7-Ethyl-10-hydroxycamptothecin (SN38) and vorinostat (SAHA) are quite promising combination therapy agents applied to the clinical treatment of cancer. In this study, we designed and synthesized a series of novel SN38-SAHA co-prodrugs, which were conjugated by four different amino acids including glycine, alanine, aminobutyric acid, and 6-aminocaproic acid. The hydrolytic reconversion rate to SN38 and SAHA critically depended on the carbon chain length, which were evaluated in PBS (pH 6.0/7.4) and plasma (human/mouse). With decreasing amino acid chain length, the hydrolytic reconversion rate increased gradually. The in vitro cytotoxicity test was evaluated by the sulforhodamine B (SRB) assay on the human lung adenocarcinoma cell line A549 and human colorectal cancer cell line HCT116. With the evaluation of stability and in vitro cytotoxicity, an appropriate linker was found, and the active drug can be released efficiently from compound 3a, which exhibited strong antiproliferative activity in A549 and HCT-116 cell lines correspondingly. These results indicated that the well-designed co-prodrug 3a and this kind of strategy can be a promising approach for anticancer therapy.

中文翻译：

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7-乙基-10-羟基喜树碱和伏立诺他的共同前药具有体外水解和抗癌作用。

7-乙基-10-羟基喜树碱（SN38）和伏立诺他（SAHA）是非常有前途的联合治疗药物，可用于癌症的临床治疗。在这项研究中，我们设计和合成了一系列新颖的SN38-SAHA共前药，它们与四种不同的氨基酸（包括甘氨酸，丙氨酸，氨基丁酸和6-氨基己酸）缀合。SN38和SAHA的水解转化率关键取决于碳链长度，碳链长度在PBS（pH 6.0 / 7.4）和血浆（人/小鼠）中进行了评估。随着氨基酸链长度的减少，水解转化率逐渐增加。通过磺基罗丹明B（SRB）分析评估了人肺腺癌细胞系A549和人结肠直肠癌细胞系HCT116的体外细胞毒性测试。通过评估稳定性和体外细胞毒性，发现合适的接头，并且可以从化合物3a有效释放活性药物，化合物3a在A549和HCT-116细胞系中分别表现出强的抗增殖活性。这些结果表明，精心设计的前药3a和这种策略可能是抗癌治疗的有前途的方法。