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

Dahong Li; Xu Hu; Tong Han; Jie Liao; Wei Xiao; Shengtao Xu; Zhanlin Li; Zhenzhong Wang; Huiming Hua; Jinyi Xu

doi:10.3390/molecules21091193

Molecules (Sep 2016)

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

Dahong Li,
Xu Hu,
Tong Han,
Jie Liao,
Wei Xiao,
Shengtao Xu,
Zhanlin Li,
Zhenzhong Wang,
Huiming Hua,
Jinyi Xu

Affiliations

Dahong Li: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Xu Hu: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Tong Han: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Jie Liao: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Wei Xiao: State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China
Shengtao Xu: State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
Zhanlin Li: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Zhenzhong Wang: State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China
Huiming Hua: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
Jinyi Xu: State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China

DOI: https://doi.org/10.3390/molecules21091193
Journal volume & issue: Vol. 21, no. 9
p. 1193

Abstract

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A series of nine enmein-type ent-kaurane diterpenoid and furoxan-based nitric oxide (NO) donor hybrids (10a–i) 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 10a–i 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.

Published in Molecules

ISSN: 1420-3049 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.mdpi.com/journal/molecules

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