Synthesis and antiretrovirus properties of 5'-isocyano-5'-deoxythymidine, 5'-isocyano-2',5'-dideoxyuridine, 3'-azido-5'-isocyano-3',5'-dideoxythymidine, and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine.

Abstract

The 5'-azidonucleosides 3 and 4 were obtained by treating thymidine and 2'-deoxyuridine with TPP/DEAD/HN3. The 3'-O-silylated 5'-azido-5'-deoxythymidine 5 and the corresponding 2'-deoxyuridine derivative 6 were transformed to the formamides (7 and 8, respectively) and dehydrated to the protected 5'-isocyano derivatives 9 and 10; deblocking gave 5'-isocyano-5'-deoxythymidine (11) and 5'-isocyano-2',5'-dideoxyuridine (12). 2,3'-Anhydro-5'-formamido derivatives of thymidine and 2'-deoxyuridine (19 and 20, respectively) were prepared by three different ways. In the most direct synthesis 3 and 4 were transformed to the 2,3'-anhydro-5'- azidonucleosides 17 and 18 by using TPP/DEAD; following the reaction with TPP/HCO2COCH3 gave 19 and 20. Nucleophilic opening reaction with LiN3 yielded the 3'-azido-5'-formylamino derivatives 21 and 22. Dehydration to 3'-azido-5'-isocyano-3',5'-dideoxythymidine (23) and 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine (24) was achieved with tosyl chloride/pyridine. In contrast with 3'-azido-3'-deoxythymidine, compounds 11, 12, 23, and 24 were devoid of any marked inhibitory effect against DNA and RNA viruses including human immunodeficiency virus type I (HIV).

• Authors: J Hiebl, E Zbiral, J Balzarini, E De Clercq
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 34 Issue 4 Pg. 1426-30 (Apr 1991) ISSN: 0022-2623 [Print] United States
• PMID: 2016718 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Azides
• Dideoxynucleosides
• Indicators and Reagents
• 5'-isocyano-5'-deoxythymidine
• 3'-azido-5'-isocyano-3',5'-dideoxythymidine
• 3'-azido-5'-isocyano-2',3',5'-trideoxyuridine
• 5'-isocyano-2',5'-dideoxyuridine
• Zidovudine
• Deoxyuridine

Topics

• Animals
• Antiviral Agents (chemical synthesis)
• Azides (chemical synthesis, chemistry, pharmacology)
• Cell Line
• Cell Survival (drug effects)
• Deoxyuridine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Dideoxynucleosides (chemical synthesis, chemistry, pharmacology)
• HIV-1 (drug effects)
• HeLa Cells (cytology, drug effects)
• Humans
• Indicators and Reagents
• Molecular Structure
• Retroviridae (drug effects)
• Structure-Activity Relationship
• Vero Cells
• Zidovudine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)