Enmein-type diterpenoid analogs from natural kaurene-type oridonin: Synthesis and their antitumor biological evaluation

• Published in: European journal of medicinal chemistry 2013-06, Vol.64, p.215-221
• Main Authors: Li, Dahong, Xu, Shengtao, Cai, Hao, Pei, Lingling, Zhang, Hengyuan, Wang, Lei, Yao, Hequan, Wu, Xiaoming, Jiang, Jieyun, Sun, Yijun, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Cycle - drug effects; Cell cycle analysis; Cell Line, Tumor; Diterpenes - chemical synthesis; Diterpenes - chemistry; Diterpenes - pharmacology; Diterpenes, Kaurane - chemistry; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enmein-type diterpenoid; Humans; Molecular Conformation; Oridonin; Structure-Activity Relationship
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.04.012

A series of enmein-type diterpenoid analogs (11–20) derived from natural kaurene-type diterpenoid oridonin were synthesized and biologically evaluated. All target compounds showed improved anti-proliferative activities against four human cancer cell lines compared with natural oridonin and parent compound 10. Some compounds were more potent than positive control Taxol. Furthermore, mechanistic investigation showed that the representative compound 17 affected cell cycle and induced apoptosis at low micro-molar level in human hepatoma Bel-7402 cells, via an oxidative stress triggered mitochondria-related caspase-dependent pathway. The synthetic enmein-type diterpenoid analog 17 exhibited potent anti-proliferative activities and induced apoptosis via mitochondria-related caspase-dependent pathways. [Display omitted] •Promising enmein-type diterpenoid analogs were obtained from natural oridonin.•All the derivatives showed improved anti-proliferative activities.•The most promising compound 17 was selected for further mechanistic evaluation.•The influence of cell cycle progression by compound 17 was observed.•Inducing of apoptosis involves mitochondria-related caspase-dependent pathways.