The best of 40 000: Detailed structure–activity‐relationship studies revealed key structural elements of indolin‐2‐on‐3‐spirothiazolidinones (see example) and their appropriate configuration for ...strong inhibitory activity against the pathophysiologically relevant title protein.
In biology-oriented synthesis, the scaffolds of biologically relevant compound classes inspire the synthesis of focused compound collections enriched in bioactivity. This criterion is, in particular, ...met by the scaffolds of natural products selected in evolution. The synthesis of natural product-inspired compound collections calls for efficient reaction sequences that preferably combine multiple individual transformations in one operation. Here we report the development of a one-pot, twelve-step cascade reaction sequence that includes nine different reactions and two opposing kinds of organocatalysis. The cascade sequence proceeds within 10-30 min and transforms readily available substrates into complex indoloquinolizines that resemble the core tetracyclic scaffold of numerous polycyclic indole alkaloids. Biological investigation of a corresponding focused compound collection revealed modulators of centrosome integrity, termed centrocountins, which caused fragmented and supernumerary centrosomes, chromosome congression defects, multipolar mitotic spindles, acentrosomal spindle poles and multipolar cell division by targeting the centrosome-associated proteins nucleophosmin and Crm1.
The aim of this tutorial review is to introduce the reader to the concept, synthesis and application of natural product-inspired compound collections as an important field in chemical biology. This ...review will discuss how potentially interesting scaffolds can be identified (structural classification of natural products), synthesized in an appropriate manner (including stereoselective transformations for solid phase-bound compounds) and tested in biological assays (cell-based screening as well as biochemical in vitro assays). These approaches will provide the opportunity to identify new and interesting compounds as well as new targets for chemical biology and medicinal chemistry research.
Tuberculosis continues to be a major cause of morbidity and mortality throughout the world. Protein tyrosine phosphatases from
Mycobacterium tuberculosis are attractive targets for developing novel ...strategies in battling tuberculosis due to their role in the intracellular survival of
M. tuberculosis in various infection models. Here, we report on the identification and further development of thiazolidinones spiro-fused to indolin-2-ones as a new class of potent and selective inhibitors of
M. tuberculