Transformation of the furanose ring to a 3- or 4-membered ring produces compounds with interesting biological activity. Oxetanocin A, 9-(2-deoxy-2-hydroxymethyl-P-D-erythro-oxetanosyl)adenine (138) (Figure 56), is an antibiotic produced by Bacillus megate-rium, which inhibits infection of T cells by HIV-1 in vitroP9 Chemical and enzymatic modifications of oxetanocin A (OXT-A) have afforded 2,6-diamino (2-amino-OXT-A), guanine (OXT-G), hypoxanthine (OXT-H) and xanthine (OXT-X) analogs.240 In MT-4 cells, OXT-A markedly reduces the expression of HIV antigens, and 2-amino-OXT-A, OXT-G and OXT-H also show significant anti-HIV activity. In addition, OXT-G is very potent and selective in inhibiting the replication of HCMV in vitro (EC50 0.1 (ig/mL) and against HSV-2 (EC50 3.5 ng/mL).241
The thymidine analog of oxetanocin, A-73209 (139), is a potent in vitro and in vivo inhibitor of HSV-1, HSV-2 and VZV.242 A-73209 is two logs more potent against five TK+ strains of VZV in vitro and one log more potent against TK+ HSV-1 strains than ACV. A-73209 is more effective than ACV against lethal systemic or intracerebral HSV-1 infections in mice. l-oxetanocin (l-OXT-A, 140) is inactive against HIV.243
Early reports of racemic carbocyclic analogs of OXT-A and OXT-G have described the protective effect of both carbocyclic analogs on CD4+ ATH8 cells against the in-fectivity and cytopathic effect of HIV-1, suppressing proviral DNA synthesis.244 245-246 In addition, carbocyclic OXT-G showed excellent activity against HSV and it was suggested that it is phosphorylated by virus-encoded TK prior to exerting its antiviral effect. In contrast, the adenine congener, carbocyclic OXT-A, is a good inhibitor of HCMV in vitro and in vivo. However, severe cytotoxicity to host cells has prevented further development of this compound as an anti-HCMV agent.
The active enantiomer of carbocyclic OXT-G (141, lobucavir, LBV, Figure 56) displays an impressive broad-spectrum antiviral activity against a wide variety of herpesviruses and HBV as well as HIV.247 The mechanism of action of LBV against HSV-1, HSV-2 and VZV consists in the inhibition of the viral polymerases after phosphorylation by the virally encoded TK (Figure 57).247 However, HCMV, HBV and HIV do not encode enzymes which are capable of mediating LBV phosphorylation.
It is known that HCMV has homologs of a herpesvirus-encoded protein kinase (UL97 gene), which mediates the phosphorylation of ganciclovir (GCV). In the case of VZV, both the herpesvirus TK and protein kinase may independently enable the phosphorylation of LBV. Furthermore, LBV is phosphorylated to its triphosphate intracellularly in both HCMV-infected and uninfected cells, with phosphorylated metabolites levels 2- to 30-fold higher in infected cells. These studies247 suggest that LBVTP can halt HCMV DNA replication by inhibiting the viral DNA polymerase and that LBV's phosphorylation can occur in the absence of viral factors including the UL97 protein kinase. In addition, LBV may be effective in the treatment of GCV-resistant HCMV. LBV has undergone clinical trials as an anti-HBV agent.
viral TK for HSV-1/2 and VZV
protein kinase for HCMV
Broad spectrum antiviral activity
3'-Fluorocarbocyclic oxetanocin A (142, Figure 58) exhibits a broad spectrum of antiviral activity especially against HCMV with an EC50 of 0.18 ng/mL, which is 4-fold more potent than that of ganciclovir.248 However, this compound is slightly cytotoxic at higher concentrations (100 p.g/mL) in HEL or MT-4 cells, although this toxicity is minor compared with that of carbocyclic OXT-A (CC50 for HEL; 8 )ig/mL, CC50 for MT-4; 12 |ig/mL).248
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