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A convenient and efficient procedure for the synthesis of 13C methyl-labeled thymidine by way of lithiation of t-butyldimethylsilyl protected 2′-deoxyuridine is described.

A series of heterocyclic carboxamides have been designed as mimics for the natural nucleic acid bases. The nucleosides 1-(2′-deoxy-β-d-ribofuranosyl)imidazole-4-carboxamide (1), 1-(2′ -deoxy-β-d-ribofuranosyl)pyrazole-3-carboxamide (2), and 1-(2′ -deoxy-β-d-ribofuranosyl)pyrrole-3-carboxamide (3) were synthesized and their structures confirmed by spectroscopic and analytical means. This paper is dedicated to Dr. Yoshihisa Mizuno.

The syntheses of endcaps for covalently linking the 3′ and 5′ hydroxyl groups of blunt end double-stranded DNA are described. Endcap diols were converted into DMTr protected phosphoramidites and incorporated between nucleotides 4 and 5 of a self-complementary octamer. The stabilizing effect of the endcaps on duplex DNA was determined by Tm experiments on the self-complementary octamer.

Adenosine 5′-phosphor(adamantyl)amidate (S), an analog derived by linking the antiviral drug amantadine to 5′-AMP is transported through a model membrane system in a discontinuous periodic-catastrophic fashion. The system was composed of a glass cell containing two aqueous buffer phases separated by a chloroform layer. A more lipophilic, but structurally related derivative, adenosine 5′-phosphor(n-decy1)amidate (3) showed linear transport in the same system. Less lipophilic substances, including 5′-AMP and adenosine 5′-phosphor(morpholidyl)amidate (2) did not show transport. It is hypothesized that the periodic-catastrophic transport is a result of the collecthe activity of amidate 5 at the interface between the first aqueous interface and the chloroform layer. The time between catastrophic events is thought to be a reflection of the time necessary for molecular organization at the interface. The phenomenon is a new example of molecular organization in a system far from equilibrium leading to a r...

The MINDO/3 technique was used to evaluate the geometry of thymidine and four structural analogs, 3′-fluoro-3′-deoxythymidine (Z), 3′-fluoro-2′, T-dideoxy-P-D-lyxofuranosylthymine (3), 3′-deoxythymidine (4), and 3′,3′-difluoro-3′-deoxythymidine (5). The relative proportion of N (3′-endo, 2′-exo, P = 0°) and S (2′-endo, 3′-exo, P = 180°) conformers was determined for each of the analogs. Whereas the energy difference between the N and S forms of most deoxyribonucleoside derivatives differ by at most 1 to 2 kcal/mol, the N conformation for nucleosides 4 and 5 are respectively 2.9 and 4.0 kcal/mol more stable than the S form. The optimal value of χ for each of the analogs in the N conformation was -102° (4) and -97° (5). The fluorine in the up position at C3′ of deoxyribose appears to be a strong attractor for the H-6 proton on the thymine when the the sugar is in the N conformation.

Synthetic methodology for generating a thioether linkage at C-5 of pyrimidine nucleosides via a palladium-mediated reaction of mercurated nucleosides with organic disulfides was recently reported by our laboratory. We have continued to explore the scope of the reaction with respect to both the nucleoside component and the disulfide. In particular, the reaction of N, N'-bis(trifluoroacetyl)cystamine with mercurated nucleosides has been explored in more detail.

The title compound is prepared in consistently high yield and purity by molecular sieve catalyzed pyridinium dichromate oxidation of 5′-0-tritylthymidine. Shortcomings of other preparations are described, and properties of the title compound are reported.

The common nucleosides, modified or derivatized in some way at the heterocyclic ring carbons, include examples of structures which a r e useful as biological probes and chemotherapeutic agents. Like previous authors, we will use the term “nucleoside analog” for structures related to one of the common naturally occurring nucleosides. Nucleosicle analogs can be derivatives which differ by such minor modification as replacement of hydrogen by a single atom or derivatives which are grossly modified at both the carbohydrate and the base. Examples of the former include 5-fluoro-2′-deoxyuridine, an inhibitor of thymidylate synthetase as its 5′-phosphate, and 5′-iodo-2′-deoxyuridine, a clinically useful antiviral agent. Larger groups have frequently been linked to nucleoside as probes for enzymatic processes. Side chains in “nonrestricted positions” may be used to carry spectroscopic or chemically reactive probes, or provide the means to attach a molecule to an affinity column. Ultimately with positions ...

New methods for generating phosphonate linkages in oligonucleotides are under investigation. Among reagents that react selectively with phosphite triesters and H-phosphonates are (dicarbonyl)(η5-cyclopentadienyl)(η2-olefin)iron complexes. We have found that (dicarbonyl)(η5-cyclopentadienyl)(η2-ethylene)iron reacts with 5′-O-dimethoxytritylnucleoside 3′-phosphite esters to yield (dicarbonyl)(η5-cyclopentadienyl)iron(ethyl)phosphonates. The (dicarbonyl)(η5-cyclopentadienyl)iron-derived nucleoside phosphonates are stable to the conditions commonly used to construct oligonucleotides by phosphoramidite methodology.

5-Hydroxymethyl-2-deoxyuridine (5HmdUrd) prolonged the survival of mice carrying leukemia L1210 in a dose-dependent manner. Furthermore, a dose-dependent synergism/antagonism was observed when human leukemia cells were exposed simultaneously to Ara-C and 5HmdUrd in vitro.

We have found that stable nucleoside derived phosphite ester manganese complexes can be generated by the reaction of Mn(CO)2(THF)(η5-C5H4R) with nucleoside phosphite esters. These complexes appear to be stable towards oxygen and reagents used for DNA synthesis and deprotection. The cyclopentadienyl ligand can be modified by a strong electron withdrawing group and still retain the photochemical and chemical properties necessary to complex readily to phosphite esters.