丁肽衍生物心脏保护剂的设计、合成及生物学评价

IF 4.8 3区 化学 Q1 CHEMISTRY, MEDICINAL
Yuan Liu, Fa-Qi Wang, Xin-Hao Hua, Shu-Han Yang, Li-Ning Wang, Yun-Sheng Xu, Chen-Yue Shao, Xiang-Bo Gou, Yu-Ming Liu
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引用次数: 0

摘要

天然产物是心血管药物开发的重要来源。本研究设计、合成了29种丁素衍生物,并评价了它们对心肌细胞损伤的NHE-1抑制和保护作用。化合物的结构经1H-NMR、13C-NMR和HR-ESI-MS确证。在1 μM靶点化合物中,化合物9d、9f、9k、9m和9n对H9c2心肌细胞的保护作用强于阳性对照右唑嗪和丁酮a,保护率均超过30%。化合物9k、9m和90对H9c2心肌细胞的NHE-1抑制活性显著,dpHi/min值均小于0.23。化合物9k、9m、90和buthutin A均表现出抑制NHE-1的特异性。分子模拟研究表明,化合物9m和90能够与NHE-1的Asp267和Glu346建立3个氢键相互作用,并且具有比阳性对照cariporide和buthtin a低得多的CDOCKER能量。构效关系(SAR)研究表明,酰胺基团、四碳连接体和对羟基苯环的存在是上述两种药理作用的有利药效团。本研究为开发以酰胺胍为基础的心脏保护剂开辟了新的途径。图形抽象
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Design, synthesis and biological evaluation of buthutin derivatives as cardioprotective agents

Natural products are the important sources in cardiovascular drug development. In this study, twenty-nine buthutin derivatives were designed, synthesized, and evaluated for their NHE-1 inhibition and protective effects on cardiomyocyte injury. The structure of the newly synthesized compounds had been confirmed by 1H-NMR, 13C-NMR, and HR-ESI-MS spectra. Among all target compounds at 1 μM, compounds 9d, 9f, 9k, 9m, and 9n, with a protection ratio exceeding 30%, exerted stronger protective effects on H9c2 cardiomyocyte than positive control dexrazoxane and buthutin A. Meanwhile, compounds 9k, 9m, and 9o showed the significant NHE-1 inhibitory activities on H9c2 cardiomyocyte, all with a dpHi/min value less than 0.23. What is more, compounds 9k, 9m, 9o and buthutin A all exhibited the specificity on NHE-1 inhibition. Molecular modelling studies suggested the ability of compounds 9m and 9o to establish interactions with three hydrogen bonds to Asp267 and Glu346 of NHE-1, but also the ability with much lower CDOCKER energies than positive control cariporide and buthutin A. The structure–activity relationship (SAR) studies suggested that the presences of amide group, four-carbon linker, and para hydroxyl benzene ring were advantageous pharmacophores for above two pharmacological actions. This research would open new avenues for developing amide-guanidine-based cardioprotective agents.

Graphical Abstract

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来源期刊
Natural Products and Bioprospecting
Natural Products and Bioprospecting CHEMISTRY, MEDICINAL-
CiteScore
8.30
自引率
2.10%
发文量
39
审稿时长
13 weeks
期刊介绍: Natural Products and Bioprospecting serves as an international forum for essential research on natural products and focuses on, but is not limited to, the following aspects: Natural products: isolation and structure elucidation Natural products: synthesis Biological evaluation of biologically active natural products Bioorganic and medicinal chemistry Biosynthesis and microbiological transformation Fermentation and plant tissue cultures Bioprospecting of natural products from natural resources All research articles published in this journal have undergone rigorous peer review. In addition to original research articles, Natural Products and Bioprospecting publishes reviews and short communications, aiming to rapidly disseminate the research results of timely interest, and comprehensive reviews of emerging topics in all the areas of natural products. It is also an open access journal, which provides free access to its articles to anyone, anywhere.
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