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At least 19 recordsLinked to original sources
PubMed1976

Zoospore chemotaxis in Australian isolates of Phytophthora species.

Zoospores of Australian isolates of Phytophthora drechsleri, P. cryptogea, P. cinnamomi, P. nicotianae var. parasitica, and P. citricola were examined for their chemotactic responses to asparagine, glutamine, aspartate, glutamate, and structurally related compounds. Structural requirements for attraction include the alpha-amino-acid group with a short carbon chain terminating in an amide group. The one American isolate tested gave a different result and possible reasons for this are discussed. The pH of the environment was important, a neutral-charged molecule was more attractive than a negatively charged molecule, hence glutamine and aspartate were more attractive at pH 3.0 than pH 5.0. Zoospores tended to move away from regions with a high hydrogen ion concentration. Compounds other than amino acids were slightly attractive including several sugars and ethanol. Synergistic interactions between amino acids, ethanol, and sucrose were observed and may account for the high levels of attraction of zoospores to root exudates and extracts.

Amino Acids↗
PubMed1978

Potential antitumor agents via inhibitors of L-asparagine synthetase: substituted sulfonamides and sulfonyl hydrazides related to glutamine.

A series of 4-(substituted aminosulfonyl)- and 4-(substituted hydrazinosulfonyl)-2-aminobutanoic acids, compounds structurally related to glutamine, was synthesized as potential inhibitors of L-asparagine synthetase and subjected to screening as antitumor agents. Target amino acids were obtained by condensation of a blocked reactive sulfonyl chloride with the appropriate amine or hydrazide, followed by deblocking with hydrogen--palladium or liquid hydrogen fluoride--anisole. Neither the target compounds nor their protected precursors inhibited the enzyme from L5178Y/AR or prolonged the life of mice with P-388 lymphocytic leukemia. However, DL-4,4'-dithiobis[2-(benzyloxycarbonylamino)butanoic acid], an intermediate in the synthesis of the target amino acids, exhibited 90% inhibition of L-asparagine synthetase at 10 mM.

Animals↗
PubMed1976

External yeast beta-fructosidase. Affinity labeling of the active site.

Conduritol-B-epoxide, a compound structurally related to the substrates of external yeast beta-fructosidase (beta-D-fructofuranoside fructohydrolase, EC 3.2.1.26), is an active-site directed inhibitor of this enzyme. The inactivation is irreversible and first-order with respect to time and inhibitor concentration. From the kinetic data obtained, it is concluded that one molecule of inhibitor reacts with one molecule of the enzyme causing inactivation. The inactivation is prevented by the presence of substrates. The pH-dependence of inactivation shows two dissociating groups in the enzyme with pKa values 3.05 and 6.8 being involved in the inactivation process. A carboxylate at the active site with pKa 3.05 is suggested to be the reactive group with conduritol-B-epoxide.

Affinity Labels↗
PubMed2025

Untargeted metabolomics reveals anion and organ-specific metabolic responses of salinity tolerance in willow.

Willows can alleviate soil salinisation while generating sustainable feedstock for biorefinery, yet the metabolomic adaptations underlying their tolerance remain poorly understood. Salix miyabeana was treated with two environmentally abundant salts, NaCl and Na2SO4, in a 12-week pot trial. Willows tolerated salts across all treatments (up to 9.1 dS m-1 soil ECe), maintaining biomass while selectively partitioning ions, confining Na+ to roots and accumulating Cl- andin the canopy and adapting to osmotic stress via reduced stomatal conductance. Untargeted metabolomics captured >5000 putative compounds, including 278 core willow metabolome compounds constitutively produced across organs. Across all treatments, salinity drove widespread metabolic reprogramming, altering 28% of the overall metabolome, with organ-tailored strategies. Comparing salt forms at equimolar sodium, shared differentially abundant metabolites were limited to 3% of the metabolome, representing the generalised salinity response, predominantly in roots. Anion-specific metabolomic responses were extensive. NaCl reduced carbohydrates and tricarboxylic acid cycle intermediates, suggesting potential carbon and energy resource pressure, and accumulated root structuring compounds, antioxidant flavonoids, and fatty acids. Na2SO4 salinity triggered accumulation of sulphur-containing larger peptides, suggesting excess sulphate incorporation leverages ion toxicity to produce specialised salt-tolerance-associated metabolites. This high-depth picture of the willow metabolome underscores the importance of capturing plant adaptations to salt stress at organ scale and considering ion-specific contributions to soil salinity.

Salix↗
PubMed1978

Effects of pH changes and charge characteristics in the uptake of norepinephrine by synaptosomes of rat brain.

The pH dependence of the initial uptake of norepinephrine by rat whole brain synaptosomes was studied using short incubation times at 37 degrees C in order to examine the possible involvement of the phenolic OH group. The pH vs. uptake profile exhibits a maximum near pH 8.2 in H2O medium. When the medium was changed to 2H2O, the profile showed a shift of maximum corresponding to the pKa change of the phenolic OH group. The pH vs. uptake profile of tyramine was quite different from that of norepinephrine. These pH effects on uptake were explained as manifestations of the involvement of the phenolic OH group in the process. The amine and phenolic hydroxyl groups in norepinephrine were studied separately by employing two series of compounds structurally related to catecholamines, amphetamine-like and catechol-like, for their inhibitory effects on the uptake. The inhibitions were affected by changes in pH with changes in opposite directions found for the two series indicating the need for a positive charge in the side chain and suggesting an effect of the negative charge on the ring. These charge characteristics agreed with the pH profile observed in uptake. Consequently, the two groups with opposite charge characteristics in norepinephrine both appear to function in the uptake process.

Amphetamines↗
PubMed1976

Evaluation of the discriminative effects of morphine in the rat.

The discriminative effects produced by morphine in the rat were evaluated using a two-choice, discrete trial avoidance task. Stimulus control of behavior was attained with a dose of morphine one-third to one-tenth of that used in previous studies. Morphine produced dose-related discriminative effects over a 100-fold dose range. The stimulus control produced by the discriminative effects of morphine met the following criteria for classification as a specific narcotic effect: 1) oxymorphone, levorphanol, methadone and meperidine, narcotic analgesics from diverse chemical families, also produced dose-related morphine-like discriminative effects; 2) dextrorphan and thebaine, compounds structurally related to the narcotics but lacking narcotic activity, failed to produce morphine-like discriminative effects; 3) effects were blocked by the narcotic antagonist naloxone; and 4) tolerance to the discriminative effects developed upon the repeated administration of morphine and cross-tolerance extended to methadone. The discriminative effects produced by morphine were further characterized by evaluating the capacity of prototypes of other classes of psychoactive drugs to produce morphine-like discriminative effects. Profadol and pentazocine, euphorogenic analgesics with mixed agonist and narcotic antagonist properties, produced dose-related morphine-like discriminative effects whereas cyclazocine, a dysphorogenic analgesic with mixed agonist and narcotic-antagonist properties, did not. In addition, the nonopioid psychoactive drugs d-amphetamine, pentobarbital and chlorpromazine also failed to produce morphine-like discriminative effects. Thus, morphine-like discriminative effects were produced uniquely by the narcotic analgesics and euophorogenic analgesics with mixed agonist and narcotic antagonist properties. These results suggest that the component of action of morphine that enables it to function as a discriminative stimulus in the rat is analogous to the component of action of morphine responsible for producing subjective effects in man.

Analgesics, Opioid↗
PubMed2026

Expansion of the allelic and phenotypic spectrum of MED25-related developmental disorder: novel compound heterozygous variants with structural domain implications.

