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本文引用的文献

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Human serum albumin binding of certain antimalarials.某些抗疟药物与人血清白蛋白的结合。
Spectrochim Acta A Mol Biomol Spectrosc. 2018 Mar 5;192:128-139. doi: 10.1016/j.saa.2017.10.061. Epub 2017 Nov 9.
2
Small molecule metalloprotease inhibitor with in vitro, ex vivo and in vivo efficacy against botulinum neurotoxin serotype A.对A型肉毒杆菌神经毒素具有体外、离体和体内疗效的小分子金属蛋白酶抑制剂。
Toxicon. 2017 Oct;137:36-47. doi: 10.1016/j.toxicon.2017.06.016. Epub 2017 Jul 8.
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Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A.金属离子能有效消除肉毒毒素 A 的作用。
J Am Chem Soc. 2017 May 31;139(21):7264-7272. doi: 10.1021/jacs.7b01084. Epub 2017 May 19.
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Long-Chain 4-Aminoquinolines as Quorum Sensing Inhibitors in Serratia marcescens and Pseudomonas aeruginosa.长链4-氨基喹啉作为粘质沙雷氏菌和铜绿假单胞菌群体感应抑制剂
ACS Chem Biol. 2017 May 19;12(5):1425-1434. doi: 10.1021/acschembio.6b01149. Epub 2017 Apr 10.
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Challenges in searching for therapeutics against Botulinum Neurotoxins.寻找抗肉毒杆菌神经毒素疗法面临的挑战。
Expert Opin Drug Discov. 2017 May;12(5):497-510. doi: 10.1080/17460441.2017.1303476. Epub 2017 Mar 17.
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Antimalarials with Benzothiophene Moieties as Aminoquinoline Partners.具有苯并噻吩部分作为氨基喹啉伙伴的抗疟药。
Molecules. 2017 Feb 24;22(3):343. doi: 10.3390/molecules22030343.
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Newly Designed Quinolinol Inhibitors Mitigate the Effects of Botulinum Neurotoxin A in Enzymatic, Cell-Based, and ex Vivo Assays.新设计的喹啉醇抑制剂在酶促、细胞和离体实验中减轻肉毒杆菌神经毒素A的作用。
J Med Chem. 2017 Jan 12;60(1):338-348. doi: 10.1021/acs.jmedchem.6b01393. Epub 2017 Jan 3.
8
Searching for Therapeutics Against Botulinum Neurotoxins: A True Challenge for Drug Discovery.寻找抗肉毒杆菌神经毒素的疗法：药物研发面临的真正挑战。
Curr Top Med Chem. 2016;16(21):2330-49. doi: 10.2174/1568026616666160413135630.
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Cellular Protection of SNAP-25 against Botulinum Neurotoxin/A: Inhibition of Thioredoxin Reductase through a Suicide Substrate Mechanism.SNAP-25 对肉毒神经毒素/A 的细胞保护作用：通过自杀底物机制抑制硫氧还还原酶。
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10
A Novel Inhibitor Prevents the Peripheral Neuroparalysis of Botulinum Neurotoxins.一种新型抑制剂可预防肉毒神经毒素引起的外周神经瘫痪。
Sci Rep. 2015 Dec 16;5:17513. doi: 10.1038/srep17513.

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.

DOI:10.1021/acs.jmedchem.7b01710
PMID:29385334
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5833296/
Abstract

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.

摘要

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。