Synthesis and anti-acute myeloid leukemia activity of C-14 modified parthenolide derivatives

Eur J Med Chem. 2017 Feb 15:127:296-304. doi: 10.1016/j.ejmech.2016.12.044.

Zhongjin Yang ¹, Beijia Kuang ¹, Ning Kang ¹, Yahui Ding ¹, Weizhi Ge ¹, Lihui Lian ¹, Yuan Gao ¹, Yuqing Wei ¹, Yue Chen ², Quan Zhang ³

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 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.
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: zhangquan612@163.com.

PMID: 28068601 DOI: 10.1016/j.ejmech.2016.12.044

Abstract

Parthenolide (PTL) selectively ablates leukemia stem cells (LSCs). A series of PTL derivatives with modifications on C-14 of PTL was synthesized, and most of the derivatives showed high activities against HL-60 and KG1a. The most potent compound 6j exhibited IC₅₀ values of 0.4 μM and 1.1 μM against KG1a and HL-60, respectively, which were 8.7 and 3.8 folds more potent than those of PTL, respectively. Moreover, compound 6j showed relatively low toxicity to normal cells (IC₅₀ = 12.3 μM) comparing with its high anti-AML activity. The selectivity indexes for AML cells KG1a and HL-60 were 30.8 and 11.2, respectively. Preliminary study revealed that compound 6j could induce Apoptosis of KG1a cells.

Keywords

Acute myeloid leukemia; Apoptosis; KG1a; Parthenolide; Synthesis.

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