Comparative Study of the Antiviral Activity of Acyl Derivatives of 2,2′-Anhydro-1-β- d -Arabinofuranosylcytosine and Other Nucleosides Against Encephalitis in Mice

Abstract

Anti-deoxyribonucleic acid virus activities of 3′- O -acyl derivatives of 2,2′-anhydro-1-β- d -arabinofuranosyl cytosine (cyclo-C) and 1-β- d -arabinofuranosylcytosine (Ara-C) were evaluated by using an in vivo test system in mice. Among the derivatives tested, 3′- O -decanoyl cyclo-C hydrochloride was the most effective against herpes simplex virus-induced encephalitis in mice when the drug was administered directly into infected brains of mice (target-organ treatment). A comparative study of the treatment of herpetic encephalitis in mice with 3′ O -decanoyl cyclo-C and other nucleosides, including Ara-C, 9-β- d -arabinofuranosyladenine (Ara-A), and 5-iodo-2′-deoxyrudine (IUdR), proved Ara-A to be more efficacious than the other nucleosides, followed by 3′- O -decanoyl cyclo-C, which was more active than Ara-C and IUdR. Administration of 3′- O -acyl cyclo-C's by intraperitoneal injection, however, failed to demonstrate activity against herpetic encephalitis in mice. The antivaccinial activity of 3′- O -decanoyl cyclo-C was also compared with that of other compounds against encephalitis and dermal tail lesions in mice caused by vaccinia virus infection. Interaperitoneally administered 3′- O -decanoyl cyclo-C and Ara-C also showed no significant activity against the diseases. Under these test conditions, N -methylisatin-β-thiosemicarbazone (Marboran) was the most active compound, followed by Ara-A.

Antiviral agents

“…Surprisingly the 5'-monophosphate is not teratogenic in rabbits at 25 mg/kg intramuscularly, although Ara-A at 5 mg/kg is teratogenic In the search for less toxic compounds, many analogues of Ara-C have been prepared. The arabinose hydroxyls have been alkylated but gave inactive compounds [277] and acylated to give activity when the acyl groups are enzymically hydrolyzed in vivo to free 279], while the 4-NH2 group has been acylated with a large variety of groups including pep tides [280]. Removal of the elements of water between the 2-and 2'-positions of Ara-C gives 2,2'-anhydro-l-p -D-arabinofuranosylcytosine (cyclocytidine; LIX).…”

“…This derivative has activity against herpes virus in vitro at 0. [278,279]. Acylation of the 3'-and S'-hydroxyls gave a wide range of active compounds [282], while the S'-monophosphate [283] and 3',S'-cyclic monophosphate [284, 28S] have been reported equi-active with Ara-C.…”