Die ungewohnlichen Eigenschaften dieser bisher synthetisierten 2'-Desoxynucleoside haben uns veranlaot, einerseits weitere bisher unbekannte Vertreter dieser Verbindungsklasse zu synthetisieren und andererseits Nebenreaktionen der Phasentransferglycosylierung zu untersuchen, die sich ungunstig auf die Reaktionsausbeute auswirken. Ziel dieser Untersuchung ist die Synthese des bisher unbekannten 2-Amino-2'-desoxytubercidins (l), dessen Purin-Stammverbindung 2-Amino-2'-desoxyadenosin als Baustein viraler DNA nachgewiesen wurde''). In diesem Zusammenhang galt es, die Glycosylierung von solchen Aglyconen naher zu untersuchen, deren 2'-Desoxyribofuranoside sich spater problemlos in 2'-Amino-2'-desoxytubercidin (1) umwandeln lassen.Unlangst zeigten wir, daR die Dichlorverbindung 4b in 88% Ausbeute mit der Halogenose 7 regioselektiv glycosyliert werden kann"). Die Reaktion erfolgte hier in DMF rnit NaH als Base, wobei ein Gemisch der Anomeren (53% P, 35% a) erhalten wurde.Etwa gleichzeitig wurde die Reaktion von Robins'*) durchgefiihrt, der statt DMF Acetonitril verwandte. In diesem Fall konnte nur das P-Nucleosid nachgewiesen werden (60% Ausbeute). Diese Befunde legen nahe, da13 die Reaktion in Acetonitril einem SN2-Mechanismus folgt, wahrend in DMF, das ionische Zwischenstufen besser zu stabilisieren vermag, die Reaktion teilweise nach SN1 ab18Uft. Da wir schon friiher beobachtet hatten, dal3 die Phasentransferglycosylierung einem SN2-Mechanismus folgt, wenn man Dichlormethan als organische Phase verwendet und die Konzentration des Phasentransferkatalysators niedrig halt 4), wurde 4 b mit der Halogenose 7 im zweiphasigen System Dichlormethan/SOproz. Natronlauge in Gegenwart %Amho-Xdeoxytahs&h aod
The synthesis of alternating hexamers (8-13) derived from d(C-G)3 or d(G-C)3 but containing c7z8Gd (2) or c7Gd (3) instead of dG is described employing phosphoramidite-chemistry. Apart from the isobutyryl group the dimethylaminomethylene residue was used for the nucleobase-protection of 3. The methyl- and the cyanoethyl-phosphoramidites of 3 (5a-c) were synthesized. They were employed together with those of c7G or c7z8Gd in automated oligonucleotide synthesis. Tm-values as well as thermodynamic data of the oligomers 9, 10, 12, and 13 indicated that duplexes were destabilized if c7Gd replaced dG, whereas c7z8Gd stabilized the duplex structure. In contrast to d(C-G)3 which underwent salt-dependent B-Z transition, CD-spectra of oligomers containing c7Gd or c7z8Gd in place of dG showed retained B-conformation.
The synthesis of the O-3'-phosphoramidite of a suitably protected 7-deaza-2'-deoxyguanosine (c7G) which is an isostere of 2'-deoxyguanosine is described. The phosphoramidite of the modified nucleoside was used in the synthesis of the self-complementary hexamer d(c7GpCpc7GpCpc7GpC) on functionalized silica gel in a mini-reactor. As expected from the parent hexamer d(GpCpGpCpGpC) the isosteric d(c7GpCpc7GpCpc7GpC) exhibits a rigid secondary structure (22% hypochromicity at 280 nm) and forms a duplex in 1 M aqueous sodium chloride solution. Due to the altered pi-electron system of the pyrrolo[2,3-d]pyrimidine nucleobase, which affects base stacking and hydrogen bonding, the Tm of the modified duplex is decreased by 10 degrees C compared to that of the parent purine hexamer. Moreover, it is expected that the incorporation of c7G influences the pitch of the helix.
