Highly stereo- and regioselective allylations catalyzed by Mo-pyridylamide complexes: electronic and steric effects of the ligand
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Journal Article↗
Biomedical subjects
A Hallberg
Publications and source records attributed to A Hallberg.
Highly selective palladium-catalyzed synthesis of protected alpha,beta-unsaturated methyl ketones and 2-alkoxy-1,3-butadienes. High-speed chemistry by microwave flash heating
A selective and mild procedure is described for the direct synthesis of 2-alkene-2-methyl-1,3-dioxolanes via regiocontrolled Heck vinylation of commercially available 2-hydroxyethyl vinyl ether. The procedure permits chemoselective transformation of a vinylic triflate or bromide into a blocked alpha,beta-unsaturated methyl ketone. Furthermore, a significantly improved and highly regioselective synthesis of 2-alkoxy-1,3-butadienes has been developed. Flash heating by microwave irradiation promotes the palladium-catalyzed reactions, and the starting materials are fully converted after reaction times of 5-7 min.
Journal Article↗
Synthesis of two conformationally constrained analogues of the minor tobacco alkaloid anabasine.
The anabasine analogues spiro[4-azaindan-1,2'-piperidine] (7) and spiro[6-azaindan-1,2'-piperidine] (8) have been prepared. A series of palladium-catalyzed reactions, where an intramolecular cyclization constituted a key reaction, were utilized for the preparation of the two target compounds.
Acylation↗
Global field power of auditory N1 correlates with impaired verbal-memory performance in human alcoholics.
First weeks after alcohol withdrawal, associated with profound changes in neural transmission, constitute the critical period for relapse prevention and pharmacological intervention in alcoholism. Here, 20 male alcoholics with 1-6 weeks of abstinence and 20 age-matched healthy controls were studied using auditory event-related potentials (ERP), measured with a 32-channel electroencephalogram, and neuropsychological tests of auditory-verbal memory. Global field power maximum of ERP during 80-150 ms period after presentation of unattended tones (binaural 700 Hz pure tones, inter-stimulus interval 2.5 s) was significantly (P<0.01) larger in the alcoholics than controls. This effect, reflecting augmented N1 generation, significantly correlated (r=0.5) with impaired memory performance in the alcoholics. The profound change in pre-attentive auditory processing, predicting impaired memory performance, might reflect impaired cerebral inhibitory transmission in alcoholics.
Adult↗
Comparison of three gamma-turn mimetic scaffolds incorporated into angiotensin II.
Rigidification of peptides by cyclization and iterative incorporation of well-defined secondary structure mimetics constitutes one approach to the design of non-peptidergic structures with better defined conformations. We herein present the synthesis of a potential gamma-turn mimetic scaffold, and its incorporation in the 3-5 position of angiotensin II. Two analogues of angiotensin II (Ang II) incorporating this 1,3,5-trisubstituted benzene gamma-turn scaffold were synthesized. Evaluation of the compounds in a radioligand binding assay showed that they lacked affinity to the AT1 receptor. To rationalize these results a geometrical and electrostatical comparison with Ang II analogues encompassing a bicyclic scaffold that delivered inactive pseudo peptides and an azepine scaffold producing highly active ligands was made. This analysis did not provide a clear rationale for the inactivity of the benzene gamma-turn scaffolds.
Angiotensin II↗
Characterization of a set of HIV-1 protease inhibitors using binding kinetics data from a biosensor-based screen.
The interaction between 290 structurally diverse human immunodeficiency virus type 1 (HIV-1) protease inhibitors and the immobilized enzyme was analyzed with an optical biosensor. Although only a single concentration of inhibitor was used, information about the kinetics of the interaction could be obtained by extracting binding signals at discrete time points. The statistical correlation between the biosensor binding data, inhibition of enzyme activity (K(i)), and viral replication (EC(50)) revealed that the association and dissociation rates for the interaction could be resolved and that they were characteristic for the compounds. The most potent inhibitors, with respect to K(i) and EC(50) values, including the clinically used drugs, all exhibited fast association and slow dissociation rates. Selective or partially selective binders for HIV-1 protease could be distinguished from compounds that showed a general protein-binding tendency by using three reference target proteins. This biosensor-based direct binding assay revealed a capacity to efficiently provide high-resolution information on the interaction kinetics and specificity of the interaction of a set of compounds with several targets simultaneously.
Biosensing Techniques↗
Increased distractibility by task-irrelevant sound changes in abstinent alcoholics.
BACKGROUND: Chronic alcoholism is accompanied by "frontal" neuropsychological deficits that include an inability to maintain focus of attention. This might be associated with pronounced involuntary attention shifting to task-irrelevant stimulus changes and, thereafter, an impaired reorienting to the relevant task. The neural abnormalities that underlie such deficits in alcoholics were explored with event-related potential (ERP) components that disclosed different phases of detection and orienting to stimulus changes. METHODS: Twenty consecutive abstinent male alcoholics (DSM-IV) and 20 age-matched male controls (healthy social drinkers) were instructed to discriminate equiprobable 100 and 200 msec tones in a reaction-time task (RT) and to ignore occasional, either slight (7%) or wide (70%), frequency changes (hypothesized to increase RT) during an ERP measurement. RESULTS: In the alcoholics, we found pronounced distractibility, evidenced by a RT lag (p < 0.01) caused by deviants, that correlated (Spearman p = 0.5) with a significantly enhanced (p < 0.01) amplitude of mismatch negativity (MMN) to deviants. Significantly increased RT lag for trials subsequent to deviants (slight p < 0.001, wide p < 0.05) in the alcoholics suggested impaired reorienting to the relevant task. The MMN enhancement also predicted poorer hit rates in the alcoholics (Spearman p = 0.6-0.7). Both the MMN enhancement and pronounced distractibility correlated (Spearman p = 0.4) with an early onset of alcoholism. CONCLUSIONS: Attentional deficits in the abstinent alcoholics were indicated by the increased distractibility by irrelevant sound changes. The MMN enhancement suggested that this reflects impaired neural inhibition of involuntary attention shifting, being most pronounced in early-onset alcoholics.
Adult↗
Angiotensin II analogues encompassing 5,9- and 5,10-fused thiazabicycloalkane tripeptide mimetics.
A simple experimental procedure on solid phase for the construction of new tripeptidic 5,9- and 5,10-fused thiazabicycloalkane scaffolds that adopt beta-turns has been developed. This N-terminal-directed bicyclization, relying on masked aldehyde precursors derived from glutamic acid as key building blocks, provides a complement to the related bicyclization previously reported, where an aspartic acid-derived precursor was employed to induce cyclization toward the C-terminal end of the peptide. Thus, the regioselectivity of the bicyclization can be altered simply by varying the chain length of the incorporated aldehyde precursor. Four analogues of the hypertensive octapeptide angiotensin II, comprising the new scaffolds in the 3-5- and 5-7-positions, were synthesized. One of these conformationally constrained angiotensin II analogues exhibited AT(1) receptor affinity (K(i) = 750 nM). Results from theoretical conformational analysis of model compounds of the bicyclic tripeptide mimetics are presented, and they demonstrate that subtle differences in geometry have a strong impact on the affinity to the AT(1) receptor.
Angiotensin II↗
Inhibitors of the C(2)-symmetric HIV-1 protease: nonsymmetric binding of a symmetric cyclic sulfamide with ketoxime groups in the P2/P2' side chains.
Symmetric cyclic sulfamides, substituted in the P2/P2' position with functional groups foreseen to bind preferentially to the S2/S2' subsites of HIV-1 protease, have been prepared. Despite efforts to promote a symmetric binding, the sulfamides seemed prone to bind nonsymmetrically, as deduced from X-ray crystal structure analysis of one of the most potent inhibitors, possessing ketoxime groups in the P2/P2' side chains. Ab initio calculations suggested that the nonsymmetric conformation of the cyclic sulfamide scaffold had lower energy than the corresponding symmetric, cyclic urea-like conformation.
Crystallography, X-Ray↗
Design and fast synthesis of C-terminal duplicated potent C(2)-symmetric P1/P1'-modified HIV-1 protease inhibitors.
An analysis of the X-ray structure of a complex of HIV-1 protease with a linear C(2)-symmetric C-terminal duplicated inhibitor guided the selection of a series of diverse target compounds. These were synthesized with the objective to identify suitable P1/P1' substituents to provide inhibitors with improved antiviral activity. Groups with various physical properties were attached to the para-positions of the P1/P1' benzyloxy groups in the parent inhibitor. A p-bromobenzyloxy compound, prepared in only three steps from commercially available starting materials, was utilized as a common precursor in all reactions. The subsequent coupling reactions were completed within a few minutes and relied on palladium catalysis and flash heating with microwave irradiation. All of the compounds synthesized exhibited good inhibitory potency in the protease assay, with K(i) values ranging from 0.09 to 3.8 nM. A 30-fold improvement of the antiviral effect in cell culture, compared to the parent compound, was achieved with four of the inhibitors. The differences in K(i) values were not correlated to the differences in antiviral effect, efficiency against mutant virus, or reduced potency in the presence of human serum. The poorest enzyme inhibitors in fact belong to the group with the best antiviral effect. The binding features of two structurally related inhibitors, cocrystallized with HIV-1 protease, are discussed with special emphasis on the interaction at the enzyme/water phase.
Animals↗
Post-withdrawal changes in middle-latency auditory evoked potentials in abstinent human alcoholics.
We investigated the effects of chronic alcoholism on middle-latency auditory evoked potentials (MAEP) in 14 male alcoholics with 1-6 weeks of abstinence (without other severe disorders) and 13 age-matched male social-drinker controls. The peak amplitude of a positive deflection (Pa) of the MAEP, peaking at about 30 ms post-stimulus, was significantly larger in the alcoholics than in the controls (P < 0.01), and notably, a significant negative correlation (r = -0.65) was observed between the Pa amplitude and duration of abstinence in the alcoholics. The present results suggest that the post-withdrawal brain hyperexcitability in the alcoholic brain, gradually recovering with abstinence, could be objectively and non-invasively studied with the MAEP.
Adult↗
Bicyclic tripeptide mimetics with reverse turn inducing properties.
Analogues of the hypertensive octapeptide angiotensin II, comprising novel constrained 5,8-bicyclic and 5,9-bicyclic tripeptide units adopting nonclassical beta-turn geometries, as deduced from theoretical conformational analysis, have been synthesized. Spontanous bicyclization upon acid-catalyzed deprotection of a model peptide, encompassing a protected omega-formyl alpha-amino acid in position 5 and cysteine residues in positions 3 and 7, revealed a strong preference for bicyclization toward the C-terminus. The bicyclic thiazolidine related angiotensin II analogues synthesized exhibited no affinity for the angiotensin II AT1 receptor.
Angiotensin II↗
Suppression of mismatch negativity by backward masking predicts impaired working-memory performance in alcoholics.
BACKGROUND: Pronounced disruption of memory traces by subsequent distractors may result in impaired behavioral memory performance in alcoholics. METHODS: This hypothesis was investigated with an electrophysiological index of auditory sensory-memory traces, mismatch negativity, a preattentive event-related potential component elicited by a "deviant" tone within a train of "standard" tones. RESULTS: Inserting a masking stimulus after these tones abolished mismatch negativity in alcoholics (DSM-IV) but not in social-drinker controls. This effect predicted working-memory impairment in alcoholics, and correlated significantly with self-reported alcohol consumption of the subjects. Furthermore, the backward-masking mismatch negativity paradigm detected sensory-memory impairment in 9 of 20 alcoholics (sensitivity 45%), whereas all 20 social drinkers were unimpaired (specificity 100%). CONCLUSIONS: Vulnerability to memory trace disruption by shortly following sounds may be one of the factors contributing to behavioral memory dysfunction in alcoholics. The present result may provide an objective neurophysiological tool for investigation of alcohol-induced and other degenerative brain disorders.
Adult↗
Correlation of human jejunal permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate data analysis approach.
The effective permeability (Peff) in the human jejunum (in vivo) of 22 structurally diverse compounds was correlated with both experimentally determined lipophilicity values and calculated molecular descriptors. The permeability data were previously obtained by using a regional in vivo perfusion system in the proximal jejunum in humans as part of constructing a biopharmaceutical classification system for oral immediate-release products. pKa, log P, and, where relevant, log Pion values were determined using the pH-metric technique. On the basis of these experiments, log D values were calculated at pH 5.5, 6.5, and 7.4. Multivariate data analysis was used to derive models that correlate passive intestinal permeability to physicochemical descriptors. The best model obtained, based on 13 passively transcellularly absorbed compounds, used the variables HBD (number of hydrogen bond donors), PSA (polar surface area), and either log D5.5 or log D6.5 (octanol/water distribution coefficient at pH 5.5 and 6.5, respectively). Statistically good models for prediciting human in vivo Peff values were also obtained by using only HBD and PSA or HBD, PSA, and CLOGP. These models can be used to predict passive intestinal membrane diffusion in humans for compounds that fit within the defined property space. We used one of the models obtained above to predict the log Peff values for an external validation set consisting of 34 compounds. A good correlation with the absorption data of these compounds was found.
Humans↗
Design and synthesis of new potent C2-symmetric HIV-1 protease inhibitors. Use of L-mannaric acid as a peptidomimetic scaffold.
A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
Adipates↗
Mutational analysis of the FMR1 gene in 118 mentally retarded males suspected of fragile X syndrome: absence of prevalent mutations.
Fragile X syndrome is usually caused by expansion of a trinucleotide (CGG) repeat in the 5'-untranslated region of the FMR1 gene. However, both deletions and point mutations in FMR1 have been identified as rare causes of the fragile X syndrome. We have screened the FMR1 gene for mutations by single-stranded conformational polymorphism analysis in 118 mentally retarded males who were referred to us for fragile X testing, and who had a CGG repeat number in the normal size range. We found one patient with a 2-bp deletion in intron 1 and two unrelated patients with identical silent mutations in exon 1. Neither of these mutations were found in 83 controls. Further investigation of the exon 1 silent mutation by Western blot analysis showed normal expression of FMRP in lymphoblastoid cells and reverse-transcription-polymerase chain reaction analysis showed that intron 1 and 2 were spliced out as in the normal control. Furthermore, we found two common polymorphisms, one in intron 1 and one in exon 5. However, no pathogenic FMR1 mutation was found.
Adolescent↗
Computation of affinity and selectivity: binding of 2,4-diaminopteridine and 2,4-diaminoquinazoline inhibitors to dihydrofolate reductases.
Binding energy calculations for complexes of mutant and wild-type human dihydrofolate reductases with 2,4-diaminopteridine and 2,4-diaminoquinazoline inhibitors are reported. Quantitative insight into binding energetics of these molecules is obtained from calculations based on force field energy evaluation and thermal sampling by molecular dynamics simulations. The calculated affinity of methotrexate for wild-type and mutant enzymes is reasonably well reproduced. Truncation of the methotrexate glutamate tail results in a loss of affinity by several orders of magnitude. No major difference in binding strength is predicted between the pteridines and the quinazolìnes, while the N-methyl group present in methotrexate appears to confer significantly stronger binding. The recent improvement, which is used here, of our linear interaction energy method for binding affinity prediction, as well as problems with treating charged and flexible ligands are discussed. This approach should be suitable in a drug discovery context for prediction of binding energies of new inhibitors prior to their synthesis, when some information about the binding mode is available.
Computer Simulation↗
Synthesis and enzymatic hydrolysis of esters, constituting simple models of soft drugs.
One way to minimise systemic side effects of drugs is to design molecules, soft drugs, in such a way that they are metabolically inactivated rapidly after having acted on their pharmacological target. Hydrolases (esterases, peptidases, lipases, glycosidases, etc.) are enzymes well suited to use for drug inactivation since they are ubiquitously distributed. Insertion of ester bonds susceptible to enzymatic cleavage may represent one approach to make the action of a drug more restricted to the site of application. The present study describes the chemical synthesis of fourteen model compounds comprising a bicyclic aromatic unit connected by an ester-containing bridge to another aromatic ring. Initial attempts to define a) the tissue selectivity of the hydrolytic metabolism and b) the molecular structural factors affecting the rate of enzymatic ester cleavage are presented. The data show that human and rat liver fractions were more active than human duodenal mucosa and human blood leukocytes at hydrolysing the compounds. The rank order of the compounds was, however, very similar in the different biological systems. Commercially available pig liver carboxyl esterase and cholesterol esterase both reasonably well predict the rank order in the tissue fractions.
Animals↗