Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties.
Umbelliferyloxymethyl phosphonate compounds-weakly binding zinc ionophores with neuroprotective properties.
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DOI：
10.1039/d1dt02298a
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发表时间：
2021-11-30
期刊：
影响因子：
--
通讯作者：
Sullivan A
中科院分区：
文献类型：
--
作者：
Guesne S;Connole L;Kim S;Motevalli M;Robson L;Michael-Titus AT;Sullivan A
伞形酮是香豆素家族化合物的成员，已知其具有多种药理活性，包括与阿尔茨海默病（AD）相关的靶点。与某些形式的淀粉样蛋白Aβ相关的毒性以及Zn 2+（和其他生物金属）在其中的稳态异常的作用在AD中引起了极大的兴趣，并且使得金属离子载体能力在所谓的多靶药物配体MTDL中是期望的。本文报道了一系列新的伞形酮氧基甲基膦酸二乙酯化合物（伞形酮氧基甲基膦酸酯），其中化合物1、3-6在7-位上带有一个膦酸酯，化合物1的水解产物2、2a和2b以及化合物1的7-O → 7-S和1-O → 1-NH的类似物7和8。测定了化合物1、2和2a的单晶X-射线结构。在神经保护特性方面，化合物1、2、3、4、5和6在1 μM浓度下抑制Aβ1-42（Aβ42）对大鼠海马细胞的毒性，A β 42以毒性淀粉样蛋白衍生的扩散配体（ADDL）和纤维（原纤维）形式存在。化合物7显示细胞毒性，8不能抑制Aβ42毒性。关于化合物-金属离子载体活性（使用化学实验评估），尽管由ZnCl 2对1和2的31 P NMR滴定测定了与Zn 2+的弱结合，但化合物1，3，4，图5和图6显示了离子载体辅助的Zn 2+从水分配到辛醇的微摩尔浓度，其功效与螯合剂MTDL氯碘喹相当或更好（5-氯-7-碘-8-羟基喹啉）。使用炉原子吸收光谱法（AAS）评估分配。在进一步的实验中，化合物1与Zn 2+或其途径的相互作用通过（i）在用FluoZin-3处理的细胞中加入Zn 2+的延迟荧光响应和（ii）通过抑制Zn 2+促进Aβ42的聚集来推断。伞形酮氧基甲基膦酸酯：A保护大鼠海马细胞免受毒性Aβ42的非螯合离子载体B将Zn从水分配到辛醇C抑制Zn促进的Aβ42聚集，D延迟神经元细胞中FluoZin-3的Zn信号传导。
Umbelliferone is a member of the coumarin family of compounds which are known for diverse pharmacological activity including in targets relevant to Alzheimers disease, AD. The toxicity associated with some forms of the amyloid protein, Aβ, and the role of Zn2+ (and other biometals) dyshomeostasis in this, are of great interest in AD and make metal ionophore capability desirable in so called multi target drug ligands MTDLs. A new series of umbelliferyloxymethyl phosphonic acid diethylester compounds (umbelliferyloxymethyl phosphonates) bearing a phosphonate at the 7-position (compounds 1, 3–6), hydrolysis products 2, 2a and 2b from 1 and analogues 7 and 8 of 1 with 7-O to 7-S and 1-O to 1-NH substitutions, are reported. Single crystal X-ray structures of compounds 1, 2 and 2a were determined. In terms of neuroprotective properties, the compounds 1, 2, 3, 4, 5 and 6 at 1 μM concentration, inhibited the toxicity of Aβ1-42 (Aβ42) in both toxic Amyloid Derived Diffusible Ligand (ADDL) and fibrillar (fibril) forms towards rat hippocampal cells. Compound 7 displayed cytotoxicity and 8 failed to inhibit Aβ42 toxicity. Concerning compound-metal ionophore activity (assessed using chemical experiments), despite weak binding to Zn2+ determined from 31P NMR titration of 1 and 2 by ZnCl2, compounds 1, 3, 4, 5 and 6 demonstrated ionophore assisted partition of Zn2+ from water to octanol at micromolar concentrations with efficacy on a par with or better than the chelator MTDL clioquinol (5-chloro-7-iodo-8-hydroxyquinoline). Partition was assessed using furnace Atomic Absorption Spectroscopy (AAS). In further experiments interaction of compound 1 with Zn2+ or it's pathways was inferred by (i) delayed fluorescence response with added Zn2+ in cells treated with FluoZin-3 and (ii) by suppression of Zn2+ promoted aggregation of Aβ42. Umbelliferyloxymethyl phosphonates:non-chelating ionophores that A protect rat hippocampal cells from toxic Aβ42 B partition Zn from water to octanol C inhibit Zn promoted aggregation of Aβ42, D delay Zn signaling by FluoZin-3 in neuronal cells.
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