title: Novel nitric oxide-releasing spirolactone-type diterpenoid derivatives with in vitro synergistic anticancer activity as apoptosis inducer.
abstract: Herein, we reported the cytotoxicity, NO-releasing property, and apoptosis induced ability of two series of novel nitric oxide-releasing spirolactone-type diterpenoid derivatives (10a-f and 15a-f). All the title compounds were more potent than oridonin (7) and parent compound (9 or 14) against human tumor Bel-7402, K562, MGC-803 and CaEs-17 cells. SARs were concluded based on above data. Compound 15d exhibited the strongest antiproliferative activity with the IC50 of 0.86, 1.74, 1.16 and 3.75μM, respectively, and could produce high level (above 25μM) of NO at the time point of 60min. Further mechanism evaluation showed that 15d could induce S phase cell cycle arrest and apoptosis at low micromolar concentrations in Bel-7402 cells via mitochondria-related pathways. It was expected that the remarkable biological profile of the synthetic NO-releasing spirolactone-type diterpenoid analogs make them possible as promising candidates for the development of anticancer agents.
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Dahong
authors: D
authors: Li
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Tong
authors: T
authors: Han
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Kangtao
authors: K
authors: Tian
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Shuang
authors: S
authors: Tang
authors: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors: Shengtao
authors: S
authors: Xu
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Xu
authors: X
authors: Hu
authors: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China.
authors: Lei
authors: L
authors: Wang
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
authors: Zhanlin
authors: Z
authors: Li
authors: Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, and School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: huimhua@163.com.
authors: Huiming
authors: H
authors: Hua
authors: Department of Medicinal Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China. Electronic address: jinyixu@china.com.
authors: Jinyi
authors: J
authors: Xu
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D004357:Drug Synergism; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D059807:S Phase Cell Cycle Checkpoints / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013148:Spironolactone / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D013141:Spiro Compounds; D013148:Spironolactone; D009569:Nitric Oxide
keywords: Antiproliferative; Diterpenoid; NO-releasing; Oridonin; Spirolactone-type