Macrocyclic Neutralizer to Polybrene via Direct Host-Guest Complexation.
J Med Chem
; 67(12): 10425-10435, 2024 Jun 27.
Article
em En
| MEDLINE
| ID: mdl-38848302
ABSTRACT
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) × 107 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%.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos Macrocíclicos
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article