羧基柱[5]芳烃主客体包封对氮芥的超分子解毒,Journal of Materials Chemistry B

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羧基柱[5]芳烃主客体包封对氮芥的超分子解毒
Journal of Materials Chemistry B ( IF 6.1 ) Pub Date : 2023-02-13 , DOI: 10.1039/d2tb02211g
Siyuan Zhou ₁ , Yi Chen ₁ , Jie Xu ₂ , Yongfei Yin ₁ , Jianqing Yu ₂ , Wei Liu ₃ , Shigui Chen ₁ , Lu Wang ₁

Affiliation

氮芥 ( NM ) 是一种类似于硫芥的烷化剂，仍然对公众健康构成威胁。然而，几乎没有令人满意的氮芥解毒剂。在此，我们通过羧基柱[5]芳烃钾盐 ( CP[5]AK )与NM的有效络合开发了一种超分子氮芥解毒剂。甲氧基柱 [5] 芳烃 ( P5A ) 的空腔足以封装结合常数为 1.27 × 10 ² M ^-1的NM，这已通过¹ H NMR 滴定、密度泛函理论研究和独立梯度模型研究进行了研究。纳米在水相中降解为反应性氮丙啶盐 ( 2 )，不可逆地使 DNA 和蛋白质烷基化，导致严重的组织损伤。考虑到与有毒中间体2 的大小/电荷匹配，选择水溶性CP[5]AK来封装有毒氮丙啶盐 ( 2 )，从而获得 4.10 × 10 ⁴ M ^-1的高缔合常数。CP[5]AK对鸟苷5'-单磷酸( GMP )的保护实验结果表明，其形成的复合物能有效抑制DNA的烷基化。此外，体外和体内实验还表明，通过形成稳定的主客体复合物，氮丙啶盐( 2 )的毒性得到抑制， CP[5]AK对NM引起的损伤具有良好的治疗作用。该研究为纳米材料暴露引起的皮肤损伤的治疗提供了新的机制和策略。

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Supramolecular detoxification of nitrogen mustard via host–guest encapsulation by carboxylatopillar[5]arene

Nitrogen mustard (NM), a kind of alkylating agent similar to sulfur mustard, remains a threat to public health. However, there is nearly no satisfactory antidote for nitrogen mustard. Herein, we developed a supramolecular antidote to nitrogen mustard through efficient complexation of NM by carboxylatopillar[5]arene potassium salts (CP[5]AK). The cavity of methoxy pillar[5]arene (P5A) is sufficient to encapsulate NM with an association constant of 1.27 × 10² M⁻¹, which was investigated by ¹H NMR titration, density functional theory studies and independent gradient model studies. NM degrades to the reactive aziridinium salt (2) in the aqueous phase which irreversibly alkylates DNA and proteins, causing severe tissue damage. Considering the size/charge matching with toxic intermediate 2, water-soluble CP[5]AK was selected to encapsulate the toxic aziridinium salt (2), resulting in a high association constant of 4.10 × 10⁴ M⁻¹. The results of protection experiments of guanosine 5'-monophosphate (GMP) by CP[5]AK indicated that the formation of a complex could effectively inhibit the alkylation of DNA. Besides, in vitro and in vivo experiments also indicated that the toxicity of the aziridinium salt (2) is inhibited with the formation of a stable host–guest complex, and CP[5]AK has a good therapeutic effect on the damage caused by NM. This study provides a new mechanism and strategy for the treatment of NM exposure-induced skin injuries.

更新日期：2023-02-13

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