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J Zeidler

Publications and source records attributed to J Zeidler.

17 recordsLinked to original sources
PubMed2001

Fluorescent tricyclic analogues of acyclovir and ganciclovir. A structure-antiviral activity study.

Of a series of new guanine base modified tricyclic analogues of acyclovir (ACV, 1) and ganciclovir (GCV, 2), derivatives of the 3,9-dihydro-9-oxo-5H-imidazo[1,2-a]purine system, evaluated for activity against herpes simplex virus type 1 and 2, several fluorescent analogues, 6-(4-MeOPh)-TACV (8), 7-Me-6-Ph-TACV (17), 6-(4-MeOPh)-TGCV (27), and 7-Me-6-Ph-TGCV (28), were obtained that showed similar potency and selectivity as the parent compounds. The activity was found to be strongly dependent on the nature and steric demands of the substituents in the 6 and/or 7 position.

Acyclovir↗
PubMed2001

Biosynthesis of 2-methyl-3-buten-2-ol emitted from needles of Pinus ponderosa via the non-mevalonate DOXP/MEP pathway of isoprenoid formation.

The volatile hemiterpene 2-methyl-3-buten-2-ol (MBO) is emitted from the needles of several pine species from the Western United States and contributes to ozone formation in the atmosphere. It is synthesised enzymatically from dimethylallyl diphosphate (DMAPP). We show here that needles of Pinus ponderosa Laws. incorporated [1-2H1]-1-deoxy-D-xylulose (d-DOX) into the emitted MBO, but not D,L-[2-13C]mevalonic acid lactone. Furthermore, MBO emission was inhibited by fosmidomycin, a specific inhibitor of the second enzyme of the mevalonate-independent pathway of isopentenyl diphosphate and DMAPP formation, i.e. the 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate (DOXP/MEP) pathway. We thus prove that MBO emitted from needles of P. ponderosa is primarily formed via the DOXP/MEP pathway.

Hemiterpenes↗
PubMed2000

Properties and inhibition of the first two enzymes of the non-mevalonate pathway of isoprenoid biosynthesis.

Enzymes of the 1-deoxy-D-xylulose 5-phosphate/2-C-methylerythritol 4-phosphate (DOXP/MEP) pathway are targets for new herbicides and antibacterial drugs. Until now, no inhibitors for the DOXP synthase have been known of. We show that one of the breakdown products of the herbicide clomazone affects the DOXP synthase. One inhibitor of the non-mevalonate pathway, fosmidomycin, blocks the DOXP reductoisomerase (DXR) of plants and bacteria. The I(50) values of plants are, however, higher than those found for the DXR of Escherichia coli. The DXR of plants, isolated from barley seedlings, shows a pH optimum of 8.1, which is typical for enzymes active in the chloroplast stroma.

Aldose-Ketose Isomerases↗
PubMed1999

Inhibitors of the nonmevalonate pathway of isoprenoid biosynthesis as antimalarial drugs.

A mevalonate-independent pathway of isoprenoid biosynthesis present in Plasmodium falciparum was shown to represent an effective target for chemotherapy of malaria. This pathway includes 1-deoxy-D-xylulose 5-phosphate (DOXP) as a key metabolite. The presence of two genes encoding the enzymes DOXP synthase and DOXP reductoisomerase suggests that isoprenoid biosynthesis in P. falciparum depends on the DOXP pathway. This pathway is probably located in the apicoplast. The recombinant P. falciparum DOXP reductoisomerase was inhibited by fosmidomycin and its derivative, FR-900098. Both drugs suppressed the in vitro growth of multidrug-resistant P. falciparum strains. After therapy with these drugs, mice infected with the rodent malaria parasite P. vinckei were cured.

Aldose-Ketose Isomerases↗
PubMed1999

Cloning and heterologous expression of a cDNA encoding 1-deoxy-D-xylulose-5-phosphate reductoisomerase of Arabidopsis thaliana.

