氘代氨基酸的不对称合成及其在AVPI抗肿瘤多肽中的应用

Modification of a drug by deuteration may prolong its biological half-life, significantly increase its metabolic stability, and thereby improve its therapeutic efficacy. On the other hand, deuterated drugs can also play an important role as isotopic tracer in pharmacokinetics and pharmacodynamics studies. This project intends to take advantage of the deuteration effect to modify peptide drugs to overcome the defects of the low oral bioavailability, poor metabolic stability and short half-life of peptide drugs, thus providing an effective alternative for ideal peptide drug development. Towards this end, we intend to make use of our research achievements in asymmetric catalysis to synthesize a series of deuterated amino acids and their analogues with different configurations and substitutions through the design of new asymmetric reactions. We then will insert the obtained deuterated amino acids and the analogues into AVPI peptides. With these compounds in hand, we will investigate the parameters of structure-activity relationship, pharmacological mechanism and pharmacokinetics and pharmacodynamics of the obtained deuterated AVPI peptides. Through the screening and feedback cycle, we would like to provide ideal lead compounds for novel peptide drug developments. Based on these achievements, we intend to carry out more detailed investigation on the selection of deuteration sites, mechanism of function and metabolic level of deuterated peptide drugs, and thus summarize some theoretical rules for deuterated drug research, providing theoretical support for further research.

将药物氘代修饰后可显著提高其代谢稳定性，增强疗效、安全性和耐受性；同时，氘代药物又可作为示踪剂研究药代动力学。本项目拟将氘代作用的这些优势应用于多肽药物的修饰与改造当中，以解决多肽药物代谢稳定性差、半衰期短等缺陷，从而为理想的多肽新药研发提供有效的解决途径。为此，我们拟利用课题组在不对称催化方面的研究成果，通过设计新型不对称反应，合成一系列不同构型和取代的氘代氨基酸及其类似物，将其应用到具有治疗前景AVPI四肽的化学修饰中，合成氘代的多肽模拟物，并研究其构效关系、药理学功能及代谢动力学等药学参数，通过筛选与反馈，以期为新型多肽药物研发提供理想的先导化合物。以此为契机，我们希望为多肽药物氘代位点的选择，氘代后药物的作用机制与代谢水平等进行较深入的研究，总结一些氘代药物研究的理论规律，为进一步的研究提供理论支撑。

多肽类药物因其生理活性强、疗效高、药用剂量小、产业化开发优势明显等诸多优点，在人类疾病治疗中的地位也日趋重要。然而，要想获得理想的多肽药物需要先解决多肽药物代谢稳定性差、半衰期短等固有缺陷。项目实施三年以来，项目组针对多肽药物稳定性差的关键问题，通过合理设计新型催化剂、催化体系和化学反应，高效地合成了几种非天然氨基酸，并将其应用到了一些生物活性多肽分子的化学修饰中，成功实现了多肽化学定向修饰。.项目执行以来，已在重要国际期刊发表高质量SCI论文16篇，其中Angew. Chem. Int. Ed. 3篇，ACS Catal. 2篇， Green Chem. 2篇，Chem. Commun. 2篇，Org. Lett. 3篇，Adv. Syn th. Catal. 1篇，Org. Biomol. Chem. 2篇，并应邀就项目组工作进行综述，发表Chem. Rev. 1篇。此外通过项目的实施协助培养了7名优秀的研究生。