2. Academic Validation
  3. Scutellarin derivatives as apoptosis inducers: Design, synthesis and biological evaluation

Scutellarin derivatives as apoptosis inducers: Design, synthesis and biological evaluation

  • Eur J Med Chem. 2017 Jul 28:135:270-281. doi: 10.1016/j.ejmech.2017.03.020.
Tong Han 1,  Jia Li 1,  Jingjing Xue 1,  He Li 1,  Fanxing Xu 2,  Keguang Cheng 3,  Dahong Li 4,  Zhanlin Li 1,  Ming Gao 5,  Huiming Hua 6
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
  • 2 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: fanxing0011@163.com.
  • 3 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Road, Guilin 541004, China.
  • 4 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: lidahong0203@163.com.
  • 5 School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien, Nishinomiya 663-8179, Japan.
  • 6 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China. Electronic address: huimhua@163.com.
PMID: 28458133 DOI: 10.1016/j.ejmech.2017.03.020
Abstract

To explore novel antitumor agents with high efficiency and low toxicity, a series of NO-donating scutellarin derivatives (14-17) were synthesized and the antiproliferative activities against MCF-7, HCT-116, PC-3 and HepG2 Cancer cell lines were assessed. Among them, compound 14b was the strongest with IC50 values of 2.96 μM, 7.25 μM, 0.09 μM and 0.50 μM, respectively, and displayed low toxicity against normal human liver L-O2 cells with an IC50 of 47.96 μM, showing good selectivity between normal and malignant liver cells. Moreover, NO releasing ability of the derivatives has been studied. Mechanism studies of the most promising compounds 14b and 15a were carried out. The results indicated that 14b and 15a could induce Apoptosis, cell cycle arrest at the S phase and led to mitochondrial dysfunction in the HepG2 and PC-3 cell lines, respectively. Furthermore, Human Apoptosis Protein Array kit assay demonstrated that 14b could induce Apoptosis through down-regulating the levels of procaspase-3 and inhibiting the expression of Survivin, c-IAP1, HSP27, HSP60, HSP70, HO-1/HMOX1/HSP32 and HO-2/HMOX2 in HepG2 cell line. These results guaranteed compound 14b to be a drug candidate against liver Cancer for further investigation.

Keywords

Antiproliferative activity; Apoptosis; NO; Scutellarin; Selectivity.

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