Various plant isoprenoids are synthesized via the non-mevalonate pathway of isopentenyl diphosphate formation. In this pathway, 1-deoxy-D-xylulose 5-phosphate (DOXP), the first intermediate, is transformed to 2-C-methyl-D-erythritol 4-phosphate (MEP) by an enzyme which was recently cloned from Escherichia coli. In order to find a plant homologue of this 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) we cloned a cDNA fragment from Arabidopsis thaliana which has high homology to the E. coli DXR. By expression of this fragment in E. coli we could demonstrate that it encodes a protein which transforms DOXP to MEP. The antibiotic fosmidomycin specifically inhibits this DXR enzyme activity.

Aldose-Ketose Isomerases↗
PubMed1997

Incorporation of 1-deoxy-D-xylulose into isoprene and phytol by higher plants and algae.

In further substantiating the novel mevalonate-independent pathway for isoprenoid biosynthesis, which generates isopentenyl diphosphate (IPP) via 1-deoxy-D-xylulose-5-phosphate, labeling experiments with 1-[2H(1)]deoxy-D-xylulose were performed with various higher plants and algae: efficient incorporation was observed into isoprene emitted by Populus, Chelidonium, and Salix, into the phytol moiety of chlorophylls in a red alga (Cyanidium), in two green algae (Scenedesmus, Chlamydomonas), and a higher plant (Lemna). By contrast, 13C-mevalonate applied was incorporated into isoprene and phytol to a much lower extent or not at all. This demonstrates that this '1-deoxy-D-xylulose-5-phosphate pathway' for biosynthesis of plastidic isoprenoids is widely distributed in photosynthetic organisms.

Butadienes↗
PubMed1997

[Sequelae of cholecystectomy].

The removal of the gallbladder is followed by a number of compensatory changes, which in most cases do not result in clinical symptoms: the loss of the pressure reservoir for the bile, the duodenogastric reflux with a subsequent increase in gastric pH and helicobacter infections as well as alterations in bile metabolism. An increased incidence of colon carcinoma has been suggested to be caused by cholecystectomy. However, this might also be due to cholelithiasis. Abdominal symptoms widely regarded as postcholecystectomy syndrome are often due to functional disorders of the gastrointestinal tract and the unrelated to the loss of the gallbladder. Therefore, the expression postcholecystectomy syndrome is imprecise and should not be used in the future. Changes affecting the bile ducts such as sphincter Oddi dyskinesia, stones and stenoses are rare and treatment by endoscopic interventions is generally successful.

Bile Reflux↗
PubMed1995

Synthesis of heterocyclic platelet activating factor analogues.

The synthesis of heterocyclic analogues of the platelet activating factor is described. The preparation starts with acylating rac-tetrahydro-1,3-thiazine-4-carboxylic acid ethyl ester, with palmitoyl chloride to form the amide linkage. Following ester reduction, the phosphocholine part is introduced via 2-chloro-2-oxo-1,3,2-dioxaphospholane and subsequent ring opening with trimethylamine under pressure. Furthermore, the related L-thiazolidine analogue is prepared using the same procedure. In addition the sulfinyl and sulfonyl derivatives of this compound are obtained by oxidation with 3-chloro-perbencoic acid. From one sulfinyl intermediate the diastereomeres are separated and their conformations are determinated by 13C-NMR spectroscopy.

Magnetic Resonance Spectroscopy↗
PubMed1994

Synthesis of heterocyclic platelet activating factor analogues.

The synthesis of heterocyclic analogues of the platelet activating factor is described. The preparation starts with acylating rac-tetrahydro-1,3-thiazine-4-carboxylic acid ethyl ester, with palmitoyl chloride to form the amide linkage. Following ester reduction, the phosphocholine part is introduced via 2-chloro-2-oxo-1,3,2-dioxaphospholane and subsequent ring opening with trimethylamine under pressure. Furthermore, the related L-thiazolidine analogue is prepared using the same procedure. In addition the sulfinyl and sulfonyl derivatives of this compound are obtained by oxidation with 3-chloro-perbencoic acid. From one sulfinyl intermediate the diastereomeres are separated and their conformations are determinated by 13C-NMR spectroscopy.

Carbon Isotopes↗
PubMed1994

CNAD: a potent and specific inhibitor of alcohol dehydrogenase.

CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide) is an isosteric and isomeric analogue of NAD, in which the nicotinamide ring is linked to the sugar via a C-glycosyl (C5-C1') bond. CNAD acts as a general dehydrogenase inhibitor but shows unusual specificity and affinity for liver alcohol dehydrogenase (ADH, EC 1.1.1.1). The pattern of inhibition is congruent to 4 nM, with NAD as the variable substrate. These values are 3-5 orders of magnitude smaller than those obtained for CNAD in other dehydrogenases and are comparable to values observed for the tightest binding ADH inhibitors known. The specificity and affinity of CNAD for ADH are likely due to coordination of the zinc cation at the ADH catalytic site by the CNAD pyridine nitrogen. This is supported by kinetic and computational studies of ADH-CNAD complexes. These results are compared with those for a related analogue, CPAD. In this analogue, displacement of the pyridine nitrogen to the opposite side of the ring removes the specificity for ADH.

Alcohol Dehydrogenase↗
PubMed1993

Synthesis of isosteric analogues of nicotinamide adenine dinucleotide containing C-nucleotide of nicotinamide or picolinamide.

Two isosteric analogues of nicotinamide adenine dinucleotide, C-NAD (11) and C-PAD (12), in which the nicotinamide riboside portion is replaced by a C-nucleoside, were synthesized from 5-(beta-D-ribofuranosyl)nicotinamide (7) and 6-(beta-D-ribofuranosyl)picolinamide (8), respectively. Nucleoside 7 was prepared from the 2,3-O-isopropylidene-5-O-(tetrahydropyranyl)-D-ribonolactone (13) and 3-cyano-5-lithiopyridine as reported earlier. Nucleoside 8 was obtained by conversion of the bromo function of the 6-(2,3:4,5-di-O-isopropylidene-D-altro-pentitol-1-yl)-2-bromopyrid ine (14) into a carboxamido group followed by mesylation of the anomeric hydroxyl group to give derivative 18. Treatment of 18 with CF3COOH/CHCl3 caused deisopropylidenation with simultaneous cyclization into the desired 6-(beta-D-ribofuranosyl)picolinamide (8). NAD analogues, C-NAD (11) and C-PAD (12), were synthesized by imidazole-catalyzed coupling of the corresponding 5'-monophosphates of 7 and 8 with the adenosine-5'-monophosphate. Dinucleotide 11 was found to inhibit the proliferation of L1210 cells (IC50 = 7 microM) and to be a good competitive inhibitor of inosine monophosphate dehydrogenase (IMPDH, ID50 = 20 microM) as well as bovine glutamate dehydrogenase (GDH, Ki = 15 microM). Interestingly, C-NAD (11) caused extremely potent noncompetitive inhibition of horse liver alcohol dehydrogenase (ADH, Ki = 1.1 nM), whereas C-PAD (12) was found to be a much less potent competitive inhibitor (Ki = 20 microM) of ADH.

Alcohol Dehydrogenase↗
PubMed1993

The differentiation and lineage development of goblet cells in the murine small intestinal crypt: experimental and modelling studies.

The objective of this study was to provide a new insight into the origin and lineage development of mucus-producing cells in the small intestinal crypt. For this, new experimental data were obtained from both crypt sections and whole mounts. Model simulation studies were undertaken to investigate which rules are most likely to govern the dynamic cellular development and goblet cell pedigree. We have measured the frequency of mucus-secreting goblet cells (using alcian blue and periodic acid Schiff's stains) at each cell position in the ileal murine crypt. These measurements, made on sections, overestimate the number of goblet cells because of the size and centripetal position of the stained cytoplasm. The correction factor for this overscoring has been measured to be 0.25 by two independent methods. The data suggest that there are about 12 functional goblet cells per crypt many of which retain an ability to divide. We have also determined the labelling index of the crypt goblet cells at each cell position. Spatially, goblet cells exhibit a small degree of clustering in the crypt and show a good mixture with columnar cells. We have adapted our earlier dynamic matrix-based computer stimulation model to take into account goblet cell differentiation. The modelling suggested the following conclusions: firstly, goblet cells do not have their own stem cells but share a common stem cell with the columnar cells; secondly, the goblet lineage differentiates from the transit population two to three generations before the end of the lineage; and thirdly, the decision to switch on goblet properties is stochastic at a specific step in the development of columnar cells.