Due to the reactivity of the chromophore halogens removal of the toluoyl residues by sodium methoxide resulted in rapid displacement of the chloro substituents which prevented the isolation of the free deoxyriboside of 3b and led to the 2,4-dimethoxynucleoside 7. As shown by the conversion of 5a into 2, regioselective displacement of the halogen in position 4 can be accomplished under conditions which maintain the protecting groups of the sugar moiety.In einer von uns unlangst durchgefuhrten Untersuchung konnten wir zeigen, daB 2,CDichlor-7H-pyrrolo[2,3-d]pyrimidin (3 b) in guter Ausbeute regioselektiv an N-7 mit l-Brom-2,3,5-tri-Obenzylarabinofuranose glycosyliert werden kann. Das dabei entstehende Arabinonucleosid besitzt ein hohes Potential fur die Synthese von Nucleosiden'). Im folgenden versuchen wir den Chromophor 3b auch fur die Darstellung von P-~-2'-Desoxynucleosiden, hier speziell fur die Synthese von 7-Desaza-2'-desoxyxanthosin (1 a) und 7-Desaza-2'-desoxyspongosin (2) einzusetzen.Die Purin-Stammnucleoside von 1 a und 2 sind seit langerem bekannt. 2'-Desoxy-2-methoxyadenosin2) wurde von Broom et. al. 3, aus einem 2,4-Dichlorpurin-P-~-2'-desoxyribosid durch selektiven Halogenaustausch erhalten, wahrend 2'-Desoxyxanthosin enzymatisch mittels Purinnucleosid-Phophorylase aus Xanthin und Desoxyrib~se-l-phosphat~~~) hergestellt wurde.
(11) but containing 8-aza-7-deaza-2'-deoxyguanosine (2) instead of 2'-deoxyguanosine (I) have been prepared by solid-phase synthesis employing P(II1) chemistry. Isobutyrylation of 2, followed by 4,4'-dimethoxytritylation and subsequent phosphitylation yielded the methyl or the cyanoethyl phosphoramidites 6a or 6b, respectively. They were used as building blocks in automated DNA synthesis. The resulting octanucleotides 12-14 containing 2 showed increased T, values compared to the parent oligomer 11. The oligomers 11-14 were employed as sequence-specific probes in endodeoxyribonuclease Eco R1 oligonucleotide recognition. Whereas displacement of dG-2 (enzymic cleavage site of 11) abolished phosphodiester hydrolysis, replacement of dG-1 enhanced the cleavage rate compared to 11.Introduction. -Recently, 8-aza-7-deaza-2'-deoxyguanosine (z8c7Gd; 2) has been synthesized by phase-transfer glycosylation [l] [2] and was later converted into the 2',3'-dideoxyribofuranoside [2]'). As compound 2 represents one of the most closest structural analoga of the DNA constituent 2-deoxyguanosine (dG; l), being still capable to form Watson-Crick base pairs, we decided to synthesize phosphoramidites of 2, which are applicable in automated DNA synthesis machines.Due to the altered electronic state of 2 compared to that of 2'-deoxyguanosine (l), changes in the reactivities of nucleobase-protecting groups have to be considered. Kinetic data of base-catalyzed hydrolysis of acyl-or amidine-protected 2 were determined in order to select the most appropriate protecting group. Then, protection of the 5'-OH of the sugar moiety allowed phosphoramidite synthesis by established procedures Combining the resulting phosphoramidites 6a or 6b with regular phosphoramidites, oligonucleotides are accessable with compound 2 at any position of incorporation.Here we present the synthesis of octanucleotides derived from d(G1 -G2-A-A-T-T-C-C)') (11) containing the recognition sequence of the endodeoxyribonuclease Eko RI [6]. We have chosen these oligomers as 11 forms duplexes under appropriate salt condition and is regioselectively hydrolyzed by the endonuclease [7]. As the phosphodiester bond is cleaved between dG and dA, it is of interest whether the enzyme accepts compound 2 as a substitute of dG-1 or dG-2 within an oligomer. Earlier studies have considered the N7 and O6 atoms of dG-2 within 11 as the most probable
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