Search

L-beta-Deoxythymidine (L-dT), the optical enantiomer of D-beta-deoxythymidine (D-dT), and L-enantiomers of nucleoside analogs, such as 5-iodo-2'-deoxy-L-uridine (L-IdU) and E-5-(2-bromovinyl)-2'-deoxy-L-uridine (L-BVdU), are not recognized in vitro by human cytosolic thymidine kinase (TK), but are phosphorylated by herpes simplex virus type 1 (HSV-1) TK and inhibit HSV-1 proliferation in infected cells. Here we report that: (i) L-dT is selectively phosphorylated in vivo to L-dTMP by HSV-1 TK and L-dTMP is further phosphorylated to the di- and triphosphate forms by non-stereospecific cellular kinases; (ii) L-dTTP not only inhibits HSV-1 DNA polymerase in vitro, but also human DNA polymerase alpha, gamma, delta and epsilon, human immunodeficiency virus reverse transcriptase (HIV-1 RT), Escherichia coli DNA polymerase 1 and calf thymus terminal transferase, although DNA polymerase beta was resistant; (iii) whereas DNA polymerase beta, gamma, delta and epsilon are unable to utilize L-dTTP as a substrate, the other DNA polymerases clearly incorporate at least one L-dTMP residue, with DNA polymerase alpha and HIV-1 RT able to further elongate the DNA chain by catalyzing the formation of the phosphodiester bond between the incorporated L-dTMP and an incoming L-dTTP; (iv) incorporated L-nucleotides at the 3'-OH terminus make DNA more resistant to 3'-->5' exonucleases. In conclusion, our results suggest a possible mechanism for the inhibition of viral proliferation by L-nucleosides.

A simple, rapid and high-yielding method for the synthesis of oligonucleotides by the phosphotriesters approach is described. The use of polyethylene glycol (PEG) as soluble polymeric support preserves some convenient features of the solid-phase synthesis with new interesting advantages. Short oligonucleotides in hundred milligrams scale can be obtained from few grams of functionalized PEG.

The binding between Distamycin 3 and the palindromic duplexes d(CGTTTAAACG)2 and d(CGTACGTACG)2 was investigated by two independent techniques: UV-Vis absorption in the Job's plot approach and Induced Circular Dichroism. Both decamers bind two molecules of peptide per duplex, with close overall affinities. This result indicates that a row of six A:T base pairs can accommodate two molecules of drug and that the minimal binding site of Distamycin 3 can consist of just two A:T base pairs.

Unnatural L-2'-deoxyribonucleosides L-T, L-dC, L-dA and L-dG were prepared from L-arabinose and assembled, by solution or solid phase synthesis, to give L-oligonucleotides (L-DNAs), which contain all four natural bases. The affinity of these modified oligomers for complementary D-ribo- and D-deoxyribo-oligomers was studied with NMR, UV and CD spectroscopies and mobility shift assay on native PAGE. All experimental results indicate that L-DNAs do not, in general, recognize single-stranded, natural DNA and RNA. Hence, contrary to previous suggestions, it is not possible to envisage their use as wide scope antimessenger agents in the selective control of gene expression.

The radical adducts resulting from the reaction between group IVB organometallic radicals MR 3 (M = Si, Ge, Sn; R = alkyl or aryl) and a number of thioketones of the chromone and flavone series have been investigated by ESR spectroscopy. The spectral parameters obtained for these species have been compared with those of similar adducts of the corresponding ketones. Both classes of radicals adopt an orthogonal conformation, and the differences between the former and the latter paramagnetic species can be accounted for by the different electronegativity of oxygen and sulphur. the effects of substitution of the heterocyclic oxygen with a sulphur or selenium atom on the spin density distribution are likewise explained. INDO calculations have been carried out on the model systems CH 2 XSiH 3 (X = O, S).

The 15N and 13C chemical shifts of the sodium salt of deoxycytidylyl-(3′,5′)-guanosine have been measured in dimethylsulfoxide in the presence of variable amounts of CF3COOH. N3(cyt) is protonated first, followed by N7(gua) and the phosphate anion. These results vary from those reported for the binding of the methylmercuric cation to d(CpG).

The ESR spectra of the paramagnetic species produced by photoreaction of benzo[2,1-b;3,4-b]dithiophen-4,5-dione with a number of organomercurials, RHgR, have been recorded. The spectral parameters and the temperature dependence of the 199Hg coupling constants are consistent with a structure of the adducts in which the Hg atom is bound to both carbonyl oxygens.