MED25-related developmental disorder (Basel-Vanagaite-Smirin-Yosef syndrome) is a rare autosomal recessive disorder, defined by severe neurodevelopmental delay, corpus callosum abnormalities, ocular involvement, epilepsy, and marked facial appearance. MED25 pathogenic variants interfere with the functioning of the Mediator complex, which is responsible for RNA polymerase II transcription. We report a 9-year-old girl who presents with significant global developmental delay, agenesis of the corpus callosum, congenital cataracts, epilepsy, hypotonia, musculoskeletal abnormalities, and typical craniofacial features. Trio-based whole-exome sequencing revealed compound heterozygous variants in MED25: a maternally transmitted truncating variant (c.1366 C > T; p.Gln456*) and a paternally inherited missense variant (c.430 C > T; p.Leu144Phe). The new classification of the missense variant as potentially pathogenic is supported by a systematic ACMG re-evaluation supported by segregation analysis, phenotypic specificity, computational prediction, and structural localization in the MED25 Activator Interaction Domain (ACID). Comparative phenotypic analyses show strong agreement with reported cases but add more data to fine-tune clinical spectrum. This article broadens the allelic and phenotypic spectrum of MED25-related developmental disorder and highlights the need for comprehensive evaluation across molecular, structural, and phenotypic pathways to elucidate variant signature in rare genetic disease models correctly.

Humans↗
PubMed2026

Selective Macrocyclic WEE1 Kinase Inhibitors with Strong Efficacy against Patient-Derived Colorectal Cancer Organoids.

Macrocyclization can enhance the selectivity of acyclic compounds toward structurally similar biological targets such as kinases. WEE1 regulates cellular homeostasis and is a promising target in oncology. The clinical candidate AZD1775 (1) failed to progress past Phase II trials because of patient tolerability issues, likely due to off-target inhibition of polo-like kinase 1 (PLK1). Herein, a computer-aided drug design approach was conducted to develop a macrocycle based on the 1-WEE1 X-ray cocrystal structure. Significantly enhanced WEE1 inhibitory selectivity over PLK1 was determined for leading macrocycle 2, which also demonstrated broader kinome-wide selectivity. Patient-derived organoids from colorectal cancer (CRC) peritoneal and liver metastases, treated with 2, demonstrated comparably strong or enhanced anticancer efficacy compared to that of 1. Against patient-matched normal colon vs primary CRC organoids, 2 potently and selectively treated CRC, as well as enhanced DNA damage compared to 1. Finally, the X-ray cocrystal structure of 2 bound to WEE1 validated its computationally predicted bioactive binding mode.

Humans↗
PubMed1976

Compound X. An intermediate in enzymatic halogenation.

Previous studies have shown that chlorite serves as a halogenation substrate for horseradish peroxidase. In its substrate role, chlorite serves both as a halogen donor and as a source of oxidizing equivalents in the chlorination reaction. We now show that a new spectral intermediate, which we have termed Compound X, can be detected as the initial product of the reaction of chlorite with horseradish peroxidase. The reaction of chlorite with horseradish peroxidase to form Compound X is a relatively fast reaction especially at acidic pH values. The second order rate constant (Kf) for the formation of Compound X at pH 4.5 (optimum pH) is 0.9 X 10(6) M-1 S-1. Compound X, in the absence of a halogen acceptor, decomposes to Compound I and chloride ion. The first order rate constant (Kd) for the decay of Compound X to Compound I is 0.2 s-1 at pH 4.5. The pH optimum for enzymatic chlorination with chlorite compares favorably with the pH profile for the lifetime of Compound X (Kf/Kd). These observations indicate that Compound X is the halogenating intermediate in the chlorite reaction and that the rate of enzymatic chlorination is directly related to the stability of Compound X. We propose an -OCl ligand on a ferric heme as the most likely structure for Compound X.

Binding Sites↗
PubMed1979

Pharmacological characterization of perifornical hypothalamic dopamine receptors mediating feeding inhibition in the rat.

Mapping studies with central drug injections in the hungry rat have identified the perifornical lateral hypothalamus as being uniquely sensitive to the feeding suppressive effects of exogenous dopamine, as well as anorexic drugs which release endogenous catecholamines. In the present study, the hypothalamic dopamine-receptive sites mediating this phenomenon were pharmacologically characterized. These sites, studied via direct drug injection into the perifornical hypothalamus of freely moving, brain-cannulated rats, were found to be most responsive to dopamine, in a dose-dependent manner, but were also activated by other catecholamine receptor stimulants, with the order of potency being dopamine greater than apomorphine = epinine greater than norepinephrine. Clinically effective neuroleptic compounds antagonized these dopamine-sensitive sites, apparently in a competitive and stereochemically specific manner. The relative potency of the neuroleptics and structurally related compounds was calculated to be haloperidol greater than fluphenazine greater than chlorpromazine greater than pimozide greater than promazine. The ineffective neuroleptic promethazine, the tricyclic antidepressants imipramine and desipramine, and the antagonists of alpha-adrenergic, beta-adrenergic, cholinergic, and serotonergic receptors, did not manifest the ability to reverse dopamine's action. These results thus reveal properties of these hypothalamic dopamine-sensitive, feeding inhibitory sites which match to a large extent the characteristics recently identified for dopamine receptors in the periphery and extrahypothalamic brain areas.

