Solid‐Phase Synthesis of (Poly)phosphorylated Nucleosides and Conjugates

Tonn, Viktoria Caroline; Meier, Chris

doi:10.1002/chem.201101291

Cited by 34 publications

(28 citation statements)

References 36 publications

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“…Here, we report the synthesis of C8‐ N ‐acetyl‐ and C8‐ N H‐arylamine‐modified 2′‐deoxyguanosine‐5′‐triphosphates. The triphosphorylated adducts were synthesized by using cyclo Sal technology, which has been used successfully for the synthesis of various phosphorylated biomolecules . Conformation data on the C8‐ N ‐arylamine‐modified 2′‐deoxyguanosine‐5′‐triphosphates were collected by NOE spectroscopy and compared with DFT data.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

2015

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C8-N-arylamine adducts of 2'-deoxyguanosine (2'-dG) play an important role in the induction of the chemical carcinogenesis caused by aromatic amines. C8-N-acetyl-N-arylamine dG adducts that differ in their substitution pattern in the aniline moiety were converted by cycloSal technology into the corresponding C8-N-acetyl-N-arylamine-2'-deoxyguanosine-5'-triphosphates and C8-NH-arylamine-2'-deoxyguanosine-5'-triphosphates. Their conformation preference has been investigated by NOE spectroscopy and DFT calculations. The substrate properties of the C8-dG adducts were studied in primer-extension assays by using Klenow fragment exo(-) of Escherichia coli DNA polymerase I and human DNA polymerase β. It was shown that the incorporation was independent of the substitution pattern in the aryl moiety and the N-acetyl group. Although the triphosphates were poor substrates for the human polymerases, they were incorporated twice before the termination of the elongation process occurred; this might demonstrate the importance of C8-N-arylamine-2'-deoxyguanosine-5'-triphosphates in chemical carcinogenesis.

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Section: Methodsmentioning

confidence: 99%

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

2015

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“…Mainly, the Ludwig method is used. [7][8][9][10][11][12][13] With this method the synthesis of nucleoside-5Ј-triphosphates (both natural and non-natural compounds) was accomplished in yields of up to 80 % starting from the cycloSal-compound (64 % starting from the nucleoside). This might explain the low yields that were obtained by this method.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pyranonucleoside‐6′‐triphosphates through the cycloSal‐Method

Huchting

Meier

2014

Eur J Org Chem

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The high yielding synthesis of pyranonucleoside‐6′‐triphosphates by using the cycloSal‐method is described. Synthesis of the activated cycloSal‐pyranonucleoside‐6′‐phosphate triesters was achieved by applying a synthetic route that had been developed for the synthesis of cycloSal‐(glycopyranosyl‐6)‐phosphates by us. The route involved regioselective 6′‐tert‐butyldimethylsilyl protection and exchange of the silyl protecting group by the fluorenylmethyloxycarbonyl (Fmoc) group. The 6′‐Fmoc‐protected derivatives were selectively converted into the cycloSal‐triester. These were then very efficiently converted into triphosphates by a “titration‐like” reaction with pyrophosphate. Simple purification by first ion exchange followed by reversed phase (RP) column chromatography afforded the triphosphates in very good yields.

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“…This approach applied cleavage conditions using trifluoroacetic acid (TFA) and ammonium formate, which resulted in poor yields of the nucleoside derivatives 5 . In a separate study, Caroline et al reported the synthesis of solid phase poly-phosphorylated nucleoside analogues with decent yields and mild cleaving conditions, but extremely slow reaction times 6 . Therefore, we have explored microwave assisted solid phase nucleoside synthesis in order to optimize reaction conditions and to create a platform to perform combinatorial chemistry on solid phase nucleosides.…”

Section: Introductionmentioning

confidence: 99%

Efficient microwave-assisted solid phase coupling of nucleosides, small library generation, and mild conditions for release of nucleoside derivatives

Paritala

Suzuki

Carroll

2013

Tetrahedron Letters

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Nucleosides are essential bio-molecules that participate in a wide array of biological processes involved in maintaining physiologic homeostasis. Recent efforts geared towards the synthesis of nucleoside analogues and development of nucleoside combinatorial libraries using solid phase synthesis has contributed invaluable information towards drug design and development. These studies have provided information concerning the structural requirements of substrate binding pockets of enzymes and evaluation of enzyme kinetics. However, the synthesis of nucleosides and its corresponding analogues remains a challenging and time consuming process. Herein, we report an efficient, microwave assisted solid phase coupling of nucleosides, combinatorial chemistry on the coupled nucleosides to generate small library and mild cleavage conditions to release nucleoside derivatives from its solid support. We anticipate these findings will accelerate the development of synthetic methods or combinatorial library design of nucleoside analogues in similar settings.

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Solid‐Phase Synthesis of (Poly)phosphorylated Nucleosides and Conjugates

Cited by 34 publications

References 36 publications

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

Synthesis of C8‐N‐Arylamine‐Modified 2′‐Deoxyguanosine‐5′‐Triphosphates and Their Effects on Primer Extension by DNA Polymerases

Synthesis of Pyranonucleoside‐6′‐triphosphates through the cycloSal‐Method

Efficient microwave-assisted solid phase coupling of nucleosides, small library generation, and mild conditions for release of nucleoside derivatives

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