(Z)- and (E)-2-(hydroxymethylcyclopropylidene)-methylpurines and pyrimidines as antiviral agents.
Several Z- and E-methylenecyclopropane nucleoside analogues were synthesized and tested for antiviral activity in vitro against human and murine cytomegalovirus (HCMV, MCMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), hepatitis B virus (HBV), herpes simplex virus types 1 and 2 (HSV-1, HSV-2), human herpesvirus 6 (HHV-6) and human immunodeficiency virus type 1 (HIV-1). The Z-2-amino-6-cyclopropylaminopurine analogue was the most effective agent against HCMV (EC50 or EC90 0.4-2 microM) followed by syncytol and the Z-2,6-diaminopurine analogues (EC50 or EC90 3.4-29 and 11-24 microM, respectively). The latter compound was also a strong inhibitor of MCMV (EC50 0.6 microM). Syncytol was the most potent against EBV (EC50 < 0.41 and 2.5 microM) followed by the Z-2,6-diaminopurine (EC50 1.5 and 6.9 microM) and the Z-2-amino-6-cyclopropyl-aminopurine derivative (EC50 11.8 microM). Syncytol was also most effective against VZV (EC50 3.6 microM). Activity against HSV-1, HSV-2 and HHV-6 was generally lower; synthymol had an EC50 of 2 microM against HSV-1 (ELISA) and 1.3 microM against EBV in Daudi cells but was inactive in other assays. The 2-amino-6-cyclopropylamino analogue displayed EC50 values between 215 and > 74 microM in HSV-1 and HSV-2 assays. 2-Amino-6-cyclopropylaminopurine and 2,6-diaminopurine derivatives were effective against HBV (EC50 2 and 10 microM, respectively), whereas none of the analogues inhibited HIV-1 at a higher virus load. Syncytol and the E isomer were equipotent against EBV in Daudi cells but the E isomer was much less effective in DNA hybridization assays. The E-2,6-diaminopurine analogue and E isomer of synthymol were devoid of antiviral activity.
Qiu
Y L
YL
Department of Chemistry, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201-1379, USA.
Ptak
R G
RG
Breitenbach
J M
JM
Lin
J S
JS
Cheng
Y C
YC
Kern
E R
ER
Drach
J C
JC
Zemlicka
J
J
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D006678:HIV / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D004854:Herpesvirus 4, Human / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis*; D011743:Pyrimidines / Q000138:chemical synthesis*; D051381:Rats; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D003521:Cyclopropanes; D011687:Purines; D011743:Pyrimidines