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Biomedical subjects

K Harms

Publications and source records attributed to K Harms.

At least 19 recordsLinked to original sources
PubMed2004

The common and distinct target genes of the p53 family transcription factors.

p53 is the most commonly mutated gene in human cancer. After activation by cellular stresses such as DNA damage or oncogene activation, p53, a sequence-specific DNA-binding protein, induces the expression of target genes which mediate tumor suppression. Two recently identified p53 homologues, p63 and p73, appear to function similarly to p53, that is, they both activate target gene expression and suppress cell growth when overexpressed; however, the p63 and p73 genes are rarely mutated in human cancer and do not adhere to Knudson's classical model of a tumor suppressor gene. Recently, exciting observations suggest nonoverlapping functions for the family members. Herein, we outline the recent literatures identifying and characterizing both the common and distinct target genes of the p53 family transcription factors in relation to their signaling pathways.

Apoptosis↗
PubMed2001

The [2+2]-photocycloaddition of aromatic aldehydes and ketones to 3,4-dihydro-2-pyridones: regioselectivity, diastereoselectivity, and reductive ring opening of the product oxetanes.

3,4-Dihydro-2-pyridones [3,4-Dihydropyridin-2(1H)-ones] 6 were evaluated with respect to their use as alkene components in stereoselective Paternò-Büchi reactions. The parent compound 6a was shown to be a versatile synthetic building block that reacted with various photoexcited aromatic carbonyl compounds (benzaldehyde, benzophenone, acetophenone, methyl phenylglyoxylate, 3-pivaloyloxybenzaldehyde) with high regio- and diastereo-selectivity (51-63% yield). The products can be subjected to hydrogenolysis, opening a new and efficient route for the synthesis of 2-arylmethyl-3-piperidinols. As examples, the oxetanes 7a and 8a were hydrogenolytically cleaved and yielded the products 12 (88%) and 13 (93%). The ability of compound 6a to bind to a chiral lactam host through two hydrogen bonds was used favorably to differentiate the enantiotopic faces of its double bond. In the photocycloaddition to the chiral aldehyde 15, which was conducted at -10 degrees C in toluene, a high facial diastereoselectivity (>90% de. 56% yield) was recorded. The stereoselectivity results from a 1:1 association of dihydropyridone 6a to the aldehyde. The 4-substituted dihydropyridones 6b-6d (R = methyl, isopropyl, phenyl) were found to be less suited for potential use in photochemistry. The yields and facial diastereoselectivities recorded in their photocycloaddition to benzophenone remained low.

Aldehydes↗
PubMed2001

Phosphabenzenes as monodentate pi-acceptor ligands for rhodium-catalyzed hydroformylation.

A new class of phosphinine/rhodium catalysts for the hydroformylation of terminal and internal alkenes is presented in this study. A series of phosphabenzenes 1-14 has been prepared by condensation of phosphane or tris(trimethylsilyl)phosphane with the corresponding pyrylium salt. Trans-[(phosphabenzene)2RhCl(CO)] complexes 21-25 have been prepared and studied spectroscopically and by X-ray crystal-structure analysis. The hydroformylation of oct-1-ene has been used to identify optimal catalyst preformation and reaction conditions. Hydroformylation studies with 15 monophosphabenzenes have been performed. The catalytic performance is dominated by steric influences, with the phosphabenzene 8/rhodium system being the most active catalyst. Turnover frequencies of up to 45370 h(-1) for the hydroformylation of oct-1-ene have been determined. In further studies, hydroformylation activity toward more highly substituted alkenes was investigated and compared with the standard industrial triphenylphosphane/rhodium catalyst. The reactivity differences between the phosphabenzene and the triphenylphosphane catalyst increase on going to the more highly substituted alkenes. Even tetrasubstituted alkenes reacted with the phosphabenzene catalyst, whereas the triphenylphosphane system failed to give any product. In situ pressure NMR experiments have been performed to identify the resting state of the catalyst. A monophosphabenzene complex [(phosphinine 8)Ir(CO)3H] could be detected as the predominant catalyst resting state.

Journal Article↗
PubMed2001

Intramolecular iron(II)-catalyzed nitrogen transfer reactions of unsaturated alkoxycarbonyl azides: a facile and stereoselective route to 4,5-disubstituted oxazolidinones.

Intramolecular FeII-catalyzed reactions of various unsaturated alkoxycarbonyl azides are described. The reactions occur in the presence of stoichiometric amounts of trimethyl silyl chloride employing ethanol as the solvent. The corresponding 2-alkenyloxycarbonyl azides 5, 9, 18, 20, 22, and 24 gave the products 7/8, 10/11, 19, 21, 23, and 25 of an olefin chloroamination in moderate to good yields (47-72%). The facial diastereoselectivity of the ring closing C-N-bond forming step is good both in cyclic (20, 24) and in acyclic substrates (5, 18, 22) (>90% ds). The subsequent chlorine atom transfer occurs selectively in cyclic systems (20, 24) and in systems (9b, 18) which exhibit a conformational bias in the postulated radical intermediate 14. The lifetime tau of this elusive intermediate was estimated from the loss of stereochemical information in conformationally unrestricted systems (9a, 22) and from the data obtained with a radical clock (31-->32). 2-Alkynyloxycarbonyl azides 34 and 36 also yield chloroamination products which are obtained exclusively as the (Z)-isomers 35 and 37 (81-99% yield). The products of the tert-butyl-substituted substrates 38 undergo an immediate rearrangement/solvolysis reaction in the reaction mixture and gave the 5-alkoxyoxazolidinones 39 (93-99% yield).

Journal Article↗
PubMed2001

Enantioselective photochemical reactions of 2-pyridones in solution.

[reaction: see text] Two key photochemical reactions of prochiral 2-pyridones were studied in the presence of a chiral host. The [4 + 4]-photocycloaddition with cyclopentadiene (CpH) proceeded smoothly and with high enantioselectivity (84-87% ee). The absolute configuration of the endo-diastereoisomer was established by X-ray crystallography. The electrocyclic [4pi]-ring closure to 3-oxo-2-azabicyclo[2.2.0]-5-hexenes occurred with lower enantioselectivity (20-23% ee at -20 degrees C). The velocity of the latter reaction slowed significantly with decreasing temperature.

Journal Article↗
PubMed2001

Effect of continuous antistaphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis.

SUMMARY. Continuous therapy with antistaphylococcal antibiotics is advocated by some cystic fibrosis (CF) centers, but it is unclear whether this strategy favors early colonization with P. aeruginosa. We used the data base for the German Centers of the European Registry for Cystic Fibrosis (ERCF) to assess the effect of continuous antistaphyloccocal therapy on the rate of P. aeruginosa acquisition in CF patients. Patients included in this analysis had to be < 18 years of age, P. aeruginosa-negative prior to entry in the ERCF, and to have had at least 2 additional P. aeruginosa-negative respiratory cultures while followed in the ERCF. Of the 639 patients fulfilling these criteria, 48.2% received continuous antistaphyloccocal therapy, 40.4% intermittent antibiotic therapy, and 11.4% no antibiotic therapy. There were no differences between the groups in body mass index, as well as forced vital capacity (FVC) and forced expired volume in 1 sec (FEV(1)) at baseline. The rate at which patients acquired positive respiratory cultures for Staph. aureus was significantly lower in the group receiving continuous antistaphyloccocal antibiotic therapy than in those not receiving such therapy. Patients receiving continuous antistaphyloccocal antibiotic therapy had a significantly higher rate of P. aeruginosa acquisition compared to patients receiving only intermittent or no antibiotic therapy. This difference was especially apparent for children younger than age 6 years. We conclude that continuous therapy with antistapyloccocal antibiotics directed against Staph. aureus increases the risk of colonization with P. aeruginosa. How this affects the clinical outcome of these patients remains to be determined.

Adolescent↗
PubMed2001

Synthesis and evaluation of diazine containing bioisosteres of (-)-ferruginine as ligands for nicotinic acetylcholine receptors.

In this structure-affinity relationship (SAFIR) study, the bioisosteric potential of diazines in the field of ferruginine-type nAChR ligands was investigated. Novel enantiopure analogues of (-)-Ferruginine (3) such as 6-8 were synthesized utilizing enantiomerically pure N-protected (+)-2-tropanone 9 from the 'chiral pool' as versatile chiral building block and a palladium-catalyzed Stille cross-coupling of the tributylstannyl diazines 12, 14 and 16 with the vinyl triflate 11 of (+)-2-tropanone 9. The structures of the novel diazine analogues 6-8 of (-)-ferruginine (3) were assigned on the basis of spectral data, that of ligand 7 being additionally verified by X-ray crystallography. The bioisosteric replacement of the acetyl moiety as structural part of the lead compound 3 with the pyridazine, pyrimidine and pyrazine nucleus resulted in ligands with high to moderate affinity for the central alpha4beta2 and remarkably low affinity for the alpha7* nAChR subtypes. Among the compounds synthesized and tested, 7 was the most active one with K(i)=3.7 nM (alpha4beta2). Compared with the lead 3, this value represents a 30-fold improvement in the affinity for the alpha4beta2 subtype combined with a substantially improved selectivity ratio between the alpha4beta2 and alpha7* subtypes.

