College of Pharmaceutical Science, Anhui Xinhua University, Hefei 230088, China.
Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China, Hefei 230031, China.
Molecules. 2023 May 7;28(9):3936. doi: 10.3390/molecules28093936.
Despite the strong anticancer activity of SN38 (7-ethyl-10-hydroxy-camptothecin), the severe side effects and loss of anticancer activity caused by the lack of selectivity to cancer cells and hydrolysis of ring E prevent its clinical application. To address the issue, herein a multifunctional SN38 derivative (compound ) containing biotin (tumor-targeting group) and valproic acid (histone deacetylase inhibitor, HDACi) was synthesized via click chemistry and evaluated using MTT assay. The in vitro cytotoxicity study showed that compound exhibited superior cytotoxicity than irinotecan against human cervical cancer HeLa cells, albeit it was inferior to SN38. More significantly, compound significantly reduced toxicity in mouse embryonic fibroblast NIH3T3 cells, indicating that compound had the capacity to enhance tumor targeting due to its cell selectivity. Further studies demonstrated that, compared with irinotecan, compound induced similar apoptosis of cancer cells. Consequently, compound can not only improve its tumor-targeting ability mediated by biotin but also exert potent anticancer activity through the effect of SN38 and valproic acid, indicating that the design concept is an effective strategy for the structural modification of SN38.
尽管 SN38（7-乙基-10-羟基喜树碱）具有很强的抗癌活性，但由于缺乏对癌细胞的选择性和环 E 的水解，导致其严重的副作用和抗癌活性丧失，从而阻止了其在临床上的应用。为了解决这个问题，本文通过点击化学合成了一种含有生物素（肿瘤靶向基团）和丙戊酸（组蛋白去乙酰化酶抑制剂，HDACi）的多功能 SN38 衍生物（化合物），并通过 MTT 测定法进行了评价。体外细胞毒性研究表明，化合物对人宫颈癌 HeLa 细胞的细胞毒性优于伊立替康，尽管其活性低于 SN38。更重要的是，化合物在小鼠胚胎成纤维细胞 NIH3T3 细胞中显著降低了毒性，表明化合物由于其细胞选择性而具有增强肿瘤靶向的能力。进一步的研究表明，与伊立替康相比，化合物诱导了相似的癌细胞凋亡。因此，化合物不仅可以通过生物素介导提高其肿瘤靶向能力，还可以通过 SN38 和丙戊酸的作用发挥强大的抗癌活性，这表明该设计理念是 SN38 结构修饰的有效策略。
