Macrocyclic Neutralizer to Polybrene via Direct Host–Guest Complexation

作者：Yahan Zhang, Yu Xiang, Di Gao, Longming Chen, Ziliang Zhang, Yuanyuan Liu, Zhibing Zheng, Junyi Chen, Chunju Li, Qingbin Meng · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c00871 · 被引用次数：9 · 研究领域：Chemical Synthesis and Analysis、Synthetic Organic Chemistry Methods、Asymmetric Hydrogenation and Catalysis

Hexadimethrine bromide (HB), a synthetic polycationic species, was introduced to clinical practice as a heparin antidote and recently used in gene therapy. However, HB causes various complications such as severe red blood cells (RBCs) aggregation and tissue damage. Herein, we have synthesized a water-soluble quaterphen[3]arene containing multiple sulfonate moieties (SQP3) as a novel macrocyclic neutralizer to reverse HB via direct host–guest complexation. SQP3 exhibited a robust binding affinity toward HB with a considerably high association constant of (4.73 ± 0.61) × 10 7 M –1 . Co-dosed with 1 equiv of SQP3, HB-induced RBCs aggregation and blood coagulation could be effectively reversed. In vitro cellular assay verified that complexation of HB with SQP3 significantly decreased reactive oxygen species production, thereby suppressing cell apoptosis. In vivo neutralization efficacy studies demonstrated that HB/SQP3 was capable of alleviating related organic damage caused by HB and improving the survival rate of HB-treated mice from 20 to 100%.