Animals↗
PubMed2000

The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paternò-Büchi reactions of chiral 2-substituted 2,3-dihydropyrroles.

The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paternò - Büchi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paternò-Büchi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).

Anisomycin↗
PubMed2000

Highly enantiomerically enriched alpha-haloalkyl Grignard reagents

alpha-Chloro- and alpha-bromoalkyl Grignard reagents 11 and 30 with > 97% ee (enantiomeric excess) were generated by a sulfoxide/magnesium exchange reaction from the enantiomerically and diastereomerically pure sulfoxides 25 and 27. The resulting alpha-haloalkyl Grignard reagents are configurationally stable at -78 degrees C. Racemization sets in at or above -60 degrees C, especially when the solution contains bromide ions. In the absence of halide ions, the configurational stability extends up to -20 degrees C, when chemical decomposition commences.

Journal Article↗
PubMed2000

The relation between ion pair structures and reactivities of lithium cuprates

From Li+ well-solvating solvents or complex ligands such as THF, [12]crown-4, amines etc., lithium cuprates R2CuLi(*LiX) crystallise in a solvent-separated ion pair (SSIP) structural type (e.g. 10). In contrast, solvents with little donor qualities for Li+ such as diethyl ether or dimethyl sulfide lead to solid-state structures of the contact ion pair (CIP) type (e.g. 11). 1H,6Li HOESY NMR investigations in solutions of R2CuLi(*LiX) (15, 16) are in agreement with these findings: in THF the SSIP 18 is strongly favoured in the equilibrium with the CIP 17, and in diethyl ether one observes essentially only the CIP 17. Salts LiX (X=CN, Cl, Br, I, SPh) have only a minor effect on the ion pair equilibrium. These structural investigations correspond perfectly with Bertz's logarithmic reactivity profiles (LRPs) of reactions of R2CuLi with enones in diethyl ether and THF: the faster reaction in diethyl ether is due to the predominance of the CIP 17 in this solvent, which is the reacting species; in THF only little CIP 17 is present in a fast equilibrium with the SSIP 18. A kinetic analysis of the LRPs quantifies these findings. Recent quantum-chemical studies are also in agreement with the CIP 17 being the reacting species. Thus a uniform picture of structure and reactivity of lithium cuprates emerges.

Journal Article↗
PubMed2000

First confirmed case with paternal uniparental disomy of chromosome 16.

The existence of paternal uniparental disomy of chromosome 16 [upd(16)pat] has previously been suspected but has not been proven. We report prenatal detection and follow-up of isodisomic upd(16)pat in a child with minimal defects but otherwise normal development. Our results indicate that isodisomic upd(16)pat is associated with a normal outcome if no recessive mutation is reduced to homozygosity.

Adult↗
PubMed2000

Expression of a bacterial serine acetyltransferase in transgenic potato plants leads to increased levels of cysteine and glutathione.

The coding sequence of the wild-type, cys-sensitive, cysE gene from Escherichia coli, which encodes an enzyme of the cysteine biosynthetic pathway, namely serine acetyltransferase (SAT, EC 2.3.1. 30), was introduced into the genome of potato plants under the control of the cauliflower mosaic virus 35S promoter. In order to target the protein into the chloroplast, cysE was translationally fused to the 5'-signal sequence of rbcS from Arabidopsis thaliana. Transgenic plants showed a high accumulation of the cysE mRNA. The chloroplastic localisation of the E. coli SAT protein was demonstrated by determination of enzymatic activities in enriched organelle fractions. Crude leaf extracts of these plants exhibited up to 20-fold higher SAT activity than those prepared from wild-type plants. The transgenic potato plants expressing the E. coli gene showed not only increased levels of enzyme activity but also exhibited elevated levels of cysteine and glutathione in leaves. Both were up to twofold higher than in control plants. However, the thiol content in tubers of transgenic lines was unaffected. The alterations observed in leaf tissue had no effect on the expression of O-acetylserine(thiol)-lyase, the enzyme which converts O-acetylserine, the product of SAT, to cysteine. Only a minor effect on its enzymatic activity was observed. In conclusion, the results presented here demonstrate the importance of SAT in plant cysteine biosynthesis and show that production of cysteine and related sulfur-containing compounds can be enhanced by metabolic engineering.

Acetyltransferases↗
PubMed2000

Increased killing of Bacillus subtilis on the hair roots of transgenic T4 lysozyme-producing potatoes.

