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.
    No preview · Article · Apr 2006 · Helvetica Chimica Acta
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    ABSTRACT: Triplex-forming oligonucleotides (TFOs) containing 2'-deoxyisoguanosine (2), 7-bromo-7-deaza-2'-deoxyisoguanosine (2) as well as the propynylated 9-deazaguanine N7-(2'-deoxyribonucleoside) were prepared. For this the phosphoramidites 9a, b of the nucleoside 1 and, the phosphoramidites 19, 20 of compound 3b were synthesized. They were employed in solid-phase oligonucleotide synthesis to yield the protected 31-mer oligonucleotides. The deblocking of the allyl-protected oligonucleotides containing 1 was carried out by Pd(0)[PPh3]4-PPh3 followed by 25% aq. NH3. Formation of the 31-mer single-stranded intramolecular triplexes was studied by UV-melting curve analysis. In the single-stranded 31-mer oligonucleotides the protonated dC in the dCH(+)-dG-dC base triad was replaced by 2'-deoxyisoguanosine (1), 7-bromo-7-deaza-2'-deoxyisoguanosine (2) and, 9-deaza-9-propynylguanine N7-(2'-deoxyribonucleoside) (3b). The replacement of protonated dC by compounds 1 and 3b resulted in intramolecular triplexes which are formed pH-independently and are stable under neutral conditions. These triplexes contain "purine" nucleosides in the third pyrimidine rich strand of the oligonucleotide hairpin.
    No preview · Article · Dec 2006 · Organic & Biomolecular Chemistry
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    ABSTRACT: 9-Deazaguanine 9-DG, 1-methyl-9-deazaguanine AG-19-K1 and 1,7-dimethyl-9-deazaguanine AG-3 were synthesized and their antiproliferative activity against five leukemia and four solid tumor cell lines as well as inhibitory properties vs. calf spleen purine nucleoside phosphorylase (PNP) were tested. Synthesis of 9-DG involves reaction of 2-amino-6-methyl-5- nitropyrimidin-4(3H)-one (2) with DMF-dimethylacetal (amount ratio, n(2) / n(DMF-dimethylacetal) = 1:2.5) and use of the benzyloxymethyl group to protect the N-3 position of 2-(N-dimethylaminomethylene) amino-6-methyl-5- nitropyrimidin-4(3H)-one (4). Reaction of 2 with DMF-dimethylacetal (amount ratio, n(2) / n(DMF-dimethylacetal) = 1:6) gave the 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 at a concentration of 75 μmol dm-3. Cytotoxic effects of 9-deazaguanine derivatives on cell growth were determined by the MTT assay. Investigated derivatives showed moderate antiproliferative activity towards examined tumor cells. At a concentration of 10-3 mol dm-3, AG-19-K1 inhibited the growth of JURKAT, K562 and AGS cells by approximately 80 %. At the same concentration, AG-3 and 9-DG inhibited cell proliferation by 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.
    No preview · Article · Jan 2008 · Croatica Chemica Acta
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