Publications

Abstract For Abstract see ChemInform Abstract in Full Text.

Cidofovir [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC)] is recognized as a promising drug for the treatment of poxvirus infections, but drug resistance can arise by a mechanism that is poorly understood. We show here that in vitro selection for high levels of resistance to HPMPC produces viruses encoding two substitution mutations in the virus DNA polymerase (E9L) gene. These mutations are located within the regions of the gene encoding the 3'-5' exonuclease (A314T) and polymerase (A684V) catalytic domains. These mutant viruses exhibited cross-resistance to other nucleoside phosphonate drugs, while they remained sensitive to other unrelated DNA polymerase inhibitors. Marker rescue experiments were used to transfer A314T and/or A684V alleles into a vaccinia virus Western Reserve strain. Either mutation alone could confer a drug resistance phenotype, although the degree of resistance was significantly lower than when virus encoded both mutations. The A684V substitution, but not the A314T change, also conferred a spontaneous mutator phenotype. All of the HPMPC-resistant recombinant viruses exhibited reduced virulence in mice, demonstrating that these E9L mutations are inextricably linked to reduced fitness in vivo. HPMPC, at a dose of 50 mg/kg of body weight/day for 5 days, still protected mice against intranasal challenge with the drug-resistant virus with A314T and A684V mutations. Our studies show that proposed drug therapies offer a reasonable likelihood of controlling orthopoxvirus infections, even if the viruses encode drug resistance markers.

In order to obtain compounds which would give 2′-deoxy-5-vinyluridine (VdUrd) by elimination under basic conditions, a series of 5-(1-substituted ethyl)uracil derivatives has been made. Attempts to obtain 5-(1-alkyl- or -aryl-sulphonyloxy) derivatives were unsuccessful because elimination to give the 5-vinyl derivatives was extremely easy. 5-(1-Acyloxyethyl) derivatives did not eliminate, but with aqueous alkali gave 5-(1-hydroxyethyl)uracil derivatives. Reaction of VdUrd with a series of arenethiols gave 5-(1-arylthioethyl)-2′-deoxyuridines. In the absence of radical inhibitors 5-(2-arylthioethyl)-2′deoxyuridines were the major products. The arylthio compounds were oxidized to the corresponding sulphoxides and sulphones. Treatment of these 5-(1-substituted) derivatives with potassium t-butoxide in dimethylformamide gave VdUrd. As expected the reaction rate was greatest with the compound which had the best leaving group. However, with aqueous alkali the compounds gave 2′-deoxy-5-(1-hydroxyethyl)uridine and at pH 7.6 at 37 °C they were stable. When N-3 of the uracil ring was alkylated the elimination was faster. The implication of this result for the mechanism of the elimination is discussed. Two of the compounds synthesized, namely 2′-deoxy-5-[1-(2,4,5-trichlorophenylthio)ethyl]uridine and 2′-deoxy-3-methyl-5-[1-(2,4,5-trich lorophenylthio)ethyl]uridine, showed activity against vaccinia virus and murine L1210 leukaemia cells at a concentration. of 30–40 µg/ml, and 2′-deoxy-5-[(2-phenylthio)ethyl]uridine, had activity against different strains of herpes simplex viruses types 1 and 2 at a concentration of 20 µg/ml.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

In an attempt to combine the HIV-inhibitory capacity of 2',3'-dideoxynucleoside (ddN) analogues and non-nucleoside reverse transcriptase (RT) inhibitors (NNRTI), we have designed, synthesized, and evaluated for their anti-HIV activity several dimers of the general formula [ddN]-(CH2)n-[NNRTI]. These dimers combine in their structure a ddN such as AZT and a NNRTI such as TSAO-T and HEPT linked through an appropriate spacer between the N-3 of the thymine base of both compounds. The [TSAO-T]-(CH2)n-[AZT] dimers proved markedly inhibitory to HIV-1. Also, if AZT was replaced by thymidine in the dimer molecules, potent anti-HIV-1 activity was observed. However, although the compounds proved inhibitory to HIV-1, they were less potent inhibitors than the parent compounds from which they were derived. None of the dimers were endowed with anti-HIV-2 activity. In contrast with the TSAO-T monomers, none of the TSAO-T-containing dimers proved markedly cytotoxic to the cells. There was a clear trend toward decreased antiviral potency with lengthening the methylene spacer in the [TSAO-T]-(CH2)n-[AZT] dimers.

Abstract 1,5-Anhydrohexitol congeners of AZT, D4T and DDC were synthesized. These compounds did not show anti-HIV activity.

Dimensional inspection tasks are often carried out on conventional coordinate measuring machines (CMMs). These CMMs can differ in layout and size depending on the application area. They can have measurement volumes up to 100m3. However, when measuring large objects it is not always possible to bring a large object to these conventional CMMs. That is why for these applications mobile measuring systems are an ideal solution. These systems often measure the dimensions through optical techniques, like interferometry and optical triangulation. After a short survey of common optical measurement techniques for mobile and large-scale measurements, this paper focuses on two industrial cases where different techniques were used to solve a measurement problem. The first case covers the measurement of a large iron casting with an optical LED-based triangulation system. It was possible to predict problems that would occur with the machining of the part, like unfinished surfaces after milling due to material shortage, and adapt the alignment of the part to prevent these problems. The second case covers the measurement of a double-decker train by means of photogrammetry, as an alternative for the currently used total station. Despite some specific drawbacks of photogrammetry systems it was possible to obtain the same accuracy and to reduce the overall inspection time significantly in comparison with the current situation.

Several cholic acid derivatives such as taurolithocholic acid, lithocholic acid 3-sulfate, taurolithocholic acid 3-sulfate, and glycolithocholic acid 3-sulfate were shown to inhibit selectively the replication of human immunodeficiency virus type 1 (HIV-1) in vitro. These compounds completely protected MT-4 cells against HIV-1-induced cytopathogenicity at a concentration of 100 micrograms/ml, whereas no toxicity for the host cells was observed at 200 micrograms/ml. They also inhibited HIV-1 antigen expression in HIV-1-infected CEM cells. The bile acids (cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid) did not show any inhibitory effect on HIV-1 replication at concentrations that were not toxic to the host (MT-4) cells. From a structure-function analysis of a number of cholic acid derivatives, the presence of either a sulfonate (as in the tauro conjugates) or a sulfate group as well as the "litho" configuration appeared to be necessary for the expression of anti-HIV-1 activity. The active cholic acid derivatives did not directly inactivate the virus particles at the concentrations that were not toxic to the host cells. Lithocholic acid 3-sulfate, taurolithocholic acid 3-sulfate, and glycolithocholic acid 3-sulfate, but not taurolithocholic acid, partially inhibited virus adsorption to MT-4 cells. These three compounds were also inhibitory to the reverse transcriptase activity associated with HIV-1.