Water Soluable Analogy And Multi-target Drug Design Of 10-Hydroxyevodiamine

Evodiamine is the main bioactive alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. In our previous investigations, systemic structural optimization and structure-activity relationship studies of evodiamine was performed. 10-hydroxylevodiamine was identified as a highly potent antitumor lead compounds with excellent antitumor activity both in vitro and in vivo. Further mechanism studies revealed that 10-hydroxylevodiamine acted by dual inhibition of topoisomerase I and Ⅱ (Top1 and Top2). Moreover, it can effectively induce the apoptosis of A549 cells with G2/M arrest. However,10-hydroxylevodiamine has poor water solubility and other unfavorable drug-like properties and also it’s in vivo antitumor potency remains to be further improved.In recent years, with the development of network pharmacology and the deeper understanding of tumor pathogenesis, discovery of multi-targeting antitumor agents represents an important strategy to overcome drug resistance and improve therapeutic effects. Histone deacetylases (HDACs) is a family of important antitumor targets, which can serve as a good starting point to design multi-targeting antitumor agents. According to the literatures, HDACs inhibitors have synergistic effects with Top or tubulin inhibitors.This thesis mainly includes two parts:(1) Design, synthesis and antitumor activity of 10-hydroxylevodiamine-based water soluable analogy; (2) Design, synthesis and antitumor activity of evodiamine-inspired Topl/Top2/HDAC triple inhibitors.1. Design, Synthesis and Antitumor Activity of 10-Hydroxylevodiamine-based Water Soluable AnalogyIn order to improve the water solubility and drug-like properties of 10-hydroxylevodiamine, a series of novelwater soluable analogywere rationally designed. A total of 28 new derivatives were synthesized. In vitro assay revealed that most of the target compounds showed excellent antitumor activity with a broad spectrum. Several compounds were more active than camptothecin and doxorubicin. In particular, compound L217, the D-proline derivative of 10-hydroxylevodiamine, showed the best antitumor activity in vivo studies.55% of inhibition rate against HCT-116 at dose of 16mg/kg.Design, Synthesis and Antitumor Activity of Evodiamine-inspired Topl/Top2/HDAC Triple InhibitorsHDACs inhibitors have synergistic effects with Top1 and/or Top2 inhibitors. On the basis of the structural features of both evodiamine derivatives and HDAC inhibitors, novel Top1/Top2/HDAC triple inhibitors were rationally designed. A total of 35 new derivatives were synthesized. As compared with evodiamine, most of the target compounds showed improved antitumor activity. In particular, compound L328, showed the best antitumor activity with IC50 value of 1.986μM against the breast cancer cell line, which was comparable to positive drug SAHA. Enzyme inhibitory assay revealed that most of the target compounds showed good activity against Top1, Top2 and HDAC1. Several of them were more active than the positive drugs. These results validated the possibility of designing Top1/Top2/HDAC triple inhibitors and lay a foundation for further studies.