Publications

The following derivatives of 2'-deoxy-5'-O-1",3",2"-dioxaphosphacyclohex-2" -yluridine 2"-oxide have been synthesised: 5-fluoro (4), 5"-(benzyloxy)-5-methyl (6), 5"-(benzyloxy)-5-fluoro (7), 5"-hydroxy-5-methyl (8), 5-fluoro-5"-hydroxy (9), 5",5"-difluoro-5-methyl (11), and 5,5",5"-trifluoro (12). Compounds 4, 9, and 12 have been evaluated for their inhibitory effects on the growth and metabolism of murine leukemia L1210 cells. Compound 12 was nearly as potent as 2'-deoxy-5-fluorouridine in its inhibitory effect on these cells (ID50 = 0.003 and 0.001 micrograms/mL, respectively). Compounds 4 and 9 were about 300 times less active than 12. None of the compounds was an inhibitor of the cell-free thymidylate synthetase, although their antiproliferative effects were achieved by the inhibition of this enzyme.

The synthesis of novel substituted 3-aralkylthiomethylimidazo[1,2-b]pyridazines is reported. All of the synthesized compounds are devoid of antiviral activity against the replication of human immunodeficiency virus. However, compounds 6-chloro-8-methyl-3-phenethylthioimidazo[1,2-b]pyridazine and 6-chloro-2-methyl-3-phenethylthioimidazo[1,2-b]pyridazine are potent inhibitors of the replication of human cytomegalovirus in vitro, while compounds 6-chloro-2-methyl-3-benzylthiomethylimidazo[1,2-b]pyridazine and 6-chloro-2-methyl-3-phenethyl-thioimidazo[1,2-b]pyridazineare inhibitors of the replication of varicella-zoster virus. The results presented here suggest that compound 10 should be considered as a new lead in the development of antiviral agents.

The effect of intralesional injections of cidofovir, a nucleotide analog with potent in vitro activity against human herpesvirus 8 (HHV-8), was studied in vivo in an HIV-negative patient with classical Kaposi's sarcoma (KS). After five weekly injections of the drug, no clinical, histological, immunohistological, or virological changes could be detected in comparison with saline-injected lesions. These findings suggest that, once the KS tumor has developed, active viral replication is no longer involved in the pathogenesis of the disease. Alternative hypotheses are that HHV-8 replication in blood-borne cells may foster growth of spindle cells in the skin, or that blocking HHV-8 may not affect existing lesions but may prevent new lesions from developing. J. Med. Virol. 55:215–218, 1998. © 1998 Wiley-Liss, Inc.

In the present work, various Schiff’s bases of isoniazid bearing 1, 3, 4-oxadiazole nucleus were synthesized. These compounds were purified, characterized and evaluated in vitro for antibacterial, antifungal and antiviral activities. Compound 5 showed better biological profile.

Human fibroblast cells treated with a combination of inhibitors of protein and RNA synthesis [cycloheximide and actinomycin D as used to superinduce interferon beta (IFN-beta)] secrete two proteins with molecular masses of 22000 and 27000 kilodaltons (called 22-kDal and 27-kDal) that are precipitable with an antiserum raised against impure IFN-beta but are antigenically distinct from IFN-beta 1. Translation in vitro of mRNA extracted from human fibroblast cells induced for the production of IFN-beta leads to the synthesis of a 26-kDal protein that is structurally closely related to the 22- and 27-kDal proteins. This 26-kDal protein mRNA is relatively abundant and also appears in human fibroblasts induced only with cycloheximide. It has been partially purified by sucrose gradient centrifugation and more extensively by diazobenzyloxymethyl-cellulose hybridization to plasmid DNA from a bacterial cDNA clone. When translated in an in vitro reticulocyte system supplemented with dog pancreas microsomes, the 26-kDal protein and two other intermediates corresponding presumably to its signal-cleaved (19-kDal) and partially glycosylated (24-kDal) forms were observed. Crude, partially purified, and highly purified 26-kDal mRNA failed to program the synthesis of antiviral or ppp(A2'p5')nA synthetase-inducing activity when translated in Xenopus laevis oocytes. Moreover, partially purified 22-kDal and 27-kDal (i.e., the in vivo equivalents of the 26-kDal protein) are also devoid of antiviral or ppp(A2'p5')nA synthetase-inducing activity. Hence, this 26-kDal mRNA, although presumably identical to the human IFN-beta 2 mRNA described by Weissenbach et al. [Weissenbach, J., Chernajovsky, Y., Zeevi, M., Shulman, K., Soreq, H., Nir. U., Wallach, D., Perricaudet, M., Tiollais, P. & Revel, M. (1980) Proc. Natl. Acad. Sci. USA 77, 7152-7156], cannot be considered to be a fibroblast interferon mRNA.

2-(Arylcarbonylmethyl)thio-6alpha-naphthylmethyl derivatives of dihydro-alkoxy-benzyl-oxopyrimidines (DABO) were newly found to exhibit activity against both HIV-1 and HIV-2. To further explore their structure-activity relationship, the modified S-DABO analogues (5a-g and 6e-f) with a 1-naphthylthio or phenylthio group at the C-6 position were synthesized. S-Alkylation of 5-ethyl-2-thiouracil with substituted 2-bromo-acetophenones provided crude 2-[(arylcarbonylmethyl)thio]-5-ethyl-(3H)-uracil 2a-e, which was directly subjected to toluenesulfonylation with TsCl to afford disulfonate 4a-e. Substitution of 4a-e with arylthiol afforded the desired S-DABO analogues 5a-g and 6e-f. The compounds were evaluated for their in vitro anti-HIV activity in MT-4 cells. The IC(50) values for anti-HIV-1 activity fall into the range 0.37-29.50 microM, and the IC(50) values for anti-HIV-2 activity fall into the range 23.11-181.07 microM. The results indicated that these compounds are moderately active against HIV-1 and HIV-2.