Abstract

In this work, the first mutual prodrug of 5-fluorouracil and heme oxygenase1 inhibitor (5-FU/HO-1 hybrid) has been designed, synthesised, and evaluated for its in vitro chemical and enzymatic hydrolysis stability. Predicted in silico physicochemical properties of the newly synthesised hybrid (3) demonstrated a drug-like profile with suitable Absorption, Distribution, Metabolism, and Excretion (ADME) properties and low toxic liabilities. Preliminary cytotoxicity evaluation towards human prostate (DU145) and lung (A549) cancer cell lines demonstrated that 3 exerted a similar effect on cell viability to that produced by the reference drug 5-FU. Among the two tested cancer cell lines, the A549 cells were more susceptible for 3. Of note, hybrid 3 also had a significantly lower cytotoxic effect on healthy human lung epithelial cells (BEAS-2B) than 5-FU. Altogether our results served as an initial proof-of-concept to develop 5-FU/HO-1 mutual prodrugs as potential novel anticancer agents.

摘要

在这项工作中，设计、合成了第一个 5-氟尿嘧啶和血红素加氧酶 1 抑制剂（5-FU/HO-1 杂交体）的互药前药，并评估了其体外化学和酶水解稳定性。新合成的杂化物 ( 3 ) 的计算机理化特性预测表明具有合适的吸收、分布、代谢和排泄 (ADME) 特性和低毒性责任的类似药物的特性。对人前列腺 (DU145) 和肺癌 (A549) 癌细胞系的初步细胞毒性评估表明，3对细胞活力的影响与参考药物 5-FU 产生的影响相似。在两个测试的癌细胞系中，A549 细胞对3 . 值得注意的是，与 5-FU 相比，杂交3对健康人肺上皮细胞 (BEAS-2B) 的细胞毒性作用也显着降低。总而言之，我们的结果是开发 5-FU/HO-1 互用前药作为潜在新型抗癌剂的初步概念验证。