Synthesis and Evaluation of 4-Hydroxycoumarin Imines as Inhibitors of Class II Myosins.
Synthesis and Evaluation of 4-Hydroxycoumarin Imines as Inhibitors of Class II Myosins.
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DOI：
10.1021/acs.jmedchem.0c01062
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发表时间：
2020-10-08
影响因子：
7.3
通讯作者：
Cremo C
中科院分区：
文献类型：
--
作者：
Brawley J;Etter E;Heredia D;Intasiri A;Nennecker K;Smith J;Welcome BM;Brizendine RK;Gould TW;Bell TW;Cremo C
需要肌球蛋白ATP酶的抑制剂来治疗可以通过促进肌肉松弛来改善的病症。本研究的先导化合物（（3-（N-丁基乙亚胺基）乙基）-4-羟基-2H-色烯-2-酮; BHC）先前被发现可抑制骨骼肌球蛋白II。合成了六六六及其34个类似物，探讨了它们的构效关系。类似物的性质，包括溶解度，稳定性和毒性，表明BHC支架可能用于开发治疗药物。肌动蛋白激活ATP酶活性的抑制快速骨骼肌和心肌肌球蛋白II，骨骼肌收缩性的抑制离体，并在体外肌动蛋白滑动速度减慢进行了测定。与BHC相比，几种具有芳香侧臂的类似物对骨骼肌球蛋白和心肌肌球蛋白的效力（半数最大抑制浓度（IC 50）<1 μM）和选择性（≥12倍）有所改善。几种类似物阻断神经传递，表明它们对非肌肉肌球蛋白II的选择性超过骨骼肌肌球蛋白。竞争和分子对接研究表明，BHC和blebbistatin结合到肌球蛋白上的相同位点。
Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-(N-butylethanimidoyl)ethyl)-4-hydroxy-2H-chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure–activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC50) <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to BHC. Several analogues blocked neurotransmission, suggesting that they are selective for nonmuscle myosin II over skeletal myosin. Competition and molecular docking studies suggest that BHC and blebbistatin bind to the same site on myosin.
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影响因子：
13.6
作者：
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通讯作者：
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3.3
作者：
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通讯作者：
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