Kanda S. Ramasamy

The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels

ABSTRACT The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared thed-nucleoside ribavirin to its l-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential.

Remarkable enhancement of binding affinity of Heterocycle-modified DNA to DNA and RNA. Synthesis, characterization and biophysical evaluation of N2-imidazolylpropylguanine and N2-imidazolylpropyl-2-aminoadenine modified oligonucleotides

Abstract Oligonucleotides containing novel N2-Imidazolylpropylguanine and N2-Imidazolylpropyl-2-aminoadenine moieties were synthesized and studied for their hybridization and biophysical properties. Interestingly, these heterocycle modified oligonucleotides showed a remarkable enhancement of heteroduplex binding affinity when hybridized to complementary DNA.

Oligonucleotides bearing cationic groups: N2-(3-aminopropyl)deoxyguanosine. Synthesis, enhanced binding properties and conjugation chemistry

A phosphoramidite with an aminopropyl group placed at the N2- position of 2′-deoxyguonosine has been synthesized and incorporated into oligonucleotides. This modification shows enhanced binding properties against both DNA and RNA targets and is useful for conjugating other functionalities.

Amino acid nucleic acids: synthesis and hybridization properties of a novel class of antisense oligonucleotides

Abstract Oligonucleotides containing novel phoshoramidite 12 were synthesized and studied for their hybridization properties for the first time. Interestingly, these modified oligonucleotides showed a remarkable resistance to exonuclease.

Synthesis and structural studies of monocyclic 4′-Aza-L-Nucleosides

Abstract Monocyclic 4′-Aza-L-Nucleosides in which the sugar ring oxygen is replaced with a nitrogen atom are synthesized from D-lyxose. The configurational assignments of the structures of newly derived compounds were established by 1D and 2D 1H NMR experiments.

Improved Synthesis of 2-Deoxy-L-ribose

Abstract Improved synthesis of 2-deoxy-L-ribose and the corresponding 2-deoxy-3,5-di-O-p-toluoyl-α-L-erytro-pentofuranosyl chloride are described from L-arabinose.

A Simple and Convenient Method for the Deprotection of Tetrahydropyranyl Ether Using Iodine in Methanol

Abstract A simple and efficient method for the -deprotection of tetrahydropyranyl and 4,4′-dimethoxytrityl ethers using iodine in methanol is described.

A NEW SYNTHETIC METHODOLOGY FOR TIAZOFURIN

A new synthesis of tiazofurin is described from 2,3-O-isopropylidene-5-O-benzoyl-β-D-ribofuranosyl cyanide.

Solid-phase parallel synthesis of 4-β-D-ribofuranosylpyrazolo[4,3-d]pyrimidine nucleosides

The synthesis of pyrazolo[4,3-d]pyrimidine nucleoside library using solid-phase parallel synthesis methodology is described. Glycosylation of the trimethylsilyl (TMS) derivative of 1- and 2-(methyl)-1H and 2H-pyrazolo[4,3-d]pyrimidine-5,7-(4H,6H)-dione (5) with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose in the presence of TMS triflate provided two novel protected nucleosides 6 and 7. The structures of 6 and 7 were assigned by 1H and 2D NMR experiments. Nucleosides 6 and 7 were then transformed to the key intermediates 12 and 15 respectively. Reaction of 12 and 15 with MMTCl resin in the presence of 2,6-lutidine afforded the necessary scaffolds B and C. Different amines (96) were introduced selectively by nucleophilic substitution on scaffolds B and C using solid-phase parallel semi-automated synthesizer. Cleavage of the products from the solid support with 30% HFIP in a parallel fashion yielded nucleoside libraries simultaneously, and they were analyzed and characterized by high-throughput LC-MS.

Synthesis and biophysical studies of oligonucleotides containing hydroxamate linkages

Abstract Novel oligonucleotide dimers containing hydroxamate linkages ( 15 and 16 ) were synthesized, incorporated into oligonucleotide sequences and studied for their hybridization properties with complementary DNA and RNA targets. The modified oligonucleotides showed similar binding properties and enhanced resistance to exonucleases compared to natural oligonucleotides.