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

Autor: Mironiuk-Puchalska E; Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland. Electronic address: ewa.puchalska@pw.edu.pl., Karatsai O; Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland., Żuchowska A; Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland., Wróblewski W; Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland., Borys F; Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland., Lehka L; Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland., Rędowicz MJ; Laboratory of Molecular Basis of Cell Motility, Nencki Institute of Experimental Biology Polish Academy of Science, 3 Pasteur St., 02-093-Warsaw, Poland., Koszytkowska-Stawińska M; Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Nov; Vol. 140, pp. 106784. Date of Electronic Publication: 2023 Aug 23.
DOI: 10.1016/j.bioorg.2023.106784
Abstrakt: 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.
Competing Interests: 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.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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