9-deazaguanine and its methyl derivatives: Synthesis, antitumor activity in vitro and effects on purine nucleoside phosphorylase gene expression

Suver, Mirjana; Žinić, Biserka; Portada, Tomislav; Bzowska, Agnieszka; Glavaš-Obrovac, Ljubica (2008) 9-deazaguanine and its methyl derivatives: Synthesis, antitumor activity in vitro and effects on purine nucleoside phosphorylase gene expression. Croatica Chemica Acta, 81 (1). pp. 147-156. ISSN 0011-1643

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Abstract

9-Deazaguanine 9-DG, 1-methyl-9-deazaguanine AG-19-K1 and 1,7-dimethyl-9-deazaguanine AG-3 were synthesized and their antiproliferative activity against five leukemia and four solid tumor cell lines as well as inhibitory properties us. calf spleen purine nucleoside phosphorylase (PNP) were tested. Synthesis of 9-DG involves reaction of 2-amino-6-methyl-5-nitropyrimidin-4(3H)-one (2) with DMF-dimethylacetal (amount ratio, n(2) / n(DMF-dimethylacetal) = 1:2.5) and use of the benzyloxymethyl group to protect the N-3 position of 2-(N-dimethylaminomethylene)amino-6-methyl-5-nitropyrimidin-4(3H)-one (4). Reaction of 2 with DMF-dimethylacetal (amount ratio, n(2) / n(DMF-dimethylacetal) = 1:6) gave the 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 at a concentration of 75 mu mol dm(-3). Cytotoxic effects of 9-deazaguanine derivatives on cell growth were determined by the MTT assay. Investigated derivatives showed moderate antiproliferative activity towards examined tumor cells. At a concentration of 10(-3) mol dm(-3), AG-19-K1 inhibited the growth of JURKAT, K562 and AGS cells by approximately 80 %. At the same concentration, AG-3 and 9-DG inhibited cell proliferation by 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.

Item Type:	Article
Uncontrolled Keywords:	synthesis; 9-deazaguanine derivatives; purine nucleoside phosphorylase; antiproliferative effects; leukemia cells; solid tumors cells; mechanism; inhibitor; carcinoma; 7-methylguanosine; proliferation; antibiotics; catalysis; invitro; bcx-34; cells
Subjects:	NATURAL SCIENCES > Chemistry
Divisions:	Division of Organic Chemistry and Biochemistry
Projects:	Project title Project leader Project code Project type Sinteza novih biološki aktivnih derivata nukleobaza i nukleotida [95066] Biserka Žinić 098-0982914-2935 MZOS Mehanizam bioloških učinaka novih malih molekula na stanice tumora čovjeka [162671] Ljubica Glavaš Obrovac 219-0982914-2176 MZOS
Depositing User:	Biserka Žinić
Date Deposited:	25 Oct 2013 12:11
URI:	http://fulir.irb.hr/id/eprint/841

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