新型甾体 4-氨基喹啉类化合物在后毒素染毒模型中拮抗小鼠胚胎干细胞源性运动神经元中 A 型肉毒神经毒素。
New Steroidal 4-Aminoquinolines Antagonize Botulinum Neurotoxin Serotype A in Mouse Embryonic Stem Cell Derived Motor Neurons in Postintoxication Model.
机构信息
Faculty of Chemistry, University of Belgrade , Studentski trg 16, P.O. Box 51, 11158 Belgrade, Serbia.
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute , Frederick, Maryland 21702, United States.
出版信息
J Med Chem. 2018 Feb 22;61(4):1595-1608. doi: 10.1021/acs.jmedchem.7b01710. Epub 2018 Feb 6.
The synthesis and inhibitory potencies against botulinum neurotoxin serotype A light chain (BoNT/A LC) using in vitro HPLC based enzymatic assay for various steroidal, benzothiophene, thiophene, and adamantane 4-aminoquinoline derivatives are described. In addition, the compounds were evaluated for the activity against BoNT/A holotoxin in mouse embryonic stem cell derived motor neurons. Steroidal derivative 16 showed remarkable protection (up to 89% of uncleaved SNAP-25) even when administered 30 min postintoxication. This appears to be the first example of LC inhibitors antagonizing BoNT intoxication in mouse embryonic stem cell derived motor neurons (mES-MNs) in a postexposure model. Oral administration of 16 was well tolerated in the mouse up to 600 mg/kg, q.d. Although adequate unbound drug levels were not achieved at this dose, the favorable in vitro ADMET results strongly support further work in this series.
本文描述了各种甾体、苯并噻吩、噻吩和金刚烷 4-氨基喹啉衍生物的合成及其对肉毒梭菌神经毒素 A 型轻链（BoNT/A LC）的抑制活性，采用基于 HPLC 的体外酶促测定法进行测定。此外，还评估了这些化合物对 BoNT/A 全毒素在小鼠胚胎干细胞衍生运动神经元中的活性。甾体衍生物 16 表现出显著的保护作用（SNAP-25 未被切割的比例高达 89%），即使在中毒后 30 分钟给药也是如此。这似乎是首例 LC 抑制剂在体外暴露后模型中拮抗 BoNT 中毒作用的实例，在小鼠胚胎干细胞衍生运动神经元（mES-MNs）中发挥作用。16 经口给予小鼠，高达 600mg/kg，每天一次，耐受良好。尽管在该剂量下未达到足够的游离药物水平，但有利的体外 ADMET 结果强烈支持该系列的进一步研究。
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