Total synthesis of tubulysin U and V.
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Molecular Conformation↗
Biomedical subjects
Barbara Beck
Publications and source records attributed to Barbara Beck.
Towards erythropoietin mimicking small molecules.
Small molecules potentially mimicking the hormone erythropoietin have been discovered by screening of a library of rationally designed multicomponent reaction molecules in a functional cell-based assay.
Animals↗
Effects of six months of daily low-dose perchlorate exposure on thyroid function in healthy volunteers.
CONTEXT: Perchlorate has been detected in U.S. drinking water supplies at levels ranging from 4 to 200 microg/liter as well as in agricultural products. Perchlorate is known to be a competitive inhibitor of iodine uptake by the thyroid through the sodium-iodide symporter. OBJECTIVE: The objective of the study was to determine whether prolonged exposure (6 months) to low levels of perchlorate would perturb thyroid function. DESIGN: This was a prospective, double-blinded, randomized trial. PARTICIPANTS: The study population consisted of 13 healthy volunteers. INTERVENTION: INTERVENTIONs included placebo vs. 0.5 mg or 3.0 mg potassium perchlorate daily. MAIN OUTCOME MEASURES: Serum thyroid function tests, 24-h radioactive iodine uptake, serum thyroglobulin (Tg), urinary iodine and perchlorate, and serum perchlorate were measured. RESULTS: Mean urinary perchlorate value during ingestion of 0.5 mg perchlorate daily was 332.7 +/- 66.1 microg per 24 h or 248.5 +/- 64.5 microg/g creatinine and mean values for the four subjects who received 3 mg perchlorate daily were 2079.5 +/- 430.0 microg per 24 h or 1941.7 +/- 138.5 microg/g creatinine. There was no significant change in the thyroid (123)I uptakes during perchlorate administration. There were no significant changes in serum T(3), free T(4) index, TSH, or Tg concentrations during the exposure period, compared to baseline or postexposure values. Urine iodine values for the 3-mg perchlorate group were higher, but not significantly so, at baseline than during perchlorate exposure. CONCLUSIONS: We observed that a 6-month exposure to perchlorate at doses up to 3 mg/d had no effect on thyroid function, including inhibition of thyroid iodide uptake as well as serum levels of thyroid hormones, TSH, and Tg.
Adult↗
Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25.
Adult T-cell leukemia (ATL) consists of an overabundance of T cells, which express CD25. Therapeutic efficacy of astatine-211 ((211)At)-labeled murine monoclonal antibody 7G7/B6 alone and in combination with daclizumab was evaluated in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice given injections of MET-1 human T-cell leukemia cells. Daclizumab and 7G7/B6 are directed toward different epitopes of CD25. Either a single dose of 12 microCi (0.444 MBq) (211)At-7G7/B6 per mouse given intravenously or receptor-saturating doses of daclizumab given at 100 microg weekly for 4 weeks intravenously inhibited tumor growth as monitored by serum levels of human beta-2 microglobulin (beta(2)mu) and by prolonged survival of leukemia-bearing mice compared with the control groups (P < .001). The combination of 2 agents enhanced the antitumor effect when compared with groups treated with 12 microCi (0.444 MBq) of (211)At-7G7/B6 (P < .05) or daclizumab alone (P < .05). The median survival duration of the PBS group was 62.6 days and 61.5 days in the radiolabeled nonspecific antibody (211)At-11F11-treated group. In contrast, 91% of mice in the combination group survived through day 94. These results that demonstrate a significantly improved therapeutic efficacy by combining (211)At-7G7/B6 with daclizumab support a clinical trial of this regimen in patients with ATL.
Animals↗
Design and modular parallel synthesis of a MCR derived alpha-helix mimetic protein-protein interaction inhibitor scaffold.
A terphenyl alpha-helix mimetic scaffold recognized to be capable of disrupting protein-protein interactions was structurally morphed into an easily amenable and versatile multicomponent reaction (MCR) backbone. The design, modular in-parallel library synthesis, initial cell based biological data, and preliminary in vitro screening for the disruption of the Bcl-w/Bak protein-protein interaction by representatives of the MCR derived scaffold are presented.
Apoptosis↗
Arsenic toxicity at low doses: epidemiological and mode of action considerations.
