Insights on cyclophosphamide metabolism and anticancer mechanism of action: A computational study.
J Comput Chem
; 45(10): 663-670, 2024 Apr 15.
Article
en En
| MEDLINE
| ID: mdl-38088485
ABSTRACT
The oxazaphosphorine cyclophosphamide (CP) is a DNA-alkylating agent commonly used in cancer chemotherapy. This anticancer agent is administered as a prodrug activated by a liver cytochrome P450-catalyzed 4-hydroxylation reaction that yields the active, cytotoxic metabolite. The primary metabolite, 4-hydroxycyclophosphamide, equilibrates with the ring-open aldophosphamide that undergoes ß-elimination to yield the therapeutically active DNA cross-linking phosphoramide mustard and the byproduct acrolein. The present paper presents a DFT investigation of the different metabolic phases and an insight into the mechanism by which CP exerts its cytotoxic action. A detailed computational analysis of the energy profiles describing all the involved transformations and the mechanism of DNA alkylation is given with the aim to contribute to an increase of knowledge that, after more than 60 years of unsuccessful attempts, can lead to the design and development of a new generation of oxazaphosphorines.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Acroleína
/
ADN
Idioma:
En
Revista:
J Comput Chem
Asunto de la revista:
QUIMICA
Año:
2024
Tipo del documento:
Article
País de afiliación:
Egipto