Synthesis of 9‐Halogenated 9‐Deazaguanine N7‐(2′‐Deoxyribonucleosides)

Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie, Universität Osnabrück, Barbarastrasse 7, D-49069 Osnabrück and Center for Nanotechnology (CeNTech), Gievenbecker Weg 11, D-48149 Münster (phone: +49-(0)541-969-2791
Helvetica Chimica Acta (Impact Factor: 1.14). 09/2004; 87(10):2507 - 2516. DOI: 10.1002/hlca.200490224


The syntheses of N7-glycosylated 9-deazaguanine 1a as well as of its 9-bromo and 9-iodo derivatives 1b,c are described. The regioselective 9-halogenation with N-bromosuccinimide (NBS) and N-iodosuccinimide (NIS) was accomplished at the protected nucleobase 4a (2-{[(dimethylamino)methylidene]amino}-3,5-dihydro-3-[(pivaloyloxy)methyl]-4H-pyrrolo[3,2-d]pyrimidin-4-one). Nucleobase-anion glycosylation of 4a–c with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (5) furnished the fully protected intermediates 6a–c (Scheme 2). They were deprotected with 0.01M NaOMe yielding the sugar-deprotected derivatives 8a–c (Scheme 3). At higher concentrations (0.1M NaOMe), also the pivaloyloxymethyl group was removed to give 7a–c, while conc. aq. NH3 solution furnished the nucleosides 1a–c. In D2O, the sugar conformation was always biased towards S (67–61%).

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    ABSTRACT: Triplex-forming oligonucleotides (TFOs) containing 9-deazaguanine N7-(2′-deoxyribonucleoside) 1a and halogenated derivatives 1b,c were synthesized employing solid-phase oligonucleotide synthesis. For that purpose, the phosphoramidite building blocks 5a–c and 8a–c were synthesized. Multiple incorporations of 1a–c in place of dC were performed within TFOs, which involved the sequence of five consecutive 1a–c ⋅ dG ⋅ dC triplets as well as of three alternating 1a–c ⋅ dG ⋅ dC and dT ⋅ dA ⋅ dT triplets. These TFOs were designed to bind in a parallel orientation to the target duplex. Triplex forming properties of these oligonucleotides containing 1a–c in the presence of Na+ and Mg2+ were studied by UV/melting-curve analysis and confirmed by circular-dichroism (CD) spectroscopy. The oligonucleotides containing 1a in the place of dC formed stable triplexes at physiological pH in the case of sequence of five consecutive 1a ⋅ dG ⋅ dC triplets as well as three alternating 1a–c ⋅ dG ⋅ dC and dT ⋅ dA ⋅ dT triplets. The replacement of 1a by 9-halogenated derivatives 1b,c further enhanced the stability of DNA triplexes. Nucleosides 1a–c also stabilized duplex DNA.
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