2. Academic Validation
  3. Syntheses and anti-pancreatic cancer activities of rakicidin A analogues

Syntheses and anti-pancreatic cancer activities of rakicidin A analogues

  • Eur J Med Chem. 2018 May 10:151:601-627. doi: 10.1016/j.ejmech.2018.03.078.
Jian Chen 1,  Jingpei Li 2,  Lingling Wu 1,  Yan Geng 2,  Jianming Yu 2,  Chuanke Chong 2,  Mengmeng Wang 3,  Yuan Gao 2,  Cuigai Bai 4,  Yahui Ding 5,  Yue Chen 6,  Quan Zhang 7
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China.
  • 2 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China; High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine, Tianjin, 300457, People's Republic of China.
  • 3 Accendatech Company, Ltd., Tianjin, 300384, People's Republic of China.
  • 4 High-throughput Molecular Drug Discovery Center, Tianjin International Joint Academy of BioMedicine, Tianjin, 300457, People's Republic of China.
  • 5 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: 017095@nankai.edu.cn.
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: yuechen@nankai.edu.cn.
  • 7 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin, 300350, People's Republic of China. Electronic address: zhangquan@nankai.edu.cn.
PMID: 29656202 DOI: 10.1016/j.ejmech.2018.03.078
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor and resistant to most therapies. Pancreatic Cancer Stem Cells (PCSCs) had critical role in regulating PDAC progression, metastasis, and drug resistance. Therefore, targeting PCSCs is considered to be a promising strategy for treatment of PDAC. However, there is no effective drug that can selectively ablate PCSCs. A series of twenty rakicidin A analogues were synthesized via a combinatorial strategy and evaluated for their anti-PDAC activities, and the structure-activity relationship was also discussed. Compound 32g was prepared in 14 linear steps with 5.05% overall yield, which is much more efficient than our previously reported total synthesis of rakicidin A (19 linear steps with 0.19% yield). In a highly metastatic pancreatic Cancer cell line ASPC-1, compound 32g showed about 4 times higher potency (IC50 = 0.022 μM) than rakicidin A (IC50 = 0.082 μM) at hypoxia condition, and 12 folds of hypoxia selectivity (IC50 = 0.27 μM at nomoxia condition). In contrast, the activity of adriamycin in the same hypoxic condition decreased. The percentage of PCSCs (with CD24+CD44+ESA+ biomarker), activity of ALDH, and the number of tumorspheres in PANC-1 cells were greatly reduced after treatment of 32g. More importantly, the tumor-initiating frequency was reduced by 19 folds after the treatment of 32g, which is better than that of rakicidin A (reduction of 4.7 folds).

Keywords

Combinatorial strategy; Pancreatic cancer stem cells; Pancreatic ductal adenocarcinoma; Rakicidin A analogues; Total synthesis.

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