Various water-soluble polysulphonated and polycarboxylated porphyrins and some of their metallated derivatives have been prepared and their antiviral properties against human immunodeficiency virus (HIV-1, HIV-2), simian immunodeficiency virus and other viruses are reported. Besides these polyanionic compounds, two new series of porphyrins were included and studied from the perspective of bio-availability modulation: (i) acefylsulphonamido derivatives endowed with weak acidity properties (deprotonation gives the corresponding anionic derivatives in a pH range 4.5-8.5) and (ii) compounds with the anionic charge transiently masked by esterification (acetoxymethyl- and pivaloyloxymethylesters). Among the more active compounds in inhibiting HIV-induced cytopathic effects, the sulphonated and carboxylated porphyrin complexes were found to interact directly with the HIV protein gp 120 and not with the CD4 cellular receptor.
Inhibition of varicella-zoster virus (VZV) replication by (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) has been examined in vitro under various experimental conditions. The 50% inhibitory dose (ID50) of BVDU for VZV replication in human embryonal fibroblast (HEF) cultures was 0.016 micrograms/ml, if the assay was based on the reduction of visible foci. If the assay was based on the reduction of immunofluorescent foci, the ID50 was 3 times higher. There was no significant difference in ID50, whether the HEF cultures were infected with cell-free or cell-associated VZV. When the HEF cells were infected with VZV at different multiplicities of infection (MOI), the ID50 of BVDU increased in parallel with the increase of MOI. BVDU was normally added immediately after virus infection. However, the addition of BVDU could be delayed until 8 hr after infection without substantial decrease of activity. On the other hand, BVDU did not cause any inhibition of focus formation when it was removed within 8 hr after VZV infection. If removed at 24 or 48 hr after infection, BVDU caused a significant reduction in focus formation. BVDU had no effect on focus formation if added to the HEF cells before virus infection. BVDU was also found to inhibit VZV focus formation in Vero cells, but only at an ID50 that was 5-10 times higher than the ID50 noted in HEF cells.
The synthesis, hydrolysis, and antiviral evaluation of novel, lipophilic cycloSal-ddAMP (9a-d) and cycloSal-d4AMP (10a-d) derivatives of the antiviral purine dideoxynucleoside analogues 2', 3'-dideoxyadenosine (ddA) (2) and 2',3'-dideoxy-2', 3'-didehydroadenosine (d4A) (3) are reported. These potential pronucleotides release ddAMP (7) or d4AMP (8) selectively by a controlled, chemically induced tandem reaction. All new compounds 9 and 10a-d were synthesized in good yields using our previously reported phosphorus(III) method starting from substituted salicyl alcohols 14a-h. The phosphotriesters 9 and 10 were obtained with a stereochemical preference of 2:1 with respect to the configuration at the phosphorus center. In an 1-octanol/water mixture phosphotriesters 9 and 10 exhibited 7-43-fold higher lipophilicity than the parent nucleosides ddA (2) and d4A (3) as judged by their log P values. In hydrolysis studies, 9 and 10 decomposed under mild aqueous basic conditions releasing solely ddAMP (7) and d4AMP (8), as well as the diols 14. Further hydrolysis studies under acidic conditions showed a marked increase in stability with respect to the acid-catalyzed cleavage of the glycosyl bond. Phosphotriesters 9 and 10 exhibited antiviral potencies against wild-type HIV-1 and HIV-2 strains in human T-lymphocyte (CEM/O) cells that were, respectively, 100- and 600-fold higher than those of ddA (2) and d4A (3). Furthermore, all triesters 9 and 10 were markedly more active than the corresponding ddI compounds 11 and 12, which supports the concept of the delivery of the adenine nucleotides. Studies with adenosine deaminase (ADA) and adenosine monophosphate deaminase (AMPDA) showed that the triesters were not substrates for enzymatic deamination. The studies reported herein demonstrate conclusively that the cycloSal triesters deliver exclusively the nucleotides ddAMP and d4AMP, not only under chemical-simulated hydrolysis but also under intracellular conditions fulfilling the adenosine deaminase bypass premise.
Following topical application of (125)IVDU, the radiolabeled analogue of bromovinyldeoxyuridine ([E]-5-[2-bromovinyl]-2'-deoxyuridine), as 0.5% or 0.3% eyedrops, to rabbits, (125I)IVDU appeared in the anterior chamber fluid at drug levels well above the minimum concentration (0.01 microgram/mL) required for inhibition of herpes simplex virus type 1 replication. These findings are consistent with the efficacy of 0.5% bromovinyldeoxyuridine eyedrops in the topical treatment of herpes simplex uveitis.
The antiviral activity spectrum of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) is not restricted to herpes simplex virus type 1 (HSV-1) and varicella-zoster virus (VZV) but also encompasses several other herpesviruses such as suid herpesvirus type 1 (SHV-1), bovid herpesvirus type 1 (BHV-1), simian varicella virus (SVV), herpesvirus saimiri, herpesvirus platyrrhinae, and the baculovirus Trichoplusia ni multiple nuclear polyhedrosis virus. Other herpesviruses such as herpes simplex virus type 2, cytomegalovirus and Epstein-Barr virus are also inhibited by BVdU, albeit to a lesser extent than HSV-1, VZV, SHV-1, BHV-1 and SVV.
