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

Accumulating evidence indicates that natural <i>ent</i>-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 <i>in vitro</i> and <i>in vivo</i>. However, this diterpenoid could merely be isolated in a limited amount from a rare source of <i>Isodon pseudoirrorata</i>. 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>I. flexicaulis</i> 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.