Efficient Semisynthesis of (−)-Pseudoirroratin A from (−)-Flexicaulin A and Assessment of Their Antitumor Activities

• Published in: ACS medicinal chemistry letters Vol. 8; no. 3; pp. 372 - 376
• Main Authors: Guo, Lei, Tsang, Siu Wai, Zhang, Tong-Xin, Liu, Kang-Lun, Guan, Yi-Fu, Wang, Bo, Sun, Han-Dong, Zhang, Hong-Jie, Wong, Man Shing
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.03.2017; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; apoptosis; (−)-Pseudoirroratin A; (−)-flexicaulin A; antitumor activity; ENT-KAURANE DITERPENOIDS; LEUKEMIC-CELLS; (-)-Pseudoirroratin A; DEATH; (-)-flexicaulin A; DIFFERENTIATION
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.7b00033

Accumulating evidence indicates that natural ent-kaurane diterpenoids show great potential for medical treatment of different pathological conditions including cytotoxicity, antibacterial, and anti-inflammatory activity. Among a variety of diterpenoids tested, (−)-pseudoirroratin A displayed a promising antitumor property in vitro and in vivo. However, this diterpenoid could merely be isolated in a limited amount from a rare source of Isodon pseudoirrorata. To overcome such scanty source, we developed a novel, facile, and efficient semisynthetic strategy to prepare (−)-pseudoirroratin A from natural (−)-flexicaulin A, which can be expediently obtained from I. flexicaulis in a great quantity. The three-dimensional structure and the absolute configuration of our synthetic diterpenoid have been determined and confirmed with the X-ray crystallographic analysis. More importantly, we demonstrated for the first time that pseudoirroratin A exerted significant cytotoxicity against human colorectal carcinoma cells via an induction of apoptosis, as well as a remarkable suppression on tumor growth in a colon cancer xenograft mouse model.