Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis


YAVUZ S. , Cetin A., AKDEMİR A., DOYDUK D. , DİŞLİ A. , Celik Turgut G., ...More

ARCHIV DER PHARMAZIE, vol.350, no.11, 2017 (Journal Indexed in SCI) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 350 Issue: 11
  • Publication Date: 2017
  • Doi Number: 10.1002/ardp.201700185
  • Title of Journal : ARCHIV DER PHARMAZIE
  • Keywords: CCRF-CEM cells, Cladribine, Molecular modeling studies, Multiple sclerosis, RAJI cells, NUCLEOSIDE ANALOGS, CELL-DEATH, APOPTOSIS, PATHOGENESIS, MECHANISMS, THERAPIES

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.