Steve Tam

Solid phase synthesis of directly linked PNA-DNA-hybrids

Abstract The synthesis of directly linked PNA-DNA-hybrids and the results of thermal melting studies are described.

Synthesis of iso-ddA, member of a novel class of anti-HIV agents

Abstract Iso-ddA ( 3 ) represents a new class of potential anti-AIDS drugs. Synthetic approaches to this compound involving nucleophilic additions to a novel carbohydrate framework are discussed.

Synthesis of 3′-deoxy-3′-(2-propynyl)thymidine and 3′-cyanomethyl-3′-deoxythymidine, analogs of AZT☆

Abstract An efficient procedure using free radical chemistry for introducing a carbon substituent to the 3′-position of 3′-deoxythymidine is described. An application of this procedure to the synthesis of 3′-deoxy-3′-(2-propynyl)thymidine and 3′-cyanomethyl-3′-deoxythymidine, two close analogs of AZT, is presented.

Oligomer synthesis and DNA/RNA recognition properties of a novel oligonucleotide backbone analog: Glucopyranosyl nucleic amide (GNA)

Abstract A general solid phase synthesis is described for the construction of novel amide linked oligonucleotide analogs having the glucopyranosyl configuration via solid phase N-Fmoc-type peptide chemistry. The selective binding to DNA and RNA sequences by these oligomers is characterized by measurement of melting temperatures and related thermodynamic constants.

Synthesis of thymine, cytosine, adenine, and guanine containing N-Fmoc protected amino acids: Building blocks for construction of novel oligonucleotide backbone analogs

Abstract A convenient synthesis is described for thymine, cytosine, adenine, and guanine containing, glucosamine-based N-Fmoc protected amino acids. These molecules are building blocks for the construction of novel oligonucleotide analogs via N-Fmoc type peptide chemistry.

Synthesis of the 6′-Fluoro Derivatives of Carbocyclic 2′,3′-Dideoxy-3′-oxa-adenosine

Abstract Different strategies for the synthesis of the 6′-α and β-fluoro derivatives of carbocyclic 2′,3′-dideoxy-3′-oxa-adenosine are described.

Synthesis of 3′-C-Substituted-2′,3′-Dideoxynucleosldes as Potential Antcaids Agents

Abstract In this paper we report an efficient synthetic route to some novel 3′-C-substituted-2,3′-dideoxy-nucleosides. The critical 3′- C-C bond was constructed by an application of free radical methodology. This type of reaction was found to be stereoselective forming exclusively the 3′-“down” isomer. The stereo-chemical assignment at C-3′ was confirmed by both nmr nOe experiments and single crystal X-ray analysis.

A new polymer-bound N-hydroxysuccinimidyl active ester linker

Abstract Synthesis of a new N -hydroxysuccinimidyl resin is described and the N -acylation with this resin provides amide products in high yields and excellent purities. This new linker is suitable for combinatorial library synthesis.

Anabolism and Mechanism of Action of Ro24-5098, an Isomer of 2′,3′-Dideoxyadenosine (ddA) with Anti-HIV Activity

The potential of dideoxynucleosides as inhibitors of HIV replication has been demonstrated in vitro by Mitsuya and Broder. This stimulated a great deal of interest in possible use of these compounds for therapy of HIV infections and led to clinical trials with 2,3-dideoxycytidine (ddC)2 and 2,3-dideoxyinosine (ddI).3 One factor that may limit the clinical utility of dideoxypurine nucleosides is the instability of the glycosidic bond at low pH, resulting in destruction of a pharmacologically active compound. This creates difficulties when oral administration is desired. A second factor affecting the usefulness of ddA and ddI is biochemical catabolism. Studies in cell culturec7 revealed that ddA is readily converted to ddI by adenosine deaminase (ADA). A portion of ddI is then degraded by purine nucleoside phosphorylase (PNP),* whereas the remainder is anabolized, possibly by S-nucle~tidase.~ The end result of cellular anabolism of both ddA and ddI is ddATP, which interacts with HIV reverse transcriptase. Although ddA can be anabolized directly by deoxyadenosine kinase (dAK) and deoxycytidine kinase (dCK) to ddAMP, these reactions occur to a small extent compared to the indirect route of anabolism by way of ddI. Therefore, both ddI and ddA (following deamination) are subject to catabolism by PNP.

Synthesis and Evaluation of 2′,3′-Dideoxy-9-Deazaadenoslne and Some Related Derivatives

Abstract In this paper we report the synthesis of 2′,3′-dideoxy-9-dearaadenosine (2) and the corresponding 2′,3′-unsaturated- and 3′-deoxy- analogs, 6 and 8. These C-nucleosides are very stable towards acid and thus overcome one of the main drawbacks of 2′,3′-dideoxy-purine-nucleosides, such as the antiviral agent 2′,3′-dideoxyadenosine (ddA). However, evaluation of these compounds and some related 2′-deoxy derivatives (10-14) in the antiviral assay for the human immunodeficiency virus has revealed no significant activity.