Synthesis of 21‐Alkylidenes and 21‐Alkylol Analogues of Uscharin and Their Effects on Intracellular Calcium in Cardiac Cells,ChemistrySelect

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Synthesis of 21‐Alkylidenes and 21‐Alkylol Analogues of Uscharin and Their Effects on Intracellular Calcium in Cardiac Cells
ChemistrySelect ( IF 1.9 ) Pub Date : 2019-05-20 , DOI: 10.1002/slct.201900108
Xiaobo Zhou ₁ , Li Chen _{1,

2} , Zhi‐Hong Jiang ₁ , Xiaoyi Chen ₁ , Pei Luo ₁ , Li‐Ping Bai ₁

Affiliation

Five 21‐alkylidenes (2‐6) and a 21‐alkylol (7) derivatives of uscharin (1) were synthesized by aldol condensation reaction and aldol reaction of uscharin with aromatic aldehydes, respectively. We investigated the ability of uscharin and its derivatives to interfere with the intracellular calcium level by flow cytometry and contractile characteristics at the single cell level by time‐lapse microscopy in H9c2 cells. Changes of spontaneous calcium oscillations in beating HL‐1 cells were also studied by a high‐throughput Fluorometric Imaging Plate Reader (FLIPR) assay. We reported for the first time that uscharin could produce increased contraction strength in cardiac muscle cells while it showed a significant cytotoxicity to atrial cells. Unlike uscharin, 6 induced a marked increase of myocardial contractility, whereas 6 neither caused irregular frequency of oscillations nor cardiac cytotoxic effects under tested conditions. Structural modification on the butenolide moiety of uscharin showed a reduction of cardiac cytotoxicity and exhibited potential for use as an inotropic agent for the treatment of heart failure.

中文翻译：

Uscharin的21-炔烃和21-烷醇类似物的合成及其对心脏细胞内钙的影响

五21亚烷基（2 - 6）和21羟烷基（7 uscharin的）衍生物（1）分别通过糖精蛋白与芳香醛的醛醇缩合反应和醛醇缩合反应合成。我们通过流式细胞术和时移显微镜在H9c2细胞中研究了uscharin及其衍生物干扰细胞内钙水平的能力以及单细胞水平的收缩特性。还通过高通量荧光成像板读数器（FLIPR）分析研究了跳动的HL-1细胞中自发钙振荡的变化。我们首次报道了uscharin可以在心肌细胞中产生增加的收缩强度，同时对心房细胞显示出显着的细胞毒性。与uscharin不同，6诱导心肌收缩力显着增加，而6在测试条件下，既不会引起不规则的振荡频率，也不会引起心脏细胞毒性作用。uscharin丁烯内酯部分的结构修饰显示出降低的心脏细胞毒性，并具有用作治疗心脏衰竭的正性肌力药的潜力。

更新日期：2019-05-20

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