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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.

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Apigenin and quercetin compounds, which are polyphenolic compounds, are used in the treatment of many diseases, including cancer treatment. Many researchers have investigated the bioactivity of apigenin and quercetin derivatives by attaching a fluorine atom or atoms due to the bioactivity of the fluorine atom. In this study, 16 new compounds were synthesized by attaching one or more trifluoromethyl groups to apigenin and quercetin‐like compounds; the structures of these compounds were verified by spectroscopic methods, and the cytotoxic activities of compound (5–8 and 13–16) were evaluated by MTT assay. Compound 5 (IC50=150.95 μM) was found to be the most effective of these compounds.