2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2016 Jun 15;26(12):2795-2800. doi: 10.1016/j.bmcl.2016.04.068.
Shengtao Xu 1,  Guangyu Wang 1,  Yan Lin 1,  Yanju Zhang 2,  Lingling Pei 1,  Hong Yao 1,  Mei Hu 1,  Yangyi Qiu 1,  Zhangjian Huang 3,  Yihua Zhang 4,  Jinyi Xu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
  • 2 School of Computer Science and Information Security, Guilin University of Electronic Technology, 1 Jinji Road, Guilin 541004, China.
  • 3 Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China.
  • 4 Center of Drug Discovery, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: zyhtgd@163.com.
  • 5 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China. Electronic address: jinyixu@china.com.
PMID: 27158140 DOI: 10.1016/j.bmcl.2016.04.068
Abstract

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.

Keywords

Anticancer activity; Apoptosis; NONOate; Nitric oxide; Oridonin.

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