9-Deazaguanine and its Methyl Derivatives: Synthesis, Antitumor Activity in Vitro and Effects on Purine Nucleoside Phosphorylase Gene Expression (CROSBI ID 131928)
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Podaci o odgovornosti
Suver, Mirjana ; Žinić, Biserka ; Portada, Tomislav ; Bzowska, Agnieszka ; Glavaš-Obrovac, Ljubica
engleski
9-Deazaguanine and its Methyl Derivatives: Synthesis, Antitumor Activity in Vitro and Effects on Purine Nucleoside Phosphorylase Gene Expression
9-Deazaguanine 9-DG, 1-methyl-9-deazaguanine AG-19-K1 and 1, 7-dimethyl-9deazaguanine AG-3 were synthesized and their antiproliferative activity against five leukemia and four solid tumors cell lines as well as inhibitory properties vs. calf spleen purine nucleoside phosphorylase (PNP) were tested. The synthesis of 9-DG involves reaction of 2-amino-6-methyl-5-nitro-pyrimidin-4(3H)-one (2) with 2.5 eq. of DMFdimethylacetal and use of the benzyloxymethyl group to protect the N)(3) position of 2-(Ndimethylaminomethylene) amino-6-methyl-5-nitropyrimidin-4(3H)-one (4). Reaction of 2 with 6 eq. of DMF-dimethylacetal gave N-3 methyl substituted intermediate 3. Dithionite reduction of this product afforded N-methyl derivatives AG-19-K1 and AG-3. AG-19-K1 and AG-3 were inactive vs. calf spleen PNP in the concentration of 75 mM. The cytotoxic effects of 9-deazaguanine derivatives on cell growth were determined by MTT assay. Investigated derivatives showed moderate antiproliferative activity towards examined tumor cells. AG-19-K1 in concentration of 10-3 M inhibited growth of JURKAT, K562 and AGS cells for approximately 80%. At the same concentration, AG-3 and 9-DG inhibited cell proliferation for 40-50% of all tested lines, except MOLT-4 and HL-60. The PNP gene expression was changed in treated leukemia cells after exposure to AG-19-K1 and 9-DG in a time-dependent manner.
synthesis; 9-deazaguanine derivatives; purine nucleoside; phosphorylase;
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