Olsson Chase R, Payette Joshua N, Cheah Jaime H, Movassaghi Mohammad
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.
The Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, United States.
J Org Chem. 2020 Apr 3;85(7):4648-4662. doi: 10.1021/acs.joc.9b03371. Epub 2020 Mar 19.
We describe our design, synthesis, and chemical study of a set of functional epidithiodiketopiperazines (ETPs) and evaluation of their activity against five human cancer cell lines. Our structure-activity relationship-guided substitution of ETP alkaloids offers versatile derivatization while maintaining potent anticancer activity, offering exciting opportunity for their use as there are no examples of complex and potently anticancer (nM) ETPs being directly used as conjugatable probes or warheads. Our synthetic solutions to strategically designed ETPs with functional linkers required advances in stereoselective late-stage oxidation and thiolation chemistry in complex settings, including the application of novel reagents for dihydroxylation and -sulfidation of diketopiperazines. We demonstrate that complex ETPs equipped with a strategically substituted azide functional group are readily derivatized to the corresponding ETP-triazoles without compromising anticancer activity. Our chemical stability studies of ETPs along with cytotoxic evaluation of our designed ETPs against A549, DU 145, HeLa, HCT 116, and MCF7 human cancer cell lines provide insights into the impact of structural features on potency and chemical stability, informing future utility of ETPs in chemical and biological studies.
我们描述了一组功能性环缩二硫代二酮哌嗪（ETP）的设计、合成及化学研究，并评估了它们对五种人类癌细胞系的活性。我们基于构效关系对ETP生物碱进行的取代，在保持强大抗癌活性的同时提供了多样的衍生化，鉴于目前尚无复杂且具有强大抗癌活性（纳摩尔级）的ETP被直接用作可共轭探针或弹头的实例，这为它们的应用提供了令人兴奋的机会。我们针对具有功能性连接基的策略性设计ETP的合成方法，需要在复杂环境下的立体选择性后期氧化和硫醇化化学方面取得进展，包括应用用于二酮哌嗪二羟基化和硫化的新型试剂。我们证明，配备有策略性取代叠氮官能团的复杂ETP能够很容易地衍生化为相应的ETP - 三唑，且不影响抗癌活性。我们对ETP的化学稳定性研究以及对我们设计的ETP针对A549、DU 145、HeLa、HCT 116和MCF7人类癌细胞系的细胞毒性评估，为结构特征对效力和化学稳定性的影响提供了见解，为ETP在化学和生物学研究中的未来应用提供了参考。
