engleski

Synthesis of 9-deazaguanine derivatives as potential PNP enzime inhibitors

Purine nucleoside phosphorylase (PNP) is the key enzyme of the purine salvage pathway. It catalyzes the reversible phosphorolysis of purine ribonucleosides and 2 -deoxyribonucleosides to the free base and ribose-1-phosphate or 2 -deoxyribose-1-phosphate. The inhibitors of PNP may be useful in treatment of various autoimmune diseases, other T-cell proliferative disorders and T-cell cancers.[1] Therefore, we designed and synthesized novel pyrrolo[3, 2-d]pyrimidine derivatives (9-deazaguanine) bearing modified sugar units at N-7 I and different substituents at C-9 II positions of the 9-deazaguanine system expecting inhibition activity and biological answers. There are only very few routes to the pyrrolo[3, 2-d]-pyrimidine ring system, and the most commonly used approach starts from pyrimidines with appropriate functional groups at C-5 and C-6 positions to allow formation of the pyrrole ring. Following this procedures with some modifications we prepared 9-deazaguanine 1 as well as its 9-iodo derivative 2 and 2, 6-dichloro-9-deazapurine 3. For the preparation of N-7 substituted 9-deazaguanine derivatives I, we explored the condensation of nucleobase anion with 5-tosyl protected ribose derivative as a chiral starting material. Mannich reaction is used for preparation of C-9 substituted derivatives II that incorporate a 9-deazaguanine or a 2, 6-dichloro-9-deazapurine linked via a methylene group to a sugar substituted amine or aliphatic amine. All products were characterized by IR, UV, 1H and 13C NMR spectra. [1] Bzowska, A., Kulikowska, E., Shugar, D., Pharmacol. Ther. 88 (2000) 349.

Purine nucleoside phosphorylase; pyrrolo[3; 2-d]pyrimidine; 2; 6-dichloro-9-deazapurine; N-7-(9-deazaguanine) derivatives

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