Study of the Effects on DNA of Two Novel Nucleoside Derivatives Synthesized as Potential Anti-HIV Agents

The pursuit of antiviral active compounds against different classes of viruses, in particular HIV, HBV, and HTLV is an area of important and intense research. In the current study, two novel nucleoside derivatives belonging to a new class of isoxazolidine were successfully synthesized as potential anti-HIV agents by replacement of the furanose ring by a N,O-heterocyclic ring Both compounds were investigated for biological activity, namely, mutagenic and antimutagenic properties. Using Salmonella typhimurium strains TA97, TA100, and TA102, both compounds proved to be nonmutagenic, which may be considered an encouraging result to further elucidate other biological activities. Antimutagenic testing of the synthesized compounds revealed that they are active against the base-pair substitution mutagen sodium azide. However, they did not show any indication as antimutagenic agents against hydrogen peroxide and mitomycin C (oxidative mutagens) or against nitrophenylenediamine (a base-pair substitution and frameshift mutagen). Structure–activity relationship is also discussed. Testing these compounds as antiviral agents is highly recommended.

[1]  Erik De Clercq,et al.  Antiviral drugs in current clinical use. , 2004 .

[2]  G. Sindona,et al.  Diastereo- and enantioselective synthesis of N,O-nucleosides , 2003 .

[3]  A. Rescifina,et al.  Enantioselective synthesis of N, O-psiconucleosides , 2003 .

[4]  A. Mastino,et al.  Effects of nucleoside-based antiretroviral chemotherapy on human T cell leukaemia/lymphotropic virus type 1 (HTLV-1) infection in vitro. , 2003, The Journal of antimicrobial chemotherapy.

[5]  Erik De Clercq,et al.  New anti‐HIV agents and targets , 2002, Medicinal research reviews.

[6]  T. Hatano,et al.  Pseudouridine, an antimutagenic substance in beer towards N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). , 2002, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[7]  Erik De Clercq,et al.  New developments in anti-HIV chemotherapy , 2001 .

[8]  E. De Clercq,et al.  The HIV‐1 Reverse Transcription (RT) Process as Target for RT Inhibitors , 2000, Medicinal research reviews.

[9]  M. Summers,et al.  Structural biology of HIV. , 1999, Journal of molecular biology.

[10]  A. Rescifina,et al.  Modified dideoxynucleosides: Synthesis of 2′-N-alkyl-3′-hydroxyalkyl-1′,2′-isoxazolidinyl thymidine and 5-fluorouridine derivatives , 1996 .

[11]  D. Macphee,et al.  Frameshift mutagenesis by 9-aminoacridine: antimutagenic effects of adenosine compounds. , 1996, Mutation research.

[12]  M. Norimatsu,et al.  Mutagenic evaluation of primaquine, pentaquine and pamaquine in the Salmonella/mammalian microsome assay. , 1994, Mutation research.

[13]  M. Plewa,et al.  Antimutagenicity of three isomers of aminobenzoic acid in Salmonella typhimurium. , 1994, Mutation research.

[14]  E. Clercq HIV resistance to reverse transcriptase inhibitors , 1994 .

[15]  A. Skalka,et al.  The retroviral enzymes. , 1994, Annual review of biochemistry.

[16]  A. Rescifina,et al.  A new synthesis of streptomyces lactones by 1,3-dipolar cycloaddition , 1993 .

[17]  H. Mitsuya,et al.  Molecular targets for AIDS therapy. , 1990, Science.

[18]  E. De Clercq,et al.  Mutagenic and antimutagenic effects of 5-substituted 2'-deoxyuridines depending on the nature of the 5-substituent. , 1988, Arzneimittel-Forschung.

[19]  J. Lin,et al.  Antimutagenic activity of extracts from anticancer drugs in Chinese medicine. , 1988, Mutation research.

[20]  R. Tsukamoto,et al.  Antimutagenic effects of 5-fluorouracil and 5-fluorodeoxyuridine on UV-induced mutagenesis in Escherichia coli. , 1986, Mutation research.

[21]  A. Padwa 1,3-Dipolar Cycloaddition Chemistry , 1984 .

[22]  B. Ames,et al.  Revised methods for the Salmonella mutagenicity test. , 1983, Mutation research.

[23]  R. Schaaper,et al.  Role of depurination in mutagenesis by chemical carcinogens. , 1982, Cancer research.

[24]  A. S. Sideropoulos Physiological and genetic effects of puromycin aminonucleoside on ultraviolet-irradiated Escherichia coli strains. , 1979, Mutation research.

[25]  V. Simmon In vitro assays for recombinogenic activity of chemical carcinogens and related compounds with Saccharomyces cerevisiae D3. , 1979, Journal of the National Cancer Institute.

[26]  L. Poirier,et al.  Evaluation of the mutagenicity and DNA-modifying activity of carcinogens and noncarcinogens in microbial systems. , 1979, Journal of the National Cancer Institute.

[27]  B. Ames,et al.  Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals: discussion. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[28]  B. Ames,et al.  Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals. , 1975, Proceedings of the National Academy of Sciences of the United States of America.