Wang Mengmeng, Qu Kunyu, Zhao Peipei, Yin Xin, Meng Yiwei, Herdewijn Piet, Liu Chao, Zhang Lixin, Xia Xuekui
Biology Institute, Qilu University of Technology (Shandong Academy of Sciences) Jinan 250103 China
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven 3000 Leuven Belgium.
RSC Med Chem. 2023 Jul 6;14(8):1572-1580. doi: 10.1039/d3md00190c. eCollection 2023 Aug 16.
Gemcitabine is an antimetabolite drug approved for the treatment of various cancers. However, its use is limited due to several issues such as stability, toxicity and drug resistance. Herein, we present the design and synthesis of a series of gemcitabine prodrugs with modifications on the 4--amino group by employing an acetylated l- or d-lysine moiety masked by different substitutions. Prodrugs 1-3 and 6-8 showed up to 2.4 times greater anticancer activity than gemcitabine in A549 lung cells, while they exhibited potent activity against BxPC-3 pancreatic cells with IC values in the range of 7-40 nM. Moreover, prodrugs 2-3 and 7-8 were found to be less potent against CTSL low expression Caco-2 cells and at least 69-fold less toxic towards human normal HEK-293T cells compared to gemcitabine, leading to improved selectivity and safety profiles. Further stability studies showed that representative prodrugs 2 and 7 exhibited enhanced metabolic stability in human plasma, human liver microsomes and cytidine deaminase. Prodrug 1 can be cleaved by tumor cell-enriched CTSL to release parent drug gemcitabine. Overall, these results demonstrated that acetylated lysine conjugated gemcitabine prodrugs could serve as promising leads for further evaluation as new anticancer drugs.
吉西他滨是一种被批准用于治疗多种癌症的抗代谢药物。然而，由于稳定性、毒性和耐药性等几个问题，其应用受到限制。在此，我们展示了一系列吉西他滨前药的设计与合成，这些前药通过使用被不同取代基掩盖的乙酰化L-或D-赖氨酸部分对4-氨基进行了修饰。前药1-3和6-8在A549肺癌细胞中的抗癌活性比吉西他滨高2.4倍，同时它们对BxPC-3胰腺细胞表现出强效活性，IC值在7-40 nM范围内。此外，与吉西他滨相比，发现前药2-3和7-8对CTSL低表达的Caco-2细胞活性较低，对人正常HEK-293T细胞的毒性至少低69倍，从而提高了选择性和安全性。进一步的稳定性研究表明，代表性前药2和7在人血浆、人肝微粒体和胞苷脱氨酶中表现出增强的代谢稳定性。前药1可被富含肿瘤细胞的CTSL裂解以释放母体药物吉西他滨。总体而言，这些结果表明，乙酰化赖氨酸缀合的吉西他滨前药有望作为新的抗癌药物进行进一步评估的先导化合物。
