Donald E. Bergstrom

Fast atom bombardment combined with tandem mass spectrometry for the determination of nucleosides

The positive and negative ion fast atom bombardment (FAB) mass spectra and fast atom bombardment collisionally activated decomposition (CAD) spectra of a series of nucleosides and two dinucleotides are reported. The nucleosides studied are substituted forms of guanosine, adenosine, nebularine, tubercidin, uridine, and related pyrimidines. The FAB and CAD data both contain similar information. The CAD spectra are found to provide some structural information not found in the FAB mass spectra. Tandem mass spectrometry also allows emphasis to be put on weak fragments which are either not observed in the FAB mass spectrum or are lost in the matrix ion signals.

Broad-spectrum antiviral activity of adenosine analogues

In recent years certain aliphatic and carbocyclic adenosine analogues have been developed which are of potential clinical importance as antiviral agents. This includes (S)-9-(2,3-dihydroxypropyl)adenine [(S)-DHPA] and carbocyclic 3-deazaadenosine (C-c3Ado). (S)-DHPA and C-c3Ado are remarkably similar in their antiviral spectrum in that they are particularly active against (-) RNA viruses such as measles, para-influenza, respiratory syncytial virus, rabies virus, vesicular stomatitis virus and (+/-)RNA viruses such as reo- and rotavirus, whereas (+)RNA viruses such as polio, coxsackie and (+/-)DNA viruses such as herpes simplex are only minimally affected or not inhibited at all. In contrast with (S)-DHPA and C-c3Ado which are quite selective in their antiviral action, other adenosine analogues, i.e., 3-deazaadenosine and 7-deazaadenosine (tubercidin), exhibit little, if any, selectivity as antiviral agents. Also, tubercidin has a broader activity spectrum, encompassing (+)RNA viruses as well as herpes simplex in addition to the (-)RNA viruses. Considering the high antiviral potency of tubercidin, attempts have been undertaken to increase its selectivity, i.e., by chemical substitutions at C-5 of the pyrrolo(2,3-d)pyrimidine ring. These attempts have been partially successful.

Synthesis of 6-alkyl and 6-aryl substituted 9-β-D-ribofuranosyl purines via the nickel catalyzed coupling of grignard reagents to 2′,3′,5′-tris-0-(t-butyldimethylsilysl)-9-β-D-ribofuranosyl-6-chloropurine

Abstract A series of 6-substituted purine nucleosides have been synthesized in moderate yield by the nickel catalyzed cross coupling reaction between alkyl- and aryl- Grignard reagents and 2′,3′,5′-tris-0-(t-butyldimethylsilyl)-9-β- D -ribofuranosyl-6-chloropurine.

Organometallic Intermediates in the Synthesis of Nucleoside Analogs

Abstract 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 ...

An Improved Synthesis of 3′-Keto-5′-Tritylthymidine

Abstract 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.

Fluorine Substituted Analogs of Nucleosides and Nucleotides

Abstract The synthesis and 19F NMR spectra of dTMP and TpT analogues in which the phosphate group is replaced by a difluoromethylphosphonate group are described.

Palladium mediated reaction of organic disulfides with mercurated nucleic acid components

A method of preparing C-5 substituted nucleotides by reacting a C-5 posit mercurated nucleoside with an alkyl or aryl disulfide in the presence of palladium(II) ion. The resulting new method for attaching linker arms to nucleic acids (DNA,RNA) provides a wide ranging reaction far more useful than those heretofore developed, and allows preparation of modified components with linking reactive functionality that allows usefulness as probes, therapeutics, and for DNA sequencing.

Synthesis of (Dicarbonyl)(η5-cyclopentadieny1)iron -Derived Nucleoside Phosphonate Esters

Abstract 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: Studies of Antileukemic Properties in Vitro and in Vivo

Abstract 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.

Synthesis of (Dicarbonyl)(η5-cyclopentadienyl)Manganese Complex Stabilized Nucleoside Phosphite Esters

Abstract 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.