A series of dideoxyribonucleoside methylphosphonate analogues, dNpN and dNpNp, which contain a nonionic 3'--5' methylphosphonyl internucleoside linkage were prepared. The two diastereoisomers, designated isomers 1 and 2, of each dimer differ in configuration of the methylphosphonate group and were separated by column chromatography. The diastereoisomers of each dimer have different conformations in solution as shown by ultraviolet hypochromicity data and their circular dichroism spectra. For example, dApA isomer 1 is more highly stacked than isomer 2, although both isomers are less stacked than the dinucleoside monophosphate, dApA. The circular dichroism spectrum of isomer 1 is very similar to that of dApA, while the CD spectrum of isomer 2 shows a loss of molecular ellipticity, [theta], at 270 nm and a greatly diminished [theta] at 250 nm. These results suggest that the stacked bases of dApA isomer 1 tend to orient in an oblique manner, while those in isomer 2 tend to orient in a parallel manner. This interpretation is verified by the 1H NMR study of these dimers (L. S. Kan, D. M. Cheng, P. S. Miller, J. Yano, and P. O. P. Ts'o, unpublished experiments). Both diastereoisomers of dAaA form 2U:1A and 2T:1A complexes with poly(U) and poly(dT), respectively. The higher Tm (Tm of poly(U)--isomer 1, 15.4 degrees C; Tm of poly(U)--isomer 2, 19.8 degrees C; Tm of poly(dT)--isomer 1, 18.7 degrees C; Tm of poly(dT)--isomer 2, 18.4 degrees C) values of these complexes vs. those of the corresponding dApA--polynucleotide complexes (Tm of poly(U)--dApA, 7.0 degrees C; Tm of poly(dT)--DApA, 9.2 degrees C) result from decreased charge repulsion between the nonionic dimer backbone and the negatively charged polymer backbone. The difference in conformations between dApA isomer 1 and dApA isomer 2 is reflected in the Tm of the isomer 1-poly(U) complex which is 4.4 degrees C lower than that of the isomer 2-poly(U) complex. Since these nonionic oligonucleotide analogues are taken up by cells in culture, they show promise as molecular probes for the function and structure of nucleic acids inside living cells.
Ten dinucleoside monophosphates containing 8,2'-anhydro-8-mercapto-9-/3-D-arabinofuranosyladenine (As, = 122°), 8,3'-anhydro-8-mercapto-9-/?-D-xylofuranosyladenine (As, = 75°), 8,5'-anhydro-8-mercapto-9-0-D-ribofuranosyladenine (SA, = 42°), and adenosine (A, = 0°) residues were synthesized. They are AspAs, AspAs, AspAs, (2'-5')-and (3'-5')-sApAs, AspA, AspA, ApAs, and sApA. Analyses of these molecules by UV, CD, hybridization with poly(U), and molecular model buildings suggest that (1) AspAs, the homodimer of As, can take a left-handed stacked conformation at low temperature; (2) AspAs and AspAs, the heterodimers of As and As, may take mainly a left-handed stacked conformation, the stability of which is in-between those of AspAs and AspAs; (3) AspA, AspA, and sApA, the dimers containing a S'-linked adenosine and a 3'-linked cycloadenosine residue, take a right-handed stacked conformation; (4) ApAs and ApAs, the dimers containing a S'-linked cycloadenosine and a 3'-linked adenosine residue, take a left-handed stacked conformation; (5) sApAs's may take a conformation other than ordinary stacking. Explanations for these results by considering the least strained arrangement of two nucleoside residues for base stacking in a dimer are described. Factors determining the stability and handedness of a dinucleoside monophosphate are also discussed.We have been studying oligomers containing cyclonucleosides with fixed torsion angles about their glycosidic bonds to elucidate the effect of the glycosidic torsion angle on the conformational properties of oligo-and polynucleotides.2™7 The dinucleoside monophosphate of 8,2'-anhydro-8-mercapto-9-j3-D-arabinofuranosyladenine (8,2'-5'-cycioadenosine, A8),8 AspAs (la), was shown to have a stable, stacked conformation with a left-handed screw axis by UV, CD, and NMR studies.2 The fixed torsion angle ( )9 about the glycosidic bond in a 8,2,-5'-cycloadenosine (II) residue is 122°,10 while the adenosine residue in ApA, which is assumed to have a righthanded stack,11™13 is thought to take an value near 0°.14Homooligonucleotides of As 3 and the dinucleoside monophosphate of 8,2'-0-cycloadenosine, A°pA°4 (lb), also gave CD spectra of similar patterns suggesting left-handed stacking. These oligomers with a left-handed stack did not form a complex with the right-handed helix of poly(U). But the octamer of pAs did form complexes with the octamer of 6,2'anhydro-6-oxy-1 -/3-D-arabinofuranosyluracil 5'-phosphate (6,2'-0-cyclouridine 5'-phosphate, pU°) to give either a double or a triple helix of left-handedness.6 6,2'-0-Cyclouridine15 is the complementary, pyrimidine counterpart of 8,2/-S'-cycloadenosine. The (pAs) § was also shown to form a complex
Für die Synthese von l0 Dinucleosidmonophosphaten (I) werden die Kon‐ ′ densationsmethoden (a) [Darstellung von (Ia)‐(Ic); Ausbeuten 9‐59%] und (b) [Darstellung von (Id) und (Ie); Ausbeuten 36‐63%] angewandt (Kondensationsmittel Dicyclohexylcarbodiimid; übliche Aufarbeitungsmethoden).
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