Anticancer Approach Inspired by the Hepatotoxic Mechanism of Pyrrolizidine Alkaloids with Glycosylated Artificial Metalloenzymes.
Angew Chem Int Ed Engl
; 61(43): e202205541, 2022 10 24.
Article
en En
| MEDLINE
| ID: mdl-36062554
ABSTRACT
Metabolic oxidation of pyrrolizidine alkaloids (PAs) from herbal and dietary supplements by cytochrome P450 produces dehydro-PAs (DHPs), which leads to toxicities. A highly reactive cation species generated from the active pyrrole ring of DHPs readily reacts with various cellular components, causing hepatotoxicity and cytotoxicity. Inspired by PA-induced hepatic damage, we developed a therapeutic approach based on a cyclization precursor that can be transformed into a synthetic DHP under physiological conditions through gold-catalyzed 5-endo-dig cyclization using a gold-based artificial metalloenzyme (ArM) instead of through metabolic oxidation by cytochrome P450. In cell-based assays, the synthesis of the DHP by a cancer-targeting glycosylated gold-based ArM substantially suppressed cell growth of the targeted cancer cells without causing cytotoxicity to untargeted cells, highlighting the potential of the strategy to be used therapeutically in vivo.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Alcaloides de Pirrolicidina
/
Metaloproteínas
Idioma:
En
Revista:
Angew Chem Int Ed Engl
Año:
2022
Tipo del documento:
Article
País de afiliación:
Japón