Synthesis and Biological Evaluation of Falcarinol-Type Analogues as Potential Calcium Channel Blockers,Journal of Natural Products

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Synthesis and Biological Evaluation of Falcarinol-Type Analogues as Potential Calcium Channel Blockers
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-07-28 , DOI: 10.1021/acs.jnatprod.1c00136
Yang Li ₁ , Wan-Li Tan ₁ , Kai Guo ₂ , Xiao-Wei Gao ₂ , Jun Wei ₁ , Dong Yi ₁ , Chun Zhang ₁ , Qin Wang _{1,

2}

Affiliation

A series of enantiomers of falcarinol analogues (2) were synthesized using a chiral 1,1′-binaphth-2-ol (BINOL)-based catalytic system. The neuroprotective effects of falcarinol (1a) and its analogues (2) on PC12 cells injured by sodium azide (NaN₃) were investigated. The structure–function relationships and possible mechanism were studied. Pretreatment of PC12 cells with falcarinol analogues (R)-2d and (R)-2i for 1 h following addition of NaN₃ and culture in a CO₂ incubator for 24 h resulted in significant elevation of cell viability, as determined by a CCK-8 assay and Hoechst staining, with reduction of LDH release and MDA content, increase of SOD activity, and decrease of ROS stress, when compared with the activity of natural falcarinol (1a). These observations indicated that the falcarinol analogues (R)-2d and (R)-2i can protect PC12 cells against NaN₃-induced apoptosis via increasing resistance to oxidative stress. For the first time, falcarinol (1a) and its analogue (R)-2i were found to have potential L-type calcium channel-blocking activity, as recorded using a manual patch clamp technique on HEK-293 cells stably expressing hCav1.2 (α1C/β2a/α2δ1). These findings suggest that the mechanism of the L-type calcium channel-blocking activity of falcarinol (1a) and its analogue (R)-2i might be involved in neuroprotection by falcarinol-type analogues by inhibiting calcium overload in the upstream of the signaling pathway.

中文翻译：

作为潜在钙通道阻滞剂的 Falcarinol 型类似物的合成和生物学评价

使用基于手性 1,1'-联萘-2-醇 (BINOL) 的催化系统合成了一系列镰刀菌醇类似物 ( 2 )的对映异构体。研究了镰刀菌素 ( 1a ) 及其类似物 ( 2 ) 对叠氮化钠 (NaN ₃ )损伤的 PC12 细胞的神经保护作用。研究了结构-功能关系和可能的机制。在加入 NaN ₃并在 CO _{2 中}培养后，用镰刀菌素类似物 ( R )- 2d和 ( R )- 2i预处理 PC12 细胞1 小时培养 24 小时导致细胞活力显着提高，如 CCK-8 测定和 Hoechst 染色所确定，与 LDH 释放和 MDA 含量减少、SOD 活性增加和 ROS 应激降低相比，与天然镰刀菌素 ( 1a )。这些观察结果表明，镰刀菌素类似物 ( R )- 2d和 ( R )- 2i可以通过增加对氧化应激的抵抗力来保护 PC12 细胞免受 NaN ₃诱导的细胞凋亡。第一次，falcarinol ( 1a ) 及其类似物 ( R )- 2i发现具有潜在的 L 型钙通道阻断活性，如使用手动膜片钳技术对稳定表达h Cav1.2 (α1C/β2a/α2δ1) 的HEK-293 细胞记录的那样。这些发现表明，镰刀菌素（1a）及其类似物（R）- 2i的L型钙通道阻断活性的机制可能通过抑制信号通路上游的钙超载而参与了镰刀菌素类类似物的神经保护作用。 .

更新日期：2021-08-27

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