The first two ionization energy values of p-substituted trans-azobenzenes pX-C6H4-N = N-C6H5 (X = NH2, OCH3, OH, CH3, H, Cl, COOH and NO2) are reported. These have been obtained by U.V. (HeI and HeII) photoelectron spectroscopy (UPS). The substituent effect indicates that for electron donor substituents, the highest occupied orbital is π-type. This is confirmed by semiempirical calculations. When the substituent is H or a withdrawing group, the first two bands heavily overlap, and in these cases no certain assignment was possible, in spite of the several approaches used. The UPS data are discussed along with previous polarographic and U.V. absorption measurements.

The ultraviolet photoelectron spectra of [2,2](2,5)furanophane (FUPH) and [2,2](2,5)thiophenophane (THPH) have been analyzed on the basis of a perturbational molecular orbital analysis, by comparison with CNDO/2 computations and by correlating them with the spectra of related molecules. Through space and through bond interactions between the two heteroaromatic rings are shown to be important in determining the ordering of the outermost MO’s in this class of compounds.

The photoelectron spectra of the S[X(CH3)3]2 and CH3SX(CH3)3 series (X = C, Si, Ge, Sn and Pb) are reported, and assigned on the basis of the semilocalized orbitals approximation and a consideration of symmetry and substituent effects. The electronic interactions between the X(CH3)3 substituents and the sulfur nπ orbital are discussed in terms of the relative importance of hyperconjugation (nσ mixing), (pd)π bonding and electrostatic interactions.

The analysis of dipole moment data obtained for dibenzo-p-dioxin, phenoxathiin, phenoxaselenin and phenoxatellurin in benzene at 25°C in conjunction with EHT calculations of the ocnformational energies show that these molecules adopt a non-planar conformation in solution. Each of the phenoxachalcogenins is folded along the axis connecting the two heteroatoms. A butterfly flapping motion about the planar conformation canot be excluded. The uv and photoelectron spectroscopic data support the conclusions drawn from the dipole moment studies. The spectroscopic data were interpreted with the help of SCF-PPP-CI calculations.

The first two π(a2, b1) IE’s, of monosubstituted benzenes containing di- and tri-coordinated nitrogen directly linked to the ring have been measured and analysed together with the N1s IE. These photoelectron properties are found to respond in the same sense, though to different extents, to inductive and mesomeric interactions that the N-containing substituents sustain with the aromatic ring. The different sensitivities of these properties to substituent changes are discussed in connection with mechanisms of transmission of electronic effects with the aid of the ground state electronic structures determined by means of ab-initio calculations. The relative contribution of the relaxation energy to the considered core and valence IE’s is also examined by referring to the model used by Gelius and Siegbahn. The factors determining the apparently anomalous behaviour of nitrobenzene are discussed

The low ionization energy regions of the photoelectron (He I) spectra of several p-p′-substituted thiobenzophenones (X-C6H4)2CS and of the corresponding S-oxides (sulphines) (XC6H4)2CSO (where X = H , OCH3, CH3, I, Br, Cl and NO2) have been assigned on the basis of perturbational molecular orbital theory arguments coupled with CNDO/2 computations and substituent effects. For the thioketones, the ordering of the outermost MO's results to be n(S), π7, π6, π5/π4, π3, n(S) being the HOMO; while for the sulphines the two outermost MO’s have π character and correspond to π7 and π6 in the thioketones. In the light of the above results the different behaviour toward oxidation of these two classes of compounds can be rationalized.

Since the first electron spectroscopic (ESCA) studies dealing with substituents effects upon core ionization energies (I.E.) of organic compounds1, little has been published on the subject. This was probably because the reported data did not always seem very meaningful. The absolute I.E. values obtainable in the solid phase are not very certain and also, the "shake-up" phenomena and the consequent broadening of the bands, which affect the I.E. values2, were not always taken into account. None the less we think that ESCA is a valuable tool for the study of substituent effects, and in particular of the transmission of electronic effects in aromatic systems. Previous work in this area has been published 2,3 , and more specifically an example of steric inhibition of resonance observed by means of ESCA I.E.'s and shake up data was recently reported4. Here we would like to report a further case in which the transmission of electronic effects through an aromatic ring is observed using ESCA.

Half-wave oxidation potentials (E1/2), in acetonitrile at a platinum electrode, and gas-phase ionization potentials (P) have been measured for a number of indole and indolizine derivatives, variously substituted on the five-membered ring. Except for a few compounds, a linear correlation of P vs. E1/2 was found. Deviations from linearity are discussed in terms of conformation differences between the two phases and P value uncertainties in those cases where the vibrational fine structure was resolved.