Oligonucleosides with a nucleobase-including backbone; synthesis and self-association of novel dinucleotide analogues

Matthews, Andrew John; Bhardwaj, Punit Kumar; Vasella, Andrea

doi:10.1039/b300932g

Chem. Commun.

2003

DOI: 10.1039/b300932g

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Oligonucleosides with a nucleobase-including backbone; synthesis and self-association of novel dinucleotide analogues

Andrew John Matthews

Punit Kumar Bhardwaj

Andrea Vasella

Abstract: The synthesis and self-association of protected oxymethylene-bridged UA analogues are described.

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Cited by 10 publications

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“…The energy difference between conformers with k ¼ 90 and 1808 appears to be small, as shown experimentally and computationally for benzyl methyl ether [9] and computationally for benzyl methyl thioether [10]. 6 ) There are three rather than four diastereoisomers on account of the symmetry resulting from the self-complementary nature of the dimers. Note that the notation A refers to the monoplex and A to the cyclic duplex.…”

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Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

Ritter

Egli

Bernet

et al. 2008

Helvetica Chimica Acta

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The formation of cyclic duplexes (pairing) of known oxymethylene‐linked self‐complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene‐linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson–Crick, reverse Watson–Crick, Hoogsteen, or reverse Hoogsteen H‐bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg‐conformation about the C(4′)C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt‐conformation about this bond. The temperature dependence of the chemical shift of HN(3) of the self‐complementary, oxymethylene‐linked U*[o]A(*) dinucleosides 1–6 in CDCl3 in the concentration range of 0.4–50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3, between the monoplex and cyclic duplexes for 6, and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4, and 5. The self‐complementary, thiomethylene‐linked U*[s]A(*) dinucleosides 27–32 and the sequence isomeric A*[s]U(*) analogues 33–38 were prepared by S‐alkylation of the 6‐(mesyloxymethyl)uridine 12 and the 8‐(bromomethyl)adenosine 22. The required thiolates were prepared in situ from the C(5′)‐acetylthio derivatives 9, 15, 19, and 25. The association in CHCl3 of the thiomethylene‐linked dinucleoside analogues was studied by 1H‐NMR and CD spectroscopy, and by vapour‐pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30, and 31 form cyclic duplexes connected by Watson–Crick H‐bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H‐bonds, and the resulting ribbons are cross‐linked by H‐bonds between HOCH2C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)‐hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34–36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature‐dependent CD spectra of 28, 30, 31, and 37 evidence π‐stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°.

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Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

Ritter

Egli

Bernet

et al. 2008

Helvetica Chimica Acta

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“…-Oligonucleotide analogues integrating backbone and bases (ONIBs) replace the backbone of nucleic acids by linking elements between adjacent nucleobases. ONIBs form cyclic duplexes and/or linear associates, as shown by analysing the association in CDCl 3 of partially protected, self-complementary ethynylene- [1], ethenylene- [2], ethylene- [3], oxymethylene- [4] [5], and thiomethylene-linked [6] dinucleosides of the type U*[x]A ( * )1 )) and A*[x]U ( * ) . The formation of cyclic duplexes (i.e., pairing) of partially protected, self-complementary dinucleoside analogues in CDCl 3 depends on the conformation of the linker, the orientation of the nucleobase of unit I, the sequence of nucleobases, and the conformation of the ribofuranose ring.…”

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“…-Conformational Analysis and Molecular Modelling. The pairing propensity of ethylene- [3], oxymethylene- [4] [5], and thiomethylene-linked [6] self-complementary U*[x]A ( * ) and A*[x]U ( * ) dinucleosides was analysed by evaluating the relative energy of the conformers of the diastereoisomeric constitutional isomers resulting from pairing. The analysis showed that oxymethylene-and thiomethylene-linked dinucleosides undergo pairing, but that the duplexes adopt a different conformation.…”

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confidence: 99%

“…The analysis showed that oxymethylene-and thiomethylene-linked dinucleosides undergo pairing, but that the duplexes adopt a different conformation. While the cyclic duplexes of oxymethylene-linked U*[o]A ( * ) dinucleosides adopt a gg-conformation of the linker [4] [5], those of thiomethylenelinked U*[s]A ( * ) and A*[s]U ( * ) dinucleosides adopt a gt-conformation [6]. The greater similarity of N to O rather than to S in terms of electronegativity and bond length suggests that aminomethylene-linked dinucleoside duplexes should adopt a ggconformation.…”

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Oligonucleotide Analogues with Integrated Bases and Backbones. Part 24

Chiesa

Shvoryna

Bernet

et al. 2010

Helvetica Chimica Acta

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Inspection of Maruzen models and force-field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self-complementary adenosine-and uridinederived aminomethylene-linked A*[n]U dinucleosides 15 -17 were prepared by an aza-Wittig reaction of the aldehyde 10 with an iminophosphorane derived from azide 6. The sequence-isomeric U*[n]A dinucleosides 18 -20 were similarly prepared from aldehyde 3 and azide 12. The N-ethylamine 5, the acetamides 7 and 14, and the amine 13 were prepared as references for the conformational analysis of the dinucleosides. In contradistinction to the results of calculations, the N-ethylamine 5 exists as intramolecularly H-bonded hydroxyimino tautomer. The association in CDCl 3 of these dinucleosides was studied by 1 H-NMR and CD spectroscopy. The A*[n]U dinucleosides 16 and 17 associate more strongly than the sequence isomers 19 and 20; the cyclic duplexes of 16 form preferentially Watson -Crick-type base pairs, while 17, 19, and 20 show both Watson -Crick-and Hoogsteen-type base pairing. The cyclic duplexes of the aminomethylene-linked dinucleosides prefer a gg-orientation of the linker. No evidence was found for an intramolecular H-bond of the aminomethylene group. The CD spectra of 16 and 17 show a strong, those of 19 a weak, and those of 20 almost no temperature dependence.Helvetica Chimica Acta -Vol. 93 (2010) 668 2010 Verlag Helvetica Chimica Acta AG, Zürich 1 ) Conventions for abbreviated notation: The substitution at C(6) of pyrimidines and C(8) of purines is denoted by an asterisk (*); for example, A* and U* for thiomethylated adenosine and uridine derivatives, respectively. The moiety x linking C(6)ÀCH 2 or C(8)ÀCH 2 of unit II and C(5') of unit I is indicated in square brackets, i.e., [c] for a C-, [o] for a O-, [n] for a N-, and [s] for a S-atom.

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