Water-soluble derivatives of evodiamine: Discovery of evodiamine-10-phosphate as an orally active antitumor lead compound
- Eur J Med Chem. 2021 Aug 5:220:113544. doi: 10.1016/j.ejmech.2021.113544.
- 1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, People's Republic of China.
- 2. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, People's Republic of China. Electronic address: [email protected].
- 3. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, People's Republic of China. Electronic address: [email protected].
10-Hydroxyevodiamine is a multitargeting antitumor lead compound with excellent in vitro activity. However, its in vivo antitumor potency is rather limited, which has hampered its further clinical development. To overcome this obstacle, a series of novel water-soluble derivatives of 10-hydroxyevodiamine were designed and synthesized. Most of them exhibited good to excellent antitumor activities against several Cancer cell lines. In particular, phosphate derivative 9 was orally active and showed improved in vivo antitumor efficacy in HCT116 xenograft models. Further antitumor mechanism studies indicated that compound 9 acted by triple Top1/Top2/tubulin inhibition and induced Apoptosis with G2/M cell cycle arrest. Taken together, this study extended the structure-activity relationship of evodiamine and identified phosphate derivative 9 as a promising antitumor lead compound.