NO-Releasing Enmein-Type Diterpenoid Derivatives with Selective Antiproliferative Activity and Effects on Apoptosis-Related Proteins.
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.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. lidahong0203@163.com.
Dahong
D
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. huxu105@163.com.
Xu
X
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. hantong1221@163.com.
Tong
T
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. howlris@gmail.com.
Jie
J
Liao
State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China. kanionxw2010@126.com.
Wei
W
Xiao
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. cpuxst@163.com.
Shengtao
S
Xu
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. lzl1030@hotmail.com.
Zhanlin
Z
Li
State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co. Ltd., Lianyungang 222001, China. kanionwzz2016@126.com.
Zhenzhong
Z
Wang
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. huimhua@163.com.
Huiming
H
Hua
State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. jinyixu@china.com.
Jinyi
J
Xu
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000737:chemistry / Q000494:pharmacology; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects*
D051017:Apoptosis Regulatory Proteins; D004224:Diterpenes; D009363:Neoplasm Proteins; D020030:Nitric Oxide Donors; C007594:enmein
NO donor; antiproliferative activity; apoptosis related proteins; diterpenoid; oridonin