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Molecules 2016, 21(9), 1193; doi:10.3390/molecules21091193

NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins

Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 12 July 2016 / Revised: 23 August 2016 / Accepted: 2 September 2016 / Published: 8 September 2016
(This article belongs to the Special Issue Drug Design and Discovery: Principles and Applications)
View Full-Text   |   Download PDF [5641 KB, uploaded 8 September 2016]   |  


A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10ai) were designed and synthesized from commercially available oridonin (1). These hybrids were evaluated for their antiproliferative activity against Bel-7402, K562, MGC-803, and CaEs-17 human cancer cell lines and L-02 normal liver cells. The antiproliferative activity against tumor cells was stronger than the lead compound 1 and parent molecule 9 in most cases. Especially, compound 10f showed the strongest activity against human hepatocarcinoma Bel-7402 cell line with an IC50 of 0.81 μM and could also release 33.7 μmol/L NO at the time point of 60 min. Compounds 10ai also showed cytotoxic selectivity between tumor and normal liver cells with IC50 ranging from 22.1 to 33.9 μM. Furthermore, the apoptotic properties on Bel-7402 cells revealed that 10f could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations. The effects of 10f on apoptosis-related proteins were also investigated. The potent antiproliferative activities and mechanistic studies warrant further preclinical investigations. View Full-Text
Keywords: oridonin; NO donor; antiproliferative activity; diterpenoid; apoptosis related proteins oridonin; NO donor; antiproliferative activity; diterpenoid; apoptosis related proteins

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Li, D.; Hu, X.; Han, T.; Liao, J.; Xiao, W.; Xu, S.; Li, Z.; Wang, Z.; Hua, H.; Xu, J. NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins. Molecules 2016, 21, 1193.

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