title: Synthesis, Biological Activity, and Apoptotic Properties of NO-Donor/Enmein-Type ent-Kauranoid Hybrids.
abstract: Herein, we reported on a series of synthetic nitric oxide-releasing enmein-type diterpenoid hybrids (9a-i). All the target compounds showed potent antibacterial activity against selected Gram-positive bacteria S. aureus and B. subtilis. The antiproliferative activity against human tumor K562, MGC-803, CaEs-17 and Bel-7402 cells, and human normal liver cells L-02 was tested and the structure activity relationships (SARs) were also concluded. Compounds 9b and 9d showed the best activity against S. aureus and B. subtilis with the same minimal inhibitory concentrations (MICs) of 4 and 2 μg/mL, respectively. The derivative 9f displayed IC50 values of 1.68, 1.11, 3.60 and 0.72 μM against the four cancer cell lines above and 18.80 μM against normal liver cells L-02; meanwhile, 9f also released a high level of NO at the time point of 60 min of 22.24 μmol/L. Furthermore, it was also found that 9f induced apoptosis via the mitochondria-related pathway and arrested cell cycle of Bel-7402 cells at S phase. These findings might be important to explore new chemical entities for the main causes of in-hospital mortality of S. aureus infection, combined with a solid tumor.
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. lidahong0203@163.com.|State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, and National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China. lidahong0203@163.com.|State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China. lidahong0203@163.com.
authors.forename: Dahong
authors.initials: D
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. huxu105@163.com.
authors.forename: Xu
authors.initials: X
authors.lastname: Hu
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. hantong1221@163.com.
authors.forename: Tong
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. cpuxst@163.com.
authors.forename: Shengtao
authors.initials: S
authors.lastname: Xu
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. tingtingzhou1118@hotmail.com.
authors.forename: Tingting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, and National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China. kanionwzz2016@126.com.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, China. kgcheng2008@gmail.com.
authors.forename: Keguang
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. lzl1030@hotmail.com.
authors.forename: Zhanlin
authors.initials: Z
authors.lastname: Li
authors.affiliation: Key Laboratory of Structure-Based Drug Design &amp; Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China. huimhua@163.com.
authors.forename: Huiming
authors.initials: H
authors.lastname: Hua
authors.affiliation: State Key Laboratory of New-Tech for Chinese Medicine Pharmaceutical Processes, and National Post-Doctoral Research Workstation, Jiangsu Kanion Pharmaceutical Co., Ltd., Lianyungang 222001, China. kanionxw2010@126.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. jinyixu@china.com.
authors.forename: Jinyi
authors.initials: J
authors.lastname: Xu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009569:Nitric Oxide / Q000737:chemistry*; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004224:Diterpenes; D009569:Nitric Oxide
keywords: NO-donor; antiproliferative; apoptosis; enmein-type; ent-kauranoid