Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate.

Ganciclovir cyclic phosphonate (SR3775) is a derivative of the R enantiomer (SR3773) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine), both of which are potent inhibitors of human ctyomegalovirus and murine cytomegalovirus (MCMV). Against wild-type and four drug-resistant strains of MCMV, SR3773 was 2.3- to 3-fold more potent than SR3775.

Antiviral activities of nucleosides and nucleotides against wild-type and drug-resistant strains of murine cytomegalovirus.

Resistance of human cytomegalovirus to approved antiviral drugs is becoming a problem of increasing concern. In order to further study drug resistance in a related virus, strains of murine cytomegalovirus (MCMV) have been prepared in vitro by extensive adaptation of the virus to increasingly higher concentrations of either ganciclovir, foscarnet, or (S)-9-(3-hydroxy-2-[phosphonylmethoxy]propyl)cytosine (HPMPC). Plaque reduction 50% effective concentrations (EC50) for the above inhibitors increased 9-, 7-, and 23-fold, respectively (against the corresponding virus), compared to wild-type MCMV.

Nucleotide analogs related to acyclovir and ganciclovir are effective against murine cytomegalovirus infections in BALB/c and severe combined immunodeficient mice.

Acyclovir phosphonate [9-(3-phosphono-propyloxymethyl)guanine; SR3722] and the S enantiomer (SR3772), R enantiomer (SR3773), and R,S enantiomeric mixture (SR3745A) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine) were evaluated for their antiviral activities against murine cytomegalovirus. In severe combined immunodeficient mice infected with murine cytomegalovirus, SR3773 and SR3745A (12.5, 25, and 50 mg/kg of body weight per day) were superior to ganciclovir in extending the mean time to death, whereas SR3722 and SR3772 was less potent than ganciclovir.

Selective inhibition of cytomegaloviruses by 9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)g uanine.

9-(3'-ethylphosphono-1'-hydroxymethyl-1'-propyloxy-methyl)gu anine (SR 3727A) was significantly inhibitory to strain AD169 of human cytomegalovirus (HCMV) utilizing plaque reduction and inhibition of intra- and extracellular virus yield in MRC-5 cells. The 50% effective concentrations (EC50) ranged from 6-17 microM for three laboratory strains of HCMV, whereas the 50% cytotoxic doses were > 4200 microM as determined by viable cell assay and inhibition of radiolabeled precursors into DNA, RNA and protein. EC50 values against ganciclovir-sensitive clinical isolates ranged from 8-47 microM.

Beta-deuteration of N-nitrosoethylmethylamine causes a shift in DNA methylation from rat liver to esophagus.

While N-nitrosoethylmethylamine (NEMA) is carcinogenic primarily for the liver, its beta-trideuterated derivative, N-nitroso( [2-D3]ethyl)methylamine (NEMA-d3), also produces a high incidence of tumors in the esophagus. To determine whether this shift in organ specificity is associated with an altered pattern of DNA alkylation, [methyl-14C]- and [1-ethyl-14C]-labeled NEMA-d3 were administered to adult male Fischer 344 rats as a single i.p.

Decomposition and quality control considerations in biological work with fecapentaene preparations.

Solutions of synthetic fecapentaene 12 (FP-12) intended for carcinogenicity studies were found to decompose extremely rapidly during customary dosage procedures. Apparent half-lives as short as 15 min were observed. While rates and even the qualitative course of decomposition were surprisingly variable in replicate experiments, high concentration and exposure to air were confirmed to be especially important destabilizing influences.

Combined chromatographic-isotopic dilution analysis of fecapentaenes in human feces.

Fecapentaene-12 (FP-12) and fecapentaene-14 (FP-14) are genotoxic unsaturated ether lipids produced by colonic bacteria in man. We have developed and applied to feces collections from normal volunteers direct isotopic dilution procedures using tritium-labeled (at C5) FP-12 and FP-14 for measuring these compounds. FPs were recovered from feces by solvent extraction, silica cartridge clean-up, and analytical liquid chromatography.

Evaluation of the mutagenic activity of some phenanthroisoquinolines in Salmonella typhimurium.

The mutagenic activity of 3 aza-polycyclic aromatic hydrocarbons, which are suspected of being environmental pollutants, was assessed using the Salmonella assay. The compounds tested were phenanthro[9,10-g]isoquinoline, phenanthro[2,3-h]isoquinoline, and phenanthro[3,2-h]isoquinoline. None of the compound was mutagenic in the absence of S9, but all were mutagenic in the presence of S9.

Mutagenic activities of fecapentaene derivatives in the Ames/Salmonella test system.

The direct mutagenic activities of a pair of naturally-occurring and several synthetic fecapentaenes were measured in the Ames/Salmonella test system. We found that strain TA100 with preincubation was the most sensitive procedure for the naturally-occurring fecapentaene-12 (FP-12). Its natural analog, FP-14, and the synthetic isomer, cis-FP-12, yielded similar mutagenic activities to FP-12 in the range of 1000-2000 TA100 revertants per microgram of compound.

Bacterial mutagenicity and carcinogenic potential of some azapyrene derivatives.

The mutagenic and carcinogenic activities of 5 azapyrenes, which are suspected of being environmental pollutants, were assessed using the Salmonella assay and the anchorage-independent survival assay. The compounds tested were: 1-azapyrene, 2-azapyrene, 4-azapyrene, 1-aza-2-hydroxypyrene, and 2-aza-1-hydroxypyrene. The compounds were mutagenic and some were also carcinogenic.

Potential carcinogenicity of aza-aromatic hydrocarbons: azabenz(a)anthracenes.

The potential carcinogenicity of 3 azabenz(a)anthracenes was determined in vitro. The 3 compounds tested were 1-, 2-, and 9-azabenz(a)anthracene. The initial assay was chemical carcinogen-induced enhancement of anchorage-independent survival of Rauscher leukemia virus-infected Fischer rat embryo cells, 2FR(4)50 (2FR4).

Evaluation of the mutagenic activity of some aza-aromatic hydrocarbons.

The mutagenic activity of 7 aza-aromatic hydrocarbons, which are suspected of being environmental pollutants, was assessed using the Salmonella assay. The compounds tested were: 1-azachrysene, 2-azachrysene, 4-azachrysene, 1-azabenz[a]anthracene, 2-azabenz[a]anthracene, 9-azabenz[a]anthracene, and 12-benzo[a]pyrene. None of the compounds was mutagenic in the absence of S9, but all were mutagenic in the presence of S9.

Carcinogenesis and aging. II. Modifying effect of aging on metabolism of methyl(acetoxymethyl)nitrosamine and its interaction with DNA of various tissues in rats.

Young (3 month-old) and old (14 month-old) female outbred rats received a single i.p. dose (13 mg/kg) of N-[14C]methyl-Nacetoxymethylnitrosamine [( 14C]DMN-OAc), which, under these conditions, selectively induces intestinal tumours.

Synthesis of nitrosourea derivatives of sucrose as central nervous system anticancer agents.

Nitrosourea derivatives of sucrose have been synthesized for the purpose of obtaining anticancer agents with activity against brain cancer. Two such compounds, 6,6'-dideoxy-6,6'-di(3-methyl-3-nitrosoureido) sucrose (13) and 1', 6,6'-trideoxy-1',6,6-tri(3-methyl-3-nitrosoureido) sucrose (14), and their respective acetylated derivatives 15 and 16 have been prepared from sucrose. Compounds 13 and 14 have demonstrated antitumor activity against both L1210 leukemia and ependymoblastoma brain tumor in mice.