Base‐Pairing Systems Related to TNA Containing Phosphoramidate Linkages: Synthesis of Building Blocks and Pairing Properties

Ferencic, Mathias; Reddy, G.R.; Wu, Xiaolin; Guntha, Sreenivasulu; Nandy, Jyoti Prokash; Krishnamurthy, Ramanarayanan; Eschenmoser, Albert

doi:10.1002/cbdv.200490083

Cited by 15 publications

(17 citation statements)

References 48 publications

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“…Several oligonucleotides with one or three modified acyclic building blocks were synthesized with these phosphoramidites. In addition, the protocols developed for NH–TNA10 were used, and a modified version of the phosphoramidite method described by Gryaznov for their analogues was taken into account 11. The oligomers were isolated after ion‐exchange chromatography and gel filtration.…”

Section: Resultsmentioning

confidence: 99%

New Insight into Marine Alkaloid Metabolic Pathways: Revisiting Oroidin Biosynthesis

Genta‐Jouve

Cachet

Holderith³

et al. 2011

ChemBioChem

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Section: Resultsmentioning

confidence: 99%

New Insight into Marine Alkaloid Metabolic Pathways: Revisiting Oroidin Biosynthesis

Genta‐Jouve

Cachet

Holderith³

et al. 2011

ChemBioChem

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“…34 We first sought to develop a direct route for the synthesis of the guanine 2′-NH 2 -TNA nucleoside ( 8g ). We based our synthesis on a [4 + 2] cycloaddition reaction between an azodicarboxylate and glycal that was previously developed to synthesize trans 2-amino, 3-hydroxyl carbohydates 38−40 due to its high efficiency and stereo- and regioselectivities.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Nonenzymatic Template-Directed Polymerization of 2′-Amino-2′-deoxythreose Nucleotides

2014

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Threose nucleic acid (TNA) is a potential alternative genetic material that may have played a role in the early evolution of life. We have developed a novel synthesis of 2′-amino modified TNA nucleosides (2′-NH2-TNA) based on a cycloaddition reaction between a glycal and an azodicarboxylate, followed by direct nucleosidation of the cycloadduct. Using this route, we synthesized the thymine and guanine 2′-NH2-TNA nucleosides in seven steps with 24% and 12% overall yield, respectively. We then phosphorylated the guanine nucleoside on the 3′-hydroxyl, activated the phosphate as the 2-methylimidazolide, and tested the ability of the activated nucleotide to copy C4 RNA, DNA, and TNA templates by nonenzymatic primer extension. We measured pseudo-first-order rate constants for the first nucleotide addition step of 1.5, 0.97, and 0.57 h–1 on RNA, DNA, and TNA templates, respectively, at pH 7.5 and 4 °C with 150 mM NaCl, 100 mM N-(hydroxylethyl)imidazole catalyst, and 5 mM activated nucleotide. The activated nucleotide hydrolyzed with a rate constant of 0.39 h–1, causing the polymerization reaction to stall before complete template copying could be achieved. These extension rates are more than 1 order of magnitude slower than those for amino-sugar ribonucleotides under the same conditions, and copying of the TNA template, which best represented a true self-copying reaction, was the slowest of all. The poor kinetics of 2′-NH2-TNA template copying could give insight into why TNA was ultimately not used as a genetic material by biological systems.

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“…N2′→P3′-TNA has been synthesized by the Eschenmoser laboratory and is known to be a Watson−Crick base-pairing system. ( 38 ) It is conformationally constrained relative to N2′→P5′-DNA because there is one less rotatable bond per backbone repeat unit. A second alternative is the morpholino nucleic acid system, which is conformationally constrained in a very different way, due to the presence of a six-membered ring in the backbone repeat unit.…”

Section: Discussionmentioning

confidence: 99%

Efficient and Rapid Template-Directed Nucleic Acid Copying Using 2′-Amino-2′,3′-dideoxyribonucleoside−5′-Phosphorimidazolide Monomers

et al. 2009

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The development of a sequence-general nucleic acid copying system is an essential step in the assembly of a synthetic protocell, an autonomously replicating spatially localized chemical system capable of spontaneous Darwinian evolution. Previously described nonenzymatic template-copying experiments have validated the concept of nonenzymatic replication, but have not yet achieved robust, sequence-general polynucleotide replication. The 5′-phosphorimidazolides of the 2′-amino-2′,3′-dideoxyribonucleotides are attractive as potential monomers for such a system because they polymerize by forming 2′→5′ linkages, which are favored in nonenzymatic polymerization reactions using similarly activated ribonucleotides on RNA templates. Furthermore, the 5′-activated 2′-amino nucleotides do not cyclize. We recently described the rapid and efficient nonenzymatic copying of a DNA homopolymer template (dC15) encapsulated within fatty acid vesicles using 2′-amino-2′,3′-dideoxyguanosine−5′-phosphorimidazolide as the activated monomer. However, to realize a true Darwinian system, the template-copying chemistry must be able to copy most sequences and their complements to allow for the transmission of information from generation to generation. Here, we describe the copying of a series of nucleic acid templates using 2′-amino-2′,3′-dideoxynucleotide−5′-phosphorimidazolides. Polymerization reactions proceed rapidly to completion on short homopolymer RNA and LNA templates, which favor an A-type duplex geometry. We show that more efficiently copied sequences are generated by replacing the adenine nucleobase with diaminopurine, and uracil with C5-(1-propynyl)uracil. Finally, we explore the copying of longer, mixed-sequence RNA templates to assess the sequence-general copying ability of 2′-amino-2′,3′-dideoxynucleoside−5′-phosphorimidazolides. Our results are a significant step forward in the realization of a self-replicating genetic polymer compatible with protocell template copying and suggest that N2′→P5′-phosphoramidate DNA may have the potential to function as a self-replicating system.

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Base‐Pairing Systems Related to TNA Containing Phosphoramidate Linkages: Synthesis of Building Blocks and Pairing Properties

Cited by 15 publications

References 48 publications

New Insight into Marine Alkaloid Metabolic Pathways: Revisiting Oroidin Biosynthesis

New Insight into Marine Alkaloid Metabolic Pathways: Revisiting Oroidin Biosynthesis

Synthesis and Nonenzymatic Template-Directed Polymerization of 2′-Amino-2′-deoxythreose Nucleotides

Efficient and Rapid Template-Directed Nucleic Acid Copying Using 2′-Amino-2′,3′-dideoxyribonucleoside−5′-Phosphorimidazolide Monomers

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