Animals↗
PubMed1990

Synthesis and anti-HIV-1 activity of 2'-"up"-fluoro analogues of active anti-AIDS nucleosides 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (DDC).

1-(3-Azido-2,3-dideoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (6, F-AZT) and 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12, F-DDC) were synthesized from the potent antiherpes virus nucleosides 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)thymine (1, FMAU) and 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC) in the hope that introduction of a 2-"up"-fluoro substituent might potentiate the anti-HIV activity of AZT and DDC. FMAU (1) was converted in three steps into 2,3'-anhydro-1-(2-fluoro-2-deoxy-5-O-trityl-beta-D-lyxofuranosyl)thymine (4), which when treated with NaN3 followed by detritylation afforded 6. F-DDC was prepared by two methods. Tritylation of FIAC followed by treatment of the product with thiocarbonyldimidazole afforded the 5'-O-trityl-3'-O-(imidazolyl)thiocarbonyl nucleoside 9. Upon radical reduction of 9 with Bu3SnH and AIBN, 5'-O-trityl-DDC 10 was obtained. Compound 10 was detritylated to give 12, which (when obtained by this procedure) resisted crystallization, but the diacetate 12' was obtained in crystalline form. Alternatively, FAC (14) was converted into N4,O5'-dibenzoyl derivative 15, which was treated with thiocarbonyldiimidazole. Reduction of 16 with Bu3SnH/AIBN followed by debenzoylation afforded 12, which was obtained in crystalline form. F-AZT did not exhibit any significant activity against the human immunodeficiency virus (HIV) in vitro. F-DDC, however, showed activity against HIV-1, but the therapeutic index is much inferior to that of AZT.

Antiviral Agents↗
PubMedDate not supplied

Substituent--directed aralkylation and alkylation reactions of the tricyclic analogues of acyclovir and guanosine.

Aryl or tert-butyl substituent in the 6 position of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-6-R-5H-imidazo[1,2-a]purine (6-R-TACV) 1 partly directs aralkylation reactions into unusual positions: N-4 to give 3 and C-7 to give N-5,7-disubstituted or N-4,7-disubstituted derivatives. In the case of alkylation the effect is limited to aryl substituent and position N-4. Replacement of acyclic moiety of 1 with a ribosyl one like in 7 prevents N-4 substitution. Cleavage of the third ring of 3b to give 3-benzylacyclovir 10 is an example of a new short route to 3-aralkyl-9-substituted guanines.

Acyclovir↗
PubMedDate not supplied

The non-mevalonate isoprenoid biosynthesis of plants as a test system for new herbicides and drugs against pathogenic bacteria and the malaria parasite.

Higher plants and several photosynthetic algae contain the plastidic 1-deoxy-D-xylulose 5-phosphate/2-C-methyl-D-erythritol 4-phosphate pathway (DOXP/MEP pathway) for isoprenoid biosynthesis. The first four enzymes and their genes are known of this novel pathway. All of the ca. 10 enzymes of this isoprenoid pathway are potential targets for new classes of herbicides. Since the DOXP/MEP pathway also occurs in several pathogenic bacteria, such as Mycobacterium tuberculosis, and in the malaria parasite Plasmodium falciparum, all inhibitors and potential herbicides of the DOXP/MEP pathway in plants are also potential drugs against pathogenic bacteria and the malaria parasite. Plants with their easily to handle DOXP/MEP-pathway are thus very suitable test-systems also for new drugs against pathogenic bacteria and the malaria parasite as no particular security measures are required. In fact, the antibiotic herbicide fosmidomycin specifically inhibited not only the DOXP reductoisomerase in plants, but also that in bacteria and in the parasite P. falciparum, and cures malaria-infected mice. This is the first successful application of a herbicide of the novel isoprenoid pathway as a possible drug against malaria.

Animals↗