Exploring the chemical space around chrysin to develop novel vascular CaV1.2 channel blockers, promising vasorelaxant agents

IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL
Federica Falbo, Gabriele Carullo, Alice Panti, Ottavia Spiga, Beatrice Gianibbi, Amer Ahmed, Giuseppe Campiani, Anna Ramunno, Francesca Aiello, Fabio Fusi
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Abstract

The flavonoid chrysin is an effective vascular CaV1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1–4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to CaV1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca2+ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the CaV1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular CaV1.2 channel blockers.

Abstract Image

探索蛹虫草素周围的化学空间,开发新型血管 CaV1.2 通道阻断剂和有前景的血管舒张剂。
黄酮类化合物菊黄素是一种有效的血管 CaV1.2 通道阻断剂。本研究的目的是探索菊黄素的化学空间,以确定可用于开发新型、更有效阻滞剂的结构特征。研究人员合成了四种衍生物(Chrysin 1-4),并采用功能、电生理学和分子对接方法来评估它们与 CaV1.2 通道的结合模式及其在血管制剂中的活性。蛹素骨架的 5- 和 7-OH 甲基化会导致 Ca2+ 拮抗效力和功效明显降低。然而,C-8 衍生物显示出与母体化合物相似的生物物理特征,并且与尼卡地平一样,能以高亲和力与处于失活状态的 CaV1.2 通道结合并使其稳定。这四种衍生物的血管舒张作用具有血管特异性,这说明分子的衍生物化针对不同的靶点。总之,菊黄素支架可被视为开发创新型血管 CaV1.2 通道阻断剂的宝贵起点。
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来源期刊
Archiv der Pharmazie
Archiv der Pharmazie 医学-化学综合
CiteScore
7.90
自引率
5.90%
发文量
176
审稿时长
3.0 months
期刊介绍: Archiv der Pharmazie - Chemistry in Life Sciences is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry. Emphasis is put on papers combining synthetic organic chemistry, structural biology, molecular modelling, bioorganic chemistry, natural products chemistry, biochemistry or analytical methods with pharmaceutical or medicinal aspects such as biological activity. The focus of this journal is put on original research papers, but other scientifically valuable contributions (e.g. reviews, minireviews, highlights, symposia contributions, discussions, and essays) are also welcome.
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