Phosphoralaninate Pronucleotides of Pyrimidine Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity |
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| Authors: | Amalraj Ambrose Jiri Zemlicka Earl R Kern John C Drach Elizabeth Gullen Yung-Chi Cheng |
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| Institution: | 1. Department of Chemistry , Developmental Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine , Detroit, Michigan, USA;2. Department of Pediatrics , The University of Alabama School of Medicine , Birmingham, Alabama, USA;3. Department of Biologic and Materials Sciences , School of Dentistry, University of Michigan , Ann Arbor, Michigan, USA;4. Department of Pharmacology , Yale University School of Medicine , New Haven, Connecticut, USA |
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| Abstract: | The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N4-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV. |
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| Keywords: | Antivirals HCMV EBV VZV Methylenecyclopropane analogues Pronucleotides Phenyl phosphoralaninates Prodrugs |
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