Synthesis of bridged dinucleosides

Agathocleous, D. C.; Page, Philip C. Bulman; Cosstick, Richard; Galpin, I.J.; McLennan, Alexander G.; Prescott, Mark

doi:10.1016/s0040-4020(01)89771-4

Cited by 12 publications

(10 citation statements)

References 20 publications

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“…[3] We wanted to explore the opportunity of introducing several cholesterol units to knockdown probes by utilizing the handle of amino-LNA. In order to have the effect of the cholesterol unit this was introduced to the amino-LNA via a C6 linker (Figure 1).The known nucleoside 1 [2] (Scheme 1) was alkylated with phtalimidohexanal [4] in the presence of NaCNBH 3 to nucleoside 2 in 51% yield. Nucleoside 3 was obtained by protection of the primary hydroxy group with a DMT group using DMTCl in pyridine in 56% yield.…”

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confidence: 99%

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At Tachment of Cholesterol to Amino-LNA: Synthesis and Hybridization Properties

Bryld¹,

Lomholt²

2007

Nucleosides, Nucleotides and Nucleic Acids

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“…The known nucleoside 1 [2] (Scheme 1) was alkylated with phtalimidohexanal [4] in the presence of NaCNBH 3 to nucleoside 2 in 51% yield. Nucleoside 3 was obtained by protection of the primary hydroxy group with a DMT group using DMTCl in pyridine in 56% yield.…”

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confidence: 99%

At Tachment of Cholesterol to Amino-LNA: Synthesis and Hybridization Properties

Bryld¹,

Lomholt²

2007

Nucleosides, Nucleotides and Nucleic Acids

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“…W-Alkyladenosines, bis(adenosin-ZP-yl)alkanes, bisadenosin-P-yl)dodec-6-ene, bis(adenosin-ZP-y1)dodecane 5',5'"-bisphosphate and bis(cytidin-N4-y1)alkanes were synthesized as previously described [31,321. Stock solutions (50 mM) of these nucleosides were prepared in dimethylsulphoxide (Me,SO) and stored at -20°C.…”

Section: Chemicalsmentioning

confidence: 99%

“…7a). This product was tentatively identified as the 5',5"'-bismonophosphate, pA[CH,],,Ap, by comparison with the elution profile of authentic, synthetic pA[CH,],,Ap prepared as previously described [31]. Thus, the 5'-monophosphate, pA[CH,] ,,A, does not appear to be released by the enzyme as an intermediate product, since no other peaks were seen on the chromatogram, in agreement with our previous findings [32].…”

Section: Binding Of Analogues To Adenosine Receptorsmentioning

confidence: 99%

“…A longer alkyl chain with at least 7-8 methylene groups would be required to permit this. Therefore, we have synthesized a series of bisadenosin-P-y1)alkanes (A[CH,],A), in which two Ado molecules are linked via the two N6 amino groups by aliphatic alkyl linkers comprising 2-4 methylene units with the intention that they would act as nucleoside precursors to Ap4A analogues, having two Ado moieties linked to one another, and they would cross the cell membrane, being hydrophobic and uncharged [31]. These compounds have already been shown to be potent inhibitors of Ado kinase [32].…”

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The bis(adenosin‐N⁶‐yl)alkanes, a family of potential dinucleoside‐polyphosphate analogue precursors

Chen

McLennan

1993

European Journal of Biochemistry

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A series of bis(adenosin-W-yl)alkanes, in which two adenosine residues are linked via their N" positions by alkyl bridges comprising between 2 and 14 methylene units, were synthesized as potential precursors to dinucleoside-polyphosphate analogues. These compounds were moderately cytotoxic to mammalian cells, the toxicity increasing with the length of the alkyl chain. For example, the dose of bis(adenosin-iV-yl)dodecane, A[CH,],,A, leading to 50% inhibition of cell growth (ID,,) for BHK fibroblasts, Walker 256 carcinoma cells and S-49 T-lymphoma cells were 90 ? 8, 100 ? 5 and 23 -t 4 pM respectively. A significant amount of A[CH2Il2A bound to serum albumin in the growth media: thus the ID,, for S-49 cells grown in serum-free medium was 9 t 2 pM. The corresponding bis-cytidine analogues were much less toxic ; however the presence of a second adenosine moeityimolecule had little significant effect on cell growth when compared to N6-alkyladenosines. Toxicity to S-49 cells was unaffected by the nucleoside-transporter inhibitor nitrobenzylthioinosine and was even higher (ID5, = 5 & 0.5 pM) towards nucleoside-transport-deficient AE-1 cells, showing that the analogues could pass freely through the plasma membrane. Interaction with A, adenosine receptors was shown by displacement of [3H]iV-R-phenylisopropyladenosine (Kd = 6 nM) from rat adipocyte membranes, with Ki values of 45, 65, 85 and 390 nM for the compounds containing 12, 8, 6 and 4 methylene units, respectively. Affinity for human platelet membrane A, adenosine receptors was about 100-fold less, however the compounds were weak A, agonists, producing up to a threefold increase in intracellular cyclic AMP in WI-38NA-13 cells. Thus, these compounds behave, not surprisingly, as adenosine analogues. In addition, A[CH,],,A was metabolized in vitro and intracellularly by adenosine kinase (Ki = 70 nM) and adenylate kinase to yield a number of phosphorylated derivatives with the potential to act as diadenosine polyphosphate analogues. One of these, the bismonophosphate, was recognized by and inhibited adenylate kinase more effectively than adenosine(5')tetraphospho(5')adenosine (Ap4A, Ki = 3 pM).

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