Novel anticancer oridonin derivatives possessing a diazen-1-ium-1,2-diolate nitric oxide donor moiety: Design, synthesis, biological evaluation and nitric oxide release studies

• Published in: Bioorganic & medicinal chemistry letters 2016-06, Vol.26 (12), p.2795-2800
• Main Authors: Xu, Shengtao, Wang, Guangyu, Lin, Yan, Zhang, Yanju, Pei, Lingling, Yao, Hong, Hu, Mei, Qiu, Yangyi, Huang, Zhangjian, Zhang, Yihua, Xu, Jinyi
• Format: Article
• Language: English
• Subjects: Anticancer activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Diterpenes, Kaurane - chemical synthesis; Diterpenes, Kaurane - chemistry; Diterpenes, Kaurane - pharmacology; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Hydrazines - chemistry; Hydrazines - pharmacology; Molecular Structure; Nitric oxide; Nitric Oxide - biosynthesis; Nitric Oxide Donors - chemical synthesis; Nitric Oxide Donors - chemistry; Nitric Oxide Donors - pharmacology; NONOate; Oridonin; Structure-Activity Relationship
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.04.068

[Display omitted] Oridonin (1) is a complex ent-kaurane diterpenoid with unique antitumor profile, which is isolated from Isodon rubescens. In order to develop novel derivatives of oridonin with improved potency, a series of nitric oxide (NO)-releasing oridonin derivatives were synthesized by coupling diazeniumdiolates with oridonin and its semisynthesized analogues. Their in vitro antiproliferative activity, nitric oxide release ability, and preliminary anticancer mechanism were further evaluated. The results displayed that all the target compounds exhibited potent antiproliferative activities, with IC50 values ranging from 1.84 to 17.01μM. Besides, it was observed that in most cases, the antiproliferative activity correlated well with levels of intracellular NO release. More interestingly, preliminary mechanism studies revealed that the most potent compound 14d induced apoptosis and arrested the cell cycle at the S phase in Bel-7402 cells, which is different from parent compound oridonin. Together, the above promising results warrant the further development of oridonin/NO hybrids as potential antitumor leads.