Transgenic potato plants expressing the phage T4 lysozyme gene which are resistant to the plant-pathogenic enterobacterium Erwinia carotovora subsp. carotovora have been constructed. The agricultural growth of these potatoes might have harmful effects on soil microbiota as a result of T4 lysozyme release into the rhizosphere. To assess the bactericidal effect of roots, we have developed a novel method to associate the cells of Bacillus subtilis with hair roots of plants and to quantify the survival of cells directly on the root surface by appropriate staining and fluorescence microscopy. With this technique, we found that the roots of potato plants (Désirée and transgenic control lines) without T4 lysozyme gene display measurable killing activity on root-adsorbed B. subtilis cells. Killing was largely independent of the plant age and growth of plants in greenhouse or field plots. Roots from potato lines expressing the T4 lysozyme gene always showed significantly (1.5- to 3.5-fold) higher killing. It is concluded that T4 lysozyme is released from the root epidermis cells and is active in the fluid film on the root surface. We discuss why strong negative effects of T4 lysozyme-producing potatoes on soil bacteria in field trials may not be observed. We propose that the novel method presented here to study interactions of bacteria with roots can be applied not only to bacterial killing but also to interactions leading to growth-sustaining effects of plants on bacteria.

Adsorption↗
PubMed2000

Surfactant treatment of neonates with respiratory failure and group B streptococcal infection. Members of the Collaborative European Multicenter Study Group.

OBJECTIVE: Connatal pneumonia caused by group B streptococcal (GBS) infection may be associated with surfactant dysfunction. We investigated the effects of surfactant treatment in term and preterm neonates with GBS infection and respiratory failure, in comparison with corresponding data from a control population of noninfected infants treated with surfactant for respiratory distress syndrome (RDS). DESIGN/METHODS: The study comprised 118 infants with respiratory failure, clinical and/or laboratory signs of acute inflammatory disease, and GBS infection proven by culture results. They were recruited retrospectively from a database of patients treated with surfactant at 28 neonatology units participating in European multicenter trials (1987-1993) and prospectively from the same units in the following years. A nonrandomized control group of 236 noninfected infants was selected from the same database. The primary parameters evaluated were oxygen requirement, ventilator settings, and incidence of complications. RESULTS: Median birth weight in the GBS study group was 1468 g (25th-75th percentiles: 1015-2170), and median gestational age was 30 (27-33) weeks. Thirty-one percent of the infants weighed >2000 g. Median age at surfactant treatment was 6 hours. The mean initial surfactant dose was 142 mg/kg (standard deviation: 53). Ninety of the infants were treated with Curosurf (Chiesi Farmaceutici, Parma, Italy), 13 with Survanta (Abboth GmbH, Wiesbaden, Germany), 12 with Alveofact (Dr Karl Thomae GmbH, Biberach, Germany), and 3 with Exosurf (Wellcome GmbH, Burgwedel, Germany). Within 1 hour of surfactant treatment, median fraction of inspiratory oxygen was reduced from .84 (25th-75th percentiles:.63-1.0) to.50 (.35-.80). The incidence of complications in the study group (mortality: 30%; pneumothorax: 16%; intracranial hemorrhage: 42%) was high, compared with infants with RDS. CONCLUSIONS: Surfactant therapy improves gas exchange in the majority of patients with GBS pneumonia. The response to surfactant is slower than in infants with RDS, and repeated surfactant doses are often needed. The mortality and morbidity are substantial, considering the relatively high mean birth weight of the treated infants.

Drug Administration Schedule↗
PubMed1998

Inhibition of wound-induced accumulation of allene oxide synthase transcripts in flax leaves by aspirin and salicylic acid

Allene oxide synthase (AOS) mediates the conversion of lipoxygenase-derived fatty acid hydroperoxides to unstable allene epoxides, which supply the precursors for the synthesis of the phytohormone jasmonic acid (JA). In this study the characterization of AOS gene expression in flax (Linum usitatissimum) is reported. AOS was constitutively expressed in different organs of flax plants. Additionally, AOS gene expression was enhanced after mechanical wounding in both the directly damaged leaves and in the systemic tissue located distal to the treated leaves. This wound-induced accumulation of AOS required the de novo biosynthesis of other unknown proteins involved in the signaling pathway modulating wound-induced AOS gene expression. Furthermore, the wound-induced AOS mRNA accumulation was correlated with the increase in the levels of JA. Both JA and its precursor, 12-oxo-phytodienoic acid, activated AOS gene expression in a dose-dependent manner. Thus, JA could activate its own biosynthetic pathway in flax leaves. Moreover, neither salicylic acid (SA) nor aspirin influenced AOS enzymatic activity. It is interesting that pretreatment with SA or aspirin inhibited wound-induced accumulation of AOS transcripts. These results suggest that a potent inhibition of JA biosynthetic capacity in leaves can be affected by SA or aspirin at the level of AOS gene expression.

Journal Article↗