2. Academic Validation
  3. Synthesis of scutellarein derivatives with antiproliferative activity and selectivity through the intrinsic pathway

Synthesis of scutellarein derivatives with antiproliferative activity and selectivity through the intrinsic pathway

  • Eur J Med Chem. 2018 Oct 5:158:493-501. doi: 10.1016/j.ejmech.2018.09.047.
Tong Han 1,  Yan Wang 2,  Mingying Wang 1,  Xu Li 3,  Keguang Cheng 4,  Xiang Gao 1,  Zhanlin Li 1,  Jiao Bai 1,  Huiming Hua 1,  Dahong Li 5
Affiliations

Affiliations

  • 1 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, PR China.
  • 2 Yantai Valiant Pharmaceutical Co., Ltd., 60 Taiyuan Road, Dajijia Industrial Park, YEDA Yantai, 264006, PR China.
  • 3 Jiangsu Kanion Pharmaceutical Co., Ltd., 58 Kangyuan Road, Lianyungang, 222001, PR China.
  • 4 State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, and School of Chemistry and Pharmacy, Guangxi Normal University, 15 Yucai Raod, Guilin, 541004, PR China.
  • 5 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, PR China. Electronic address: lidahong0203@163.com.
PMID: 30243153 DOI: 10.1016/j.ejmech.2018.09.047
Abstract

To explore antitumor agents with potent efficacy and low toxicity, scutellarein derivatives with benzoic acid mustard (10a-c, 11a-c and 13a-c) were designed and synthesized. The antiproliferative activities of the target derivatives against A549, MCF-7 and Bel-7402 Cancer cell lines were tested. Compound 10a showed the strongest potency with an IC50 value of 1.50 μM against MCF-7 cell line, and displayed low toxicity against human liver L-O2 normal cells (IC50 > 50 μM), showing specificity between normal and malignant cells. The mechanism studies revealed that 10a could induce Apoptosis in MCF-7 cells, arrest MCF-7 cell cycle at the G1 phase and cause mitochondrial dysfunction in a concentration-dependant manner. Furthermore, the enhanced expression of the pro-apoptotic proteins caspase-9, Caspase-3, Bax and cytochrome c, and the reduced expression of the anti-apoptotic protein Bcl-2 confirmed that 10a induced the intrinsic Apoptosis pathway in MCF-7 cells. The potent antiproliferative activity and good selectivity guaranteed 10a a lead compound for the further development into Anticancer therapeutics, especially for breast Cancer.

Keywords

Antiproliferative activity; Benzoic acid mustard; Scutellarein; Selectivity.

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