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.
- 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: [email protected].
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.