中山大学胡文浩团队报道了不对称碳烯-炔烃复分解介导的级联反应——苯并恶嗪多手性多杂环的合成和新型镇痛剂的发现。相关研究成果发表在2024年3月20日出版的国际知名学术期刊《德国应用化学》。

该研究介绍了一种通过创新的不对称碳烯-炔烃复分解触发级联，合成苯并恶嗪中心的多手性多杂环（BPCPHCs）的新方法。克服了与复杂的立体化学和多个手性中心相关的挑战，采用催化不对称碳烯-炔烃复分解介导的级联（CAMC），使用二钌催化剂/Brnsted酸共催化，确保了X射线晶体学验证的精确立体控制。系统的底物范围评估建立了特殊的非对映选择性和对映选择性，创建了一个独特的BPCPHCs库。药理学探索确定12种BPCPHCs为强效Nav离子通道阻滞剂，尤其是化合物8g。

体内研究表明，鞘内注射8g可有效逆转与化疗诱导的周围神经病变（CIPN）相关的机械性痛觉过敏，这是一种有前景的治疗途径。电生理研究揭示了8g对Nav1.7电流的抑制作用。分子对接、动力学模拟和表面等离子体共振（SPR）分析，为8g与C5aR1的稳定复合物形成和有利的结合自由能提供了见解。

该项研究代表了BPCPHCs不对称CAMC的重大进展，并揭示了BPCPHC 8g作为一种有前途的、独特作用的疼痛阻滞剂，在CIPN的背景下建立了C5aR1-Nav1.7连接。

附：英文原文

Title: Asymmetric Carbene-Alkyne Metathesis-mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker

Author: Shuhao Liu, Haoyi Yang, Jirong Shu, Linna Wu, Yukai Li, Zhijing Zhang, Weijie Guo, Shuxian Cai, Fuyi Li, Wenjiang Liu, Shikun Jia, Song Cai, Taoda Shi, Wenhao Hu

Issue&Volume: 2024-03-20

Abstract: Abstract: This study introduces a novel approach for synthesizing Benzoxazine-Centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brnsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8g. In vivo studies demonstrate that intrathecal injection of 8g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.

DOI: 10.1002/anie.202401189

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202401189