Dinucleoside phosphate

Utilizing method B, mixed anhydrides of a dinucleoside phosphate and methylsul-fonic or trifluoroacetic acid could be prepared 2043... 

Several complexes that involve intercalation of an acridine in a portion of a nucleic acid have been studied by X-ray crystallographic techniques. These include complexes of dinucleoside phosphates with ethidium bromide, 9-aminoacridine, acridine orange, proflavine and ellipticine (65-69). A representation of the geometry of an intercalated proflavine molecule is illustrated in Figure 6 (b) this is a view of the crystal structure of proflavine intercalated in a dinucleoside phosphate, cytidylyl- -S ) guano-sine (CpG) (70, TV). For comparison an example of the situation before such intercalation is also illustrated in Figure 6 (a) by three adjacent base pairs found in the crystal structure of a polynucleotide (72, 73). In this latter structure the vertical distance (parallel to the helix axis) between the bases is approximately... 

Figure 30. Schematic diagrams of overlap of ring systems in (a) the alkylated nucleoside described here, (b) daunomycin intercalated in a hexanucleotide (143), (c) proflavine intercalated in a dinucleoside phosphate (70), Td) a model of a diol epoxide of DMBA semi-intercalated in a manner analogous to that in (a) so that N2 of guanine may be alkylated, (e) a model of a diol epoxide of DMBA semi-intercalated in a manner analogous to that in (c) so that 06 of guanine may be alkylated.

Diester methods have been used to synthesize analogues of the initiator codon ApUpG in which the adenine residue has a fixed torsion angle, as for instance in (78),132 and triester methods have been used to prepare dinucleoside phosphates and codon analogues133 134 containing the hydroxyalkyl nucleosides 9-(4 -hydroxybutyl)-adenine (80), 9-(3 -hydroxypropyl)adenine (81), and 1 -(3 -hydroxypropyl)uracil (82), with a view to determining the effect of the achiral residues on the c.d. spectra. 

Electron attachment to dinucleoside phosphates leads to the formation of radical ions in which the electron has added to the more easily reduced heterocyclic base.35... 

The e.s.r. spectra of y-irradiated diethyl phosphate and its salts have been studied111 and the structures of the phosphonates(89)112 and some nucleoside phosphates113 have been studied from the e.s.r. spectra of the nitroxide spin-labelled compounds. An e.s.r. study of electron transfer in dinucleoside phosphate anions indicates preferen-... 

Schott H et al. Synthesis, characterization, and some properties of amphiphilic dinucleoside phosphate derivatives of 3 -azido-2, 3 -dideoxythymidine (AZT). Antivir Chem Chemother 1994 5 387. 

Schwendener RA, et al. New lipophilic acyl/alkyl dinucleoside phosphates as derivatives of 3 -azido-3 -deoxythymidine Inhibition of HIV-1 replication in vitro and antiviral activity against Rauscher leukemia virus infected mice with delayed treatment regimens. Antivir Res 1994 24 79. 

Peghini PA, et al. In vitro inhibition of hepatitis B vims replication and pharmacokinetic properties of new lipophilic dinucleoside phosphate derivatives. Antivir Chem Chemother 1998 9 95. 

Schott H, et al. Synthesis and in vitro antitumor activity of 2 -deoxy-5-fluoro-uridylyl-(3 -5 )-2 -deoxy-5-fluoro-N -octadecylcytidine a new amphiphilic dinucleoside phosphate. Liebigs Annalen Chemie 1997 413. 

Example 1 the phosphoroamidite coupling procedure leading to dinucleosides and employing a catalytic amount of 5-(p-nitrophenyl)-lff-tetrazole (NPT) is illustrated [12b]. Dinucleoside phosphates can be prepared by this procedure at a multigram scale in 92-98% yield. The catalyst NPT (5 mol%) is used in the presence of molecular sieves 13X in acetonitrile at 40 °C (step a). 

From data on Tg vs in NaCl solutions, (Figure 4 in ref. (1)), it is possible to solve Equation 7 for the thermodynamic parameters AH - -10.9 kcal/mol and AS = -16.6 cal/mol-deg. The fit to the gelation data is shown in Figure 2. These values compare reasonably well with values measured for stacking of bases in dinucleoside phosphates (10.11). They are in the same range, but differ somewhat from those given in Table II of ref. 

The synthesis of some dinucleoside phosphates has been achieved1680 by the reaction of 5 -chloro-5 -deoxynucleosides with nucleotide anions. In that work, the 5 -chloro-5 -deoxynucleosides were conveniently obtained by treatment of the corresponding 2, 3 -0-isopropylidene-nucleoside with thionyl chloride. 

More critical examination of the step 1 process can be made employing well-defined dinucleoside phosphate substrates or a variety of other diesters. Extensive studies have been carried out by Witzel and are referred to below. 

A partially-protected dinucleoside phosphate (d[HO-CpG-Px]) with a free 5 -hydroxy and a protected 3 -hydroxy function is also required. Treatment of the 5 -protected dinucleoside phosphates... 

These results demonstrate that the relative sequence specificity for drug intercalation at the dinucleoside phosphate level (57-63) are also observed at the stable oligonucleotide duplex level (66,67). The latter investigations have been repeated in another laboratory (68,69) with similar conclusions. 

The discovery of these base pairs, which imply the double helical structure of DNA, stimulated a series of crystal structural studies not only of complexes of purines and pyrimidines, but of other complexes involving related molecules and their derivatives. Although we can formulate a large number of possible heterocombinations in matrix form, as shown below these complexes are reluctant to crystallize even when there is spectroscopic evidence of hetero-complex formation in solution. This is presumably because self-(homo)-association is energetically more favorable and only in rare cases were crystals of hetero complexes actually formed. Because of their three hydrogen bonds, G-C complexes form and crystallize more readily. There have been many attempts to crystallize the Watson-Crick A-U base pair, but none was successful and it only formed when the dinucleoside phosphate adenylyl-3,5,-uridine (ApU [536]) or higher oligomers were crystallized (see Part III, Chapter 20). 

The data describing hydration in the nucleic acids are more limited than that of the proteins. In the RNA series, two dinucleoside phosphates [536, 538], one trinucleoside diphosphate [864] and one tetradecamer [666] have been studied by crystallographic methods in the DNA series, many more oligonucleotides were investigated. The oligonucleotide sequences are such that the molecules are self-com-plementary and therefore can readily form double helices (Thble 24.2). This implies that the duplexes exhibit inherent twofold symmetry which, however, only coincides with a crystallographic twofold axis in a few exceptional cases. 

Spada GP, Carcuro A, ColonnaFP, Garbesi A, Gottarelli G (1988) Lyomesophases formed by the dinucleoside phosphate D(GPG). Liq Cryst 3 651-654... 

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