Su Jeong Yoo

Ring contraction and rearrangement of 4-thiofuranose derivatives observed during DAST fluorination in the synthesis of l-2′-“up”-fluoro-4′-thiothymidine

Abstract Ring contraction and rearrangement of 4-thiofuranose derivatives were observed through the regioselective opening of the episulfonium ion formed during DAST fluorination in the synthesis of l -2′-“up”-fluoro-4′-thiothymidine.

Synthesis of novel (2R,4R)- and (2S,4S)-iso dideoxynucleosides with exocyclic methylene as potential antiviral agents.

Novel (2R,4R)- and (2S,4S)-iso dideoxynucleosides with exocyclic methylene have been designed and synthesized, based on the lead BMS-200475 (3) which exhibited potent anti-HBV activity. For the synthesis of D types of (2R,4R)-nucleosides, L-xylose was converted to the key intermediate 14. The intermediate 14 was converted to the uracil derivative 4a and the cytosine derivative 4b. Compound 14 was also converted to the purine derivatives such as adenine derivative 4c, hypoxanthine derivative 4d, and guanine derivative 4e. The corresponding L types of (2S,4S)-enantiomers were more efficiently synthesized from the commercially available 1,2-isopropylidene-D-xylose (20) than the synthetic method used in the synthesis of (2R,4R)-nucleosides. The key intermediate 25 was converted to the pyrimidine analogues 5a and 5b and the purine derivatives 5c, 5d, and 5e using the similar method used in the preparation of 4c, 4d, and 4e. The synthesized final (2R,4R)- and (2S,4S)-nucleosides were tested against several viruses such as HIV-1, HSV-1, HSV-2, HCMV and HBV. (2R,4R)-Adenine analogue 4c exhibited potent anti-HBV activity (EC(50)=1.5 microM in 2.2.15 cells) among compounds tested, while (2R,4R)-uracil derivative 4a was the most active against HCMV among compounds tested and (2R,4R)-adenine derivative 4c was found to be moderately active against the same virus. However, the corresponding (2S,4S)-isomers were found to be totally inactive against all tested viruses. Both (2R,4R)-adenine derivative 4c and (2S,4S)-adenine analogue 5c were totally resistant to the adenosine deaminase like iso-ddA (1). From the molecular modeling study the hydroxymethyl side chains of BMS-200475 (3) and 4c were almost overlapped, indicating that 4c may be suitable for phosphorylation by cellular kinases like the lead 3, but some discrepancy between two bases was observed, indicating why 4c is less potent against HBV than 3. It is concluded that discovery of (2R,4R)-adenine analogue 4c as potent anti-HBV agent suggested that the sugar moiety of this series can be regarded as a novel template for the development of new anti-HBV agent and oxygen atom can be acted as a bioisostere of C-OH.

Synthesis and antiviral activity of novel isodideoxy nucleosides with exocyclic methylene

Novel isodideoxy nucleosides with exocyclic methylene were synthesized starting from L-xylose utilizing anomeric demethoxylation, Wittig reaction and Mitsunobu reaction as key steps and evaluated for antiviral activity.

Synthesis and Antiviral Activity of D- and L-Isodideoxy Nucleosides with Exocyclic Methylene

Novel D- and L-isodideoxynucleosides were synthesized starting from D- and L-xylose and evaluated for antiviral activities against HIV-1, HSV-1, HSV-2, HBV and HCMV, respectively.

TOTAL SYNTHESIS OF ()-ISO-D4T AS POTENTIAL ANTIVIRAL AGENT

Abstract (±)-Iso-d4T which may act as a bioisostere of d4T was synthesized from 1,3-dihydroxyacetone using phenyl selenenium chemistry as a key step.

STRUCTURE-ACTIVITY RELATIONSHIPS OF APIO NUCLEOSIDES AS POTENTIAL ANTIVIRAL AGENTS

Several types of novel apio nucleosides were synthesized starting from 1,3-dihydroxyacetone and evaluated for antiviral activity. Among compounds tested, amino substituted apio dideoxynucleosides exhibited anti-HBV activity, while thioapio dideoxynucleosides were found to be active against HIV-1. Apio dideoxydidehydro nucleosides showed moderate to potent anti-HCMV activity, but their bioisosteric thioapio dideoxydidehydro nucleosides did not exhibit any significant antiviral activity.

Participation of sulfur occurred during the Mitsunobu reaction: synthesis of novel isodideoxythionucleosides

Novel isodideoxythionucleosides have been synthesized from our versatile intermediate, L-4-thioarabitol derivative 5 using the Mitsunobu reaction as a key step. It is found that the sulfur atom of the 4-thiofuranose derivative takes part in the Mitsunobu reaction.

SYNTHESIS AND ANTIVIRAL ACTIVITY OF D- AND L-2′-AZIDO-2′,3′-DIDEOXY-4′-THIOPYRIMIDINE AND PURINE NUCLEOSIDES

Novel D- and L-2′-azido-2′,3′-dideoxy-4′-thionucleosides were synthesized starting from L- and D-xylose via D- and L-4-thioarabitol derivative as key intermediates and evaluated for antiviral activity, respectively. When the final nucleosides were tested against HIV-1, HSV-1, HSV-2, and HCMV, they were found to be only active against HCMV without cytotoxicity up to 100 μg/ml.