Current approaches to risk assessment typically assume a linear dose-response for mutagenic compounds that directly interact with DNA or when the carcinogenic mechanism is unknown. Because the mode of action of arsenic-induced carcinogenesis is not well established, recent dose-response assessments for arsenic have assumed linearity at low doses despite evidence that arsenic is not a direct-acting mutagen. Several modes of action, including generation of oxidative stress, perturbation of DNA methylation patterns, inhibition of DNA repair, and modulation of signal transduction pathways, have been proposed to characterize arsenic's toxicity. It is probable that these mechanisms do not act in isolation, but overlap, and contribute to the complex nature of arsenic-induced carcinogenesis. All of the proposed mechanisms are likely to be nonlinear at low does. Furthermore, studies of populations outside the US exposed to arsenic in drinking water show increases in cancer only at relatively high concentrations, that is, concentrations in drinking water of several hundred micrograms per liter (microg/l). Studies in the US of populations exposed to average concentrations in drinking water up to about 190 microg/l do not provide evidence of increased cancer. Consideration of arsenic's plausible mechanisms and evidence from epidemiological studies support the use of nonlinear methods, either via biologically based modeling or use of a margin-of-exposure analysis, to characterize arsenic risks.
Adolescent↗
Novel nonpeptidic inhibitors of HIV-1 protease obtained via a new multicomponent chemistry strategy.
Using a newly developed multicomponent chemistry strategy in combination with structure based drug design, a new class of HIV-1 protease inhibitors has been obtained.
Binding Sites↗
Highly substituted pyrrolidinones and pyridones by 4-CR/2-CR sequence.
[reaction: see text] By combining a Ugi four-component reaction of isocyanides, phosphonoacetic acids, primary amines, and glyoxals or alternatively 3-keto aldehydes with a subsequent Wittig ring-closing reaction (using the Horner/Wadsworth/Emmons variant (HWE)), highly substituted 5-oxo-2,5-dihydro-1H-pyrrole-2-carboxylic acid amides and 6-oxo-1,2,3,6-tetrahydro-pyridine-2-carboxylic acid amides can be assembled, respectively. The corresponding tandem of a Passerini reaction on 3-keto aldehydes and subsequent Wittig ring closure does not afford the expected six-membered 6-oxo-3,6-dihydro-2H-pyran-2-carboxylic acid amides but instead leads to the formation of 4-oxo-pent-2-enoic acid amides via an elimination route.
Journal Article↗
Massive parallel catalyst screening: toward asymmetric MCRs.
[reaction: see text]. Hundreds of Lewis acid/ligand combinations have been screened for stereochemical induction in the Passerini multicomponent reaction. The combination of titan tetraisopropylate and (4S,5S)-4,5-bis(diphenylhydroxymethyl)-2,2-dimethyldioxolane was found to give enantiomeric excesses between 32% and 42% in several examples. The absolute stereo induction of one example was determined chemically and by means of X-ray crystallography. This comprises the first asymmetric Passerini reaction and the first example of a stereochemical induction in an isocyanide based multicomponent reaction by a chiral Lewis acid.
Journal Article↗
Short and diverse route toward complex natural product-like macrocycles.
[reaction: see text] A general strategy toward macrocyclic compounds using multicomponent reaction (MCR) chemistry, e.g., Passerini and Ugi variants, and ring-closing metathesis (RCM) is introduced. The corresponding bifunctional isocyanides carboxylic acids bearing a terminal olefin are easy to prepare from the corresponding commercially available starting materials. Advantageously, this strategy allows fast access to a diverse conformational space of natural product-like macrocycles and could thus be of interest in the discovery of novel bioactive agents.
Alkenes↗
New MCRs: the first 4-component reaction leading to 2,4-disubstituted thiazoles.
New organic reactions allow chemical transformations which were previously not possible. Therefore, new reactions are important contributions to the progress in the field of organic synthesis. In this series we describe the design, scope, and limitations of newly-discovered multi-component reactions (MCRs). Herein, a first example of a MCR is introduced which allows general access to the class of 2,4-di- and 2,4,5-trisubstituted thiazoles.
Combinatorial Chemistry Techniques↗
Parallel synthesis of arrays of amino-acid-derived isocyanoamides useful as starting materials in IMCR.
Arrays of amino-acid-derived isocyanoamides are conveniently produced on a multigram scale in one step by the solventless aminolysis of the corresponding methyl esters with primary or secondary aliphatic amines. Most of the corresponding isocyanides precipitate during the reaction and can be filtered to yield highly pure, colorless, and odorless solids. They are potentially useful in the combinatorial chemistry of multicomponent reactions.
Amides↗