engleski

Synthesis and structural characterization of novel 9-deazaguanine derivatives as potential inhibitors of purine nucleoside phosphorylase

The design of PNP inhibitors is extremely vital to the stability of antiviral and anticancer agents as well as to the suppression of T-cell activity. According to the literature procedures we prepared 9-deazaguanine with an overall yield of 50%. A synthesis of 9-deazaguanine was achieved starting from 2-amino-6-methyl-3H-pyrimidin-4-one. The method involves use of the benzyloxymethyl group to protect the N3-position of N′ -(1, 6-dihidro-4-methyl-5-nitro-6-oxopyrimidin-2-yl)-N, N-dimethylformamidine, followed by treatment with DMF-dimethylacetal, reductive cyclisation, treatment with methanolic ammonia and removal of the protecting group by catalytic hydrogenation. Additionally, all seven products were characterized by IR, UV, 1H NMR, 13C NMR and HETCOR spectra with the assignation of the proton and carbon chemical shifts. Methyl 2, 3-O-isopropylidene-5-O-p-toluenesulfonil-β -D-ribofuranoside was synthesized by using, D-ribose as the starting material. The reaction of tosyl sugar with sodium iodide, phthalimide and sodium azide gave corresponding 5-iodo, 5-phthalimido and 5-azido derivatives, and last was reduced to the corresponding amine hydrochloride. Additionally, all six products were characterized by IR, 1H NMR and 13C NMR spectra with the assignation of the proton and carbon chemical shifts. Glycosylation of 2-amino-3-benzyloxymethyl-3H-pyrrolo[3, 2-d]pyrimidin-4(5H)-one, using the sodium salt method, with activated sugar derivative methyl 2, 3-O-isopropylidene-5-O-p-toluenesulfonil-β -D-ribofuranoside gave methyl 5-deoxy-5-(1-benzyloxymethyl-9-deazaguanin-7-yl)-2, 3-O-isopropylidene-β -D-ribofuranoside as the only regiosiomer. The removal of the sugar protecting group in reversed nucleoside gave anomeric mixture of 5-deoxy-5-(1-benzyloxymethyl-9-deazaguanin-7-yl)-D-ribose and full deprotection was achieved by catalytic hydrogenation yielding 5-deoxy-5-(9-deazaguanin-7-yl)-D-ribose. The glycosylation site and the anomeric configuration of these reversed nucleosides were assigned on the basis of spectroscopic studies. These results open new possibilities for preparation of several reversed nucleosides in the 9-deazaguanine series. The reversed nucleosides could be used as starting material for the synthesis of optically active aliphatic nucleoside analogues

PNP inhibitors; synthesis; 9-deazaguanine; “ reversed” nucleosides

Eksperimentalni dio i pisanje magistarskog rada napravljeni su u Laboratoriju za supramolekularnu i nukleozidnu kemiju ( Zavod za Organsku kemiju i biokemiju, Institut Ruđer Bošković)