher cytotoxic activity toward cancer models and lower to normal cell models than the parent 5-FU itself.