Adrenergic alpha-Antagonists↗
PubMed1977

Studies of the mechanism of the periodic acid-Schiff histochemical reaction for glycogen using infrared spectroscopy and model chemical compounds.

It has been proposed in the literature that Schiffs reagent reacts with aldehydes to form one of the following types of compounds: alkylsulfonic acids, N-sulfinic acid derivatives, or Schiff bases. Model compounds whose structures are consistent with those proposed in the literature have been synthesized and subjected to infrared analysis. Also, actual products of Schiff reagent reactions with various aldehydes have been isolated and examined using infrared spectroscopy. Comparison of the spectra of the model compounds with those of Schiff-aldehyde reaction products yielded the following conclusions: 1. The reaction of simple organic aldehydes with Schiff's reagent produces an alkylsulfonate-type reaction product. 2. The reaction of periodate-oxidized glycogen with Schiff's reagent probably involves the formation of an alklsulfonate-type compound. 3. The product of the Schiff-aldehyde reaction exists as neither an N-sulfinic acid nor a Schiff base derivative of the fuchsin molecule.

Aldehydes↗
PubMed1978

[The antigen activity and structure of analogues and fragments of angiotensin, which contain enantiomeric forms of amino acids and aza-alpha'-homoamino acids].

The antigen activity of angiotensin, its fragments and analogues, which contain enantiomeric forms of amino acids and aza-alpha'-homoamino acids is studied by cross reactions with specific antibodies, obtained for angiotensin and its central tetrapeptide. It is found that the inclusion of additional NH-group between alpha carbon and carboxyl group of peptide chain, although in few cases radically changes spatial structure of compounds, does not deprivate their antigen activity. The replacement of NH-group to the C-end of the angiotensin molecule by affection the antigen determinant considerably decreases the antigen activity of the analogues. The important role in the determination of the antigen activity play the tyrosine residue and its specific orientation with respect to the antigen molecule. Low molecular weight fragments and analogues of the central part of angiotensin molecule, which have less "rigid" spatial structures, are capable to reorganize their spatial structure during interaction with antibodies.

Amino Acids↗
PubMed1976

Binding of thyroid hormones and their analogues to thyroxine-binding globulin in human serum.

The present study was undertaken to study the binding of several thyroid hormones and structurally related compounds to human serum thyroxine-binding alpha-globulin (TBG). The source of TBG was normal human serum diluted 1:100 in 0.035 M barbital buffer, pH 7.4. In the binding assays, 125I-thyroxine, unlabeled thyroxine, and diluted serum were incubated for 20 h at 37 degrees in Plexiglas equilibrium dialysis units. Two orders of binding sites were discerned: a high affinity, low capacity binding site with an affinity constant of approximately 2.5 X 10(9) M-1, and a low affinity, very high capacity binding site with an affinity constant of less than 10(6) M-1. Studies with purified TBG, serum deficient in TBG, and purified human serum albumin indicated that the high affinity site represented binding to TBG and the low affinity site represented binging to albumin. The ability of several groups of thyroid hormone analogues to bind to TBG was then investigated. As a result of these studies, the following structural features of thyroid hormones were found to be important for optimal binding activity: (a) the L-alanine side chain conformation, (b) the presence of a 4'-hydroxyl group, (c) the presence of two substituents in the inner and outer rings (positions 3, 5, 3', and 5'), and (d) the presence of either bromines or iodines in the inner ring and iodines in the outer ring. Of lesser importance was the presence of an oxygen atom in the ether position.

Alpha-Globulins↗