Synthesis and pharmacological evaluation of dehydroabietic acid thiourea derivatives containing bisphosphonate moiety as an inducer of apoptosis

Eur J Med Chem. 2016 Jan 27:108:381-391. doi: 10.1016/j.ejmech.2015.12.008.

Xiaochao Huang ¹, Rizheng Huang ², Zhixin Liao ¹, Yingming Pan ², Shaohua Gou ³, Hengshan Wang ⁴

Affiliations

1 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.
2 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.
3 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.
4 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.

PMID: 26706349 DOI: 10.1016/j.ejmech.2015.12.008

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.

Keywords

Anti-tumor; Apoptosis; Bisphosphonate; Dehydroabietic acid; Thioureas.

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