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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
9-Deazaguanine and its Methyl Derivatives: Synthesis, Antitumor Activity in Vitro and Effects on Purine Nucleoside Phosphorylase Gene Expression // Croatica Chemica Acta, 81 (2008), 1; 147-156 (međunarodna recenzija, članak, znanstveni)


Naslov
9-Deazaguanine and its Methyl Derivatives: Synthesis, Antitumor Activity in Vitro and Effects on Purine Nucleoside Phosphorylase Gene Expression

Autori
Suver, Mirjana ; Žinić, Biserka ; Portada, Tomislav ; Bzowska, Agnieszka ; Glavaš-Obrovac, Ljubica

Izvornik
Croatica Chemica Acta (0011-1643) 81 (2008), 1; 147-156

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Synthesis; 9-deazaguanine derivatives; purine nucleoside; phosphorylase;

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija



POVEZANOST RADA


Projekt / tema
098-0982914-2935 - Sinteza novih biološki aktivnih derivata nukleobaza i nukleotida (Biserka Žinić, )
219-0982914-2176 - Mehanizam bioloških učinaka novih malih molekula na stanice tumora čovjeka (Ljubica Glavaš Obrovac, )

Ustanove
Institut "Ruđer Bošković", Zagreb,
Klinički bolnički centar Osijek,
Medicinski fakultet, Osijek

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus