np7b00057_si_001.pdf (6.07 MB)
6,7-Seco-ent-Kauranoids Derived from Oridonin as Potential Anticancer Agents
journal contribution
posted on 2017-09-13, 00:00 authored by Shengtao Xu, Hong Yao, Mei Hu, Dahong Li, Zheying Zhu, Weijia Xie, Hequan Yao, Liang Wu, Zhe-Sheng Chen, Jinyi XuStructurally unique 6,7-seco-ent-kaurenes, which are widely distributed in the genus Isodon, have attracted considerable attention because of
their antitumor activities. Previously, a convenient conversion of
commercially available oridonin (1) to 6,7-seco-ent-kaurenes was developed. Herein, several novel spiro-lactone-type ent-kaurene derivatives bearing various substituents at
the C-1 and C-14 positions were further designed and synthesized from
the natural product oridonin. Moreover, a number of seven-membered
C-ring-expanded 6,7-seco-ent-kaurenes were also identified
for the first time. It was observed that most of the spiro-lactone-type ent-kaurenes tested markedly inhibited the proliferation
of cancer cells, with an IC50 value as low as 0.55 μM.
An investigation on its mechanism of action showed that the representative
compound 7b affected the cell cycle and induced apoptosis
at a low micromolar level in MCF-7 human breast cancer cells. Furthermore,
compound 7b inhibited liver tumor growth in an in vivo
mouse model and exhibited no observable toxic effects. Collectively,
the results warrant further preclinical investigations of these spiro-lactone-type ent-kaurenes as potential novel anticancer agents.