title: Synthesis and pharmacological evaluation of dehydroabietic acid thiourea derivatives containing bisphosphonate moiety as an inducer of apoptosis.
abstract: A series of DHAA thiourea derivatives containing bisphosphonate moiety were designed and synthesized as potent antitumor agents. Structures of target molecules were confirmed using HR-MS, (1)H NMR and (13)C NMR and they exhibited potent anti-tumor activities against the SK-OV-3, BEL-7404, A549, HCT-116 and NCI-H460 tumor cell lines in vitro. Especially, compound 6e (IC50 = 1.79 ± 0.43 μM) exhibited the best anticancer activity against SK-OV-3 cell line. Its role as an inducer of apoptosis was investigated in this cell line by Annexin-V/PI binding assay and by following its capability for ROS generation, depolarization of mitochondrial transmembrane potential, activation of caspases and expression of pro- and anti-apoptotic proteins. Elevated level of ROS generation, activation of caspase-3, caspase-8, caspase-9, and Fas, higher expression of Bax, lower expression of Bcl-2, and increased level of Bax/Bcl-2 ratio identified 6e as a promising inducer of apoptosis that follows both of the mitochondria dependent pathway and the death receptor-mediated pathway. In addition, the cell cycle analysis indicated that compound 6e caused cell cycle arrest at G1 phase, induced apoptosis and led to cell death by increasing the proportion of sub-G1 cells. Furthermore, molecular docking studies showed that 6e could bind to the ATP pocket sites.
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
authors.forename: Rizheng
authors.initials: R
authors.lastname: Huang
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China.
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Liao
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China.
authors.forename: Yingming
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, China; Jiangsu Province Hi-Tech Key Laboratory for Bio-medical Research, Southeast University, Nanjing 211189, China. Electronic address: sgou@seu.edu.cn.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Gou
authors.affiliation: State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China. Electronic address: whengshan@163.com.
authors.forename: Hengshan
authors.initials: H
authors.lastname: Wang
mesh_terms: D045784:Abietanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D045784:Abietanes; D000970:Antineoplastic Agents; D004164:Diphosphonates; C013913:dehydroabietic acid; D013890:Thiourea
keywords: Anti-tumor; Apoptosis; Bisphosphonate; Dehydroabietic acid; Thioureas