engleski

Synthesis of 9-deazaguanine derivatives and their effects on the growth of leukemia and solid tumors cells

Purine nucleoside phosphorylase (PNP) is a key enzyme of purine salvage pathway which is overexpressed in some carcinoma and leukemia cells. 9-deazaguanine (9-DG), 1-methyl-9-deazaguanine (AG-19-K1) and 1, 7-dimethyl-9-deazaguanine (AG-3), were synthesized as potential PNP inhibitors and tested on their antiproliferative activity against panel of tumor cells. The method for the synthesis of 9-deazaguanine (9-DG) involves use of the benzyloxymethyl group to protect the N3-position of 2-[(dimethylaminomethylene)-amino]-6-methyl-5-nitro-4(3H)-pyrimidinone, followed by treatment with DMF-dimethylacetal, reductive cyclisation, treatment with ethanolic ammonia and removal of the protecting group by catalytic hydrogenation. The reaction of N-3 unprotected 2-amino-6-methylpyrimidin-4(3H)-one with 6 eq. of DMF-dimethylacetal gave N-3-methyl substituted intermediate. Dithionite reduction of this product afforded N-methyl derivatives AG-19-K1 and AG-3. The cytotoxic effects of 9-deazaguanine derivatives on cell growth and viability were determined by MTT assay. Five different cell lines of leukemia (HL-60, JURKAT, K562, RAJI and MOLT-4) and four different cell lines of solid tumors (SW620, HT-29, AGS and HeLa) were used. Results showed that compound AG-19-K1 in concentration of 10-3 M inhibited growth of JURKAT, K562 and AGS cells for approximately 80%. At the same concentration compounds AG-3 and 9-DG, inhibited cell proliferation for 40-50% of all tested cell lines, except MOLT-4 and HL-60. In concentration of 10-4 M the investigated substances slightly inhibited cell growth for 10-20%. Lower concentration (10-5 and 10-6 M) of all tested substances have no influence on the cell proliferation. In conclusion, there is no difference in growth inhibitory effects of tested compounds between leukemia and solid tumor cell lines. Preliminary results indicate positive anti-proliferative effects of 9-deazaguanine derivatives on human tumors but further research is needed for better insight.

synthesis; 9-deazaguanine derivatives; anti-proliferative effects; leukemia; solid tumors cells

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