2. Academic Validation
  3. Design and synthesis of parthenolide and 5-fluorouracil conjugates as potential anticancer agents against drug resistant hepatocellular carcinoma

Design and synthesis of parthenolide and 5-fluorouracil conjugates as potential anticancer agents against drug resistant hepatocellular carcinoma

  • Eur J Med Chem. 2019 Dec 1:183:111706. doi: 10.1016/j.ejmech.2019.111706.
Yahui Ding 1,  Shengzu Li 1,  Weizhi Ge 1,  Zhongquan Liu 1,  Xuhai Zhang 1,  Mengmeng Wang 2,  Tianyang Chen 1,  Yue Chen 3,  Quan Zhang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China.
  • 2 Accendatech Company, Ltd., Tianjin, 300384, People's Republic of China.
  • 3 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China. Electronic address: yuechen@nankai.edu.cn.
  • 4 State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Haihe Education Park, 38 Tongyan Road, Tianjin, 300353, People's Republic of China. Electronic address: zhangquan@nankai.edu.cn.
PMID: 31553932 DOI: 10.1016/j.ejmech.2019.111706
Abstract

A series of twenty-three parthenolide-5-fluorouracil (5-FU) conjugates ware synthesized and evaluated for their anti-cancer activities against human hepatocellular carcinoma cell line Bel-7402 and 5-fluorouracil resistant human hepatocellular carcinoma cell line Bel-7402/5-FU. The preliminary structure-activity relationships were discussed. The most active compound 15d showed high activity against Bel-7402/5-FU cell line with IC50 value of 2.25 μM, which demonstrated 5.8-fold improvement compared to that of the parent compound parthenolide (IC50 = 12.98 μM). The investigation of preliminary molecular mechanism of 15d revealed that 15d could reverse drug resistance by inhibiting MDR1, ABCC1 and ABCG2 to increase the intracellular drug accumulation and induce Apoptosis of Bel-7402/5-FU cells through mitochondria mediated pathway. On the base of these results, compound 15d is deserved to be further investigated as a potential anti-HCC lead compound for ultimate discovery of pathenolide-based anti-cancer drug.

Keywords

5-Fluorouracil; Conjugation; Hepatocellular carcinoma drug resistance; Parthenolide; Structure-activity relationship.

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