Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis.
Arch Pharm (Weinheim)
; 350(11)2017 Nov.
Article
en En
| MEDLINE
| ID: mdl-28960496
ABSTRACT
Cladribine (2-CdA) is used as an anti-cancer drug but is currently studied as a potential treatment for use in relapsing-remitting multiple sclerosis (MS). In this study, we computer designed, synthesized, and characterized two novel derivatives of 2-CdA, K1-5d and K2-4c, and investigated their underlying mechanism of beneficial effect using the CCRF-CEM and RAJI cell lines. For this purpose, we first determined their effect on MS and DNA damage and repair-related gene expression profiles using custom arrays along with 2-CdA treatment at non-toxic doses. Then, we determined whether cells underwent apoptosis after treatment with 2-CdA, K1-5d, and K2-4c in CCRF-CEM and RAJI cells, using the DNA fragmentation assay. It was found that both derivatives modulated the expression of the pathway-related genes that are important in inflammatory signaling, apoptosis, ATM/ATR, double-strand break repair, and the cell cycle. Furthermore, 2-CdA, K1-5d, and K2-4c significantly activated apoptosis in both cell lines. In summary, our data demonstrate that although both derivatives act as anti-inflammatory and apoptotic agents, inducing the accumulation of DNA strand breaks and activating the ultimate tumor suppressor p53 in T and B lymphocytes, the K1-5d derivative has shown more promising activities for further studies.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Daño del ADN
/
Cladribina
/
Esclerosis Múltiple Recurrente-Remitente
/
Inmunosupresores
Límite:
Humans
Idioma:
En
Revista:
Arch Pharm (Weinheim)
Año:
2017
Tipo del documento:
Article
País de afiliación:
Turquía