Daniel W. Miles

A conformational basis for the selective action of ara-adenine.

Abstract The glycosidic “high anti” conformation is postulated to be the conformation required by the enzymes adenosine kinase and inosine phosphorylase. Purine analogs that are stable in this conformation are either effective substrates or inhibitors of these enzymes. Ara-adenine is shown to be highly unstable in the high anti conformation. The inactivity of ara-adenine as a substrate for both adenosine kinase and inosine phosphorylase is attributed to its inability to assume the high anti conformation specified by these enzymes. That adenosine itself has a local minima in the high anti conformation, as does inosine and guanosine, is required by its ability to inhibit the synthesis of uridylic acid. The minimal cytotoxic properties of ara-adenine is a consequence of its failure, in normal cells, to be converted to the toxic nucleotide form. The ability of ara-adenine to selectively inhibit DNA viruses means that in DNA virus infected cells the conversion of ara-adenine to ara-AMP is facilitated through a mechanism that does not require a substrate high anti conformation. It is apparent that selective antiviral and anticancer nucleoside analogs may be constructed if their conversion to the toxic nucleotide form is prohibited in normal tissues but allowed in cancer cells or virus infected cells. The basis for the selective effects of ara-adenine is that normal cells require a substrate conformation in which ara-adenine is unstable but that certain neoplastic and viral mechanisms for the conversion of ara-adenine to ara-AMP exist which are able to utilize ara-adenine in its stable syn or anti conformations.

A molecular orbital study of the conformation of formycin

Abstract Semiempirical quantum mechanical calculations, using the iterative extended Huckel theory, are carried out for the evaluation of conformational energies, dipole moment and net atomic charges as a function of the rotation about the glycosidic bond. Torsion about the C(4′)-C(5′) bond has also been considered. The energy diagrams for either the gg or gt rotamers of formycin predict that neither the first or the second energy minimum fall in the classical anti or syn regions. The predicted energy difference between the two most preferred conformations is rather large (3 kcal/mole). In contrast adenosine is predicted to favor the anti conformation by less than 1 kcal/mole. Barriers to internal counter-clockwise rotation about the glycosidic bond are higher for adenosine.

A conformational basis for the antiviral inactivity of tetrazole ribonucleosides

The antiviral activity of ribavirin has been associated with its inhibition of the enzyme, IMP dehydrogenase. The ability of ribavirin to inhibit this enzyme has previously been shown to be related to its stability in the high anti glycosidic conformation. The antiviral effectiveness of several analogs of ribavirin have been investigated recently. The evidence indicates their antiviral effectiveness is related to their stability in the high anti conformation. Recently the disposition of purine analogs that pass through the inosine monophosphate branch point has been investigated. The results of these studies are consistent with the concept that the conversion of IMP to XMP requires the high anti conformation and that the conversion of IMP to adenylosuccinate requires some other conformation, possibly the anti conformation.

Systematics in the Electronic Spectra of Nucleoside Derivatives

In order to calculate accurately the orientation of the sugar relative to the base in the pyrimidine nucleosides from circular dichroism data, the localized nature of the electronic transitions in both the sugar and the base have been exploited. Within the matrix formalism of the theory of optical activity, the sugar is treated by the bond exciton theory without the resonance assumption. The chromophore is treated by a semiempirical self‐consistent field calculation from which the delocalization of each transition is extracted and then compared with the results of the bond exciton treatment. In three bands, there is excellent support for the SCF CI result, and these three are then used to draw conclusions regarding the molecular geometry. The one‐electron effect on the pyrimidine nucleoside circular dichroism is shown to be small. The manner in which transitions are localized in the various chromophores is then used as a basis for a systematical discussion of various nucleoside spectral properties.

PYRAZOLOPYRIMIDINE NUCLEOSIDES PART 5, METHYLATION OF THE C‐NUCLEOSIDE ANTIBIOTIC FORMYCIN AND STRUCTURAL ELUCIDATION OF PRODUCTS BY MAGNETIC CIRCULAR DICHROISM SPECTROSCOPY

Formamidin-acetat kondensiert, wobei die Pyrazolopyrimidine (VIII) und (IX) erhalten werden.