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小白菊内酯二硫代氨基甲酸酯类化合物的合成及初步生物评价 作为潜在的抗急性髓系白血病药物。

Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents.

机构信息

a State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research , Nankai University , Tianjin , People's Republic of China.

b School of Pharmaceutical Sciences , Guangzhou Medical University , Guangzhou , People's Republic of China.

出版信息

J Enzyme Inhib Med Chem. 2018 Dec;33(1):1376-1391. doi: 10.1080/14756366.2018.1490734.

DOI:10.1080/14756366.2018.1490734
PMID:30208745
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6136352/
Abstract

A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound 7l showed greatly improved potency against AML progenitor cell line KG1a with IC value of 0.7 μM, and the efficacy was 8.7-folds comparing to that of PTL (IC = 6.1 μM). Compound 7l induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells. Furthermore, 7l suppressed the colony formation of primary human leukaemia cells. Moreover, compound 12, the salt form of 7l, prolonged the lifespan of mice in two patient-derived xenograft models and had no observable toxicity. The preliminary molecular mechanism study revealed that 7l-mediated apoptosis is associated with mitogen-activated protein kinase signal pathway. On the basis of these investigations, we propose that 12 might be a promising drug candidate for ultimate discovery of anti-LSCs drug.

摘要

设计、合成了一系列小白菊内酯（PTL）的二硫代氨基甲酸酯，并评估了它们对急性髓系白血病（AML）的抗活性。最有前途的化合物 7l 对 AML 祖细胞系 KG1a 的活性大大提高，IC 值为 0.7 μM，与 PTL（IC = 6.1 μM）相比，效力提高了 8.7 倍。化合物 7l 诱导总原代人 AML 细胞和原代 AML 细胞中的白血病干细胞（LSCs）凋亡，而对正常细胞无影响。此外，7l 抑制了原代人白血病细胞的集落形成。此外，化合物 12（7l 的盐形式）在两种患者来源的异种移植模型中延长了小鼠的寿命，且无明显毒性。初步的分子机制研究表明，7l 介导的凋亡与丝裂原活化蛋白激酶信号通路有关。基于这些研究，我们提出 12 可能是一种很有前途的候选药物，用于最终发现抗 LSCs 药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/a20a01da15dd/IENZ_A_1490734_F0012_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/196f0a9a37c4/IENZ_A_1490734_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/d5e8e8cd494a/IENZ_A_1490734_F0009_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/e34b0aac6336/IENZ_A_1490734_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/570e9eddb8a4/IENZ_A_1490734_F0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/706c8a7f41da/IENZ_A_1490734_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/ba71239f4906/IENZ_A_1490734_SCH0001_B.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/e84d37edf0e2/IENZ_A_1490734_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/6da776855809/IENZ_A_1490734_F0005_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/196f0a9a37c4/IENZ_A_1490734_F0008_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6fa9/6136352/da08cf0c6e18/IENZ_A_1490734_F0010_C.jpg
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