Semi-Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationships of Brefeldin A Derivatives with Antileukemia Activity.
Semi-Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationships of Brefeldin A Derivatives with Antileukemia Activity.
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具有抗白血病活性的 Brefeldin A 衍生物的半合成、细胞毒性评价及构效关系
DOI：
10.3390/md20010026
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发表时间：
2021-12-24
期刊：
影响因子：
5.4
通讯作者：
Wei MY
中科院分区：
文献类型：
--
作者：
Lu XX;Jiang YY;Wu YW;Chen GY;Shao CL;Gu YC;Liu M;Wei MY
Brefeldin A(1)是由海洋真菌青霉产生的一种有效的细胞毒性天然大内酯。(HS-N-29)，从药用红树林刺五加中分离得到。设计并半合成了其系列酯类化合物2-16，并用波谱方法对其结构进行了表征。体外对人慢性粒细胞白血病K562细胞株进行了细胞毒活性测定，初步的构效关系表明羟基起了重要作用。此外，单酯类化合物具有比双酯类化合物更强的细胞毒活性。其中灯盏花素A7-O-2-氯-4，5-二氟苯甲酸酯(7)对K562细胞增殖的抑制作用最强，IC50值为0.84µM。进一步研究表明，7可诱导细胞周期停滞，刺激细胞凋亡，抑制bcr-abl的磷酸化，从而使其下游的AKT信号通路失活。AKT通路下游信号分子包括mTOR和p70S6K的表达在7-羟色胺处理后也呈剂量依赖性减弱。此外，将7个对接到ARF1-GDP-Global复合体的1个结合位点的分子模拟表示了良好的耐受性。综上所述，7有可能作为一种有效的抗白血病药物或先导化合物进行进一步的探索。
Brefeldin A (1), a potent cytotoxic natural macrolactone, was produced by the marine fungus Penicillium sp. (HS-N-29) from the medicinal mangrove Acanthus ilicifolius. Series of its ester derivatives 2–16 were designed and semi-synthesized, and their structures were characterized by spectroscopic methods. Their cytotoxic activities were evaluated against human chronic myelogenous leukemia K562 cell line in vitro, and the preliminary structure–activity relationships revealed that the hydroxy group played an important role. Moreover, the monoester derivatives exhibited stronger cytotoxic activity than the diester derivatives. Among them, brefeldin A 7-O-2-chloro-4,5-difluorobenzoate (7) exhibited the strongest inhibitory effect on the proliferation of K562 cells with an IC50 value of 0.84 µM. Further evaluations indicated that 7 induced cell cycle arrest, stimulated cell apoptosis, inhibited phosphorylation of BCR-ABL, and thereby inactivated its downstream AKT signaling pathway. The expression of downstream signaling molecules in the AKT pathway, including mTOR and p70S6K, was also attenuated after 7-treatment in a dose-dependent manner. Furthermore, molecular modeling of 7 docked into 1 binding site of an ARF1–GDP-GEF complex represented well-tolerance. Taken together, 7 had the potential to be served as an effective antileukemia agent or lead compound for further exploration.
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影响因子：
7.4
作者：
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通讯作者：
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影响因子：
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酰化 Brefeldin A 衍生物作为潜在抗癌药物的合成及细胞毒性评价
影响因子：
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作者：
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通讯作者：
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