Of dinucleoside phosphates

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... 

The methods of nucleotide synthesis thus far described have involved the activation of a phosphoric moiety by increase of the electrophilic nature of phosphorus, in order to facilitate nucleophilic attack by hydroxyl group(s) of nucleosides (alcoholysis). An alternative approach is the use of an activated nucleoside which will undergo attack by a phosphono-oxy anion on carbon (phosphorolysis). Although the latter approach has had little practical advantage in the synthesis of mononucleotides, it has shown some promise in the synthesis of dinucleoside phosphates. Theoretical considerations are sufficiently compelling to warrant discussion of this approach here. 

Padyukova and Smrt (93) described the synthesis of dinucleoside phosphates containing S -o-bonded... 

ScHULTEN, H.-R., and H. M. Schiebel Sequence Specific Fragments in the Field Desorption Mass Spectra of Dinucleoside Phosphates. Nucleic Acids Res. 3, 2027 (1976). 

Fig. 4. Comparison of calculated and observed CD spectra of dinucleoside phosphates. Measured ribo ApA agrees well with calculation for a single strand in RNA geometry, while the measured deoxyribo ApA agrees well with a single strand in B-form DNA geometry. (Reprinted from C.L. Cech and 1. Tinoco, Jr. Biopolymers 15 (1976).)...

Hall, R. H Todd, A., and Webb, R. F. (1957) Nucleotides. Part XLL Mixed anhydrides as intermediates in the synthesis of dinucleoside phosphates. J Chem. Soc. 3291-3296... 

Analogues of Dinucleoside Di(Tri)phosphates and Oligonucleotides with a Di(Tri)phosphate Bridge... 

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

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. 

The base specificity has been extensively investigated by the 3 -terminal analysis of digestion products of RNA and polyribonucleotides and by the studies on the susceptibility of dinucleoside monophosphates or nucleoside 2, 3 -cyclic phosphates to the enzyme. The results are summarized in Table V (24-87). From the base specificity study, the es-... 

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. 

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