title: Synthesis of novel (2R,4R)- and (2S,4S)-iso dideoxynucleosides with exocyclic methylene as potential antiviral agents.
abstract: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, 120-750, Seoul, Republic of Korea.
authors.forename: Su Jeong
authors.initials: SJ
authors.lastname: Yoo
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.forename: Jeongmin
authors.initials: J
authors.lastname: Kim
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D006838:Hydrocarbons; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D013057:Spectrum Analysis
chemical_list: D000998:Antiviral Agents; D017931:DNA Primers; D015224:Dideoxynucleosides; D006838:Hydrocarbons; C030011:carbene; D008697:Methane