Naslov
Synthesis and Biological Effects of 9-deazaguanine Derivatives on Leukemia Cells

Autori
Suver, Mirjana ; Žinić, Biserka ; Glavaš-Obrovac, Ljubica

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Apoptosis in Drug Discovery : abstracts / - , 2007

Skup
Apoptosis in Drug Discovery

Mjesto i datum
San Diego (CA), Sjedinjene Američke Države, 22.03.2007. - 23.03.2007

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
9-deazaguanine; derivatives; leukemia; pnp; caspase-3; p53

Sažetak
9-Deazaguanine and their two derivatives, 1-methyl-9-deazaguanine (AG-19-K1) and 1, 7-dimethyl-9-deazaguanine (AG-3), were synthesized as potential purine nucleoside phosphorylase (PNP) inhibitors for treatment of leukemia diseases. The method for the synthesis of 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. Dithionite reduction of N-3-methyl substituted intermediate product afforded N-methyl derivatives AG-19-K1 and AG-3. Tested compounds had antiproliferative effects on leukemia cell lines: MOLT-4, HL-60, K562 and RAJI. The cell growth inhibition was observed in all treated cell lines. Leukemia cells exposed during 6, 12 and 24h gave different results on expression of p53, caspase-3 and pnp genes. After 6 and 12h of treatment, expression of caspase-3 and p53 genes were significantly decreased in HL-60 and MOLT-4. In the same conditions there was no expression of aim genes in RAJI and K562 cells. Results of our study showed that expression of pnp in treated cell lines were significantly decreased. The most pronounced effect on pnp gene expression displayed AG-19-K1 in concentrations of 10-3 M in all cell lines. In conclusion, investigated compounds affected synthesis of mRNA of PNP, a crucial enzyme of purine salvage pathway which is overexpressed in human leukemia. They are also able to modulate expression of some proapoptotic genes such as caspase-3 and p53. Further research will give better observation.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA