5-氟尿嘧啶（5-FU）是一种应用广泛的化疗药物，具有广谱的活性。然而，尽管具有多样化的活性，其使用仍存在许多局限性。在此，设计并合成了新型5-FU和二氯乙酸的衍生物作为一种新型的共药物，也称为相互前药，以克服5-FU的缺点并增强其治疗效果。利用不同的分析技术，即HPLC和电位滴定法，对所得化合物在不同pH值下的稳定性进行了测试。在体外实验中，评估了新型5-FU衍生物对SK-MEL-28和WM793人类黑色素瘤细胞系在2D培养条件下以及对A549人类肺癌、MDA-MB-231乳腺癌、LL24正常肺组织和HMF正常乳腺组织这些多细胞3D球体模型在标准（静态）条件下和使用微流控系统培养的抗增殖活性，后者在很大程度上类似于体内环境。在所有情况下，新型共药物在癌症模型中显示出更高的细胞毒性活性，而对正常细胞模型的细胞毒性活性则较低，相比之下，原始的5-FU本身具有更低的细胞毒性活性。版权所有 © 2023 作者（们）。Elsevier Inc. 发表，版权所有。

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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.