ANTIVIRAL ACTIVITY OF C-5 SUBSTITUTED TUBERCIDIN ANALOGS

The pyrrolo[2,3-d]pyrimidine nucleoside antibiotics tubercidin, toyocamycin and sangivamycin and the synthetic analogs 5-chloro-, 5,6-dichloro-, 5-bromo-, 6-bromo-, 5,6-dibromo-, 5-iodo-, 5-(1-hydroxyethyl)-, 5-(1-methoxyethyl)-, (E)-5-(2-bromoethenyl)-, (E)-5-(2-cyanoethenyl)-, 5-(2-buten-1-yl)-, 5-(3-hydroxypropyl)- and 5-butyltubercidin were evaluated for their antiviral properties against 6 RNA viruses and 3 DNA viruses in [human cervical carcinoma HeLa] cells, primary rabbit kidney cell and [African green monkey kidney] Vero cell cultures. Most of the derivatives had substantial activity against the RNA viruses, with the least activity shown by 6-bromo-, 5,6-dichloro- and 5,6-dibromotubericidin. The C-5 substituted derivatives were quite toxic for the host cells. 5-(1-Hydroxyethyl)-, 5-(1-methoxyethyl)- and 5-(2-buten-1-yl)tubercidin were more selective against reovirus type 1, parainfluenza virus type 3 and coxsackie virus B4 than tubercidin and the 5-halotubercidins. When tested for in vivo activity against coxsackie virus B4 infection in newborn NMRI mice, 5-(1-hydroxyethyl)- and 5-(1-methoxyethyl)tubercidin caused a significant decrease in the mortality rate at a dose level of 100 .mu.g per mouse. The inhibitory effects on [mouse leukemia] L-1210 cell growth were also determined, and toyocamycin (ID50 = 0.006 .mu.g/ml) was found to be the most active compound. This study demonstrates the significance of structural modification at C-5 and the potential of C-5 substituted analogs of tubercidin as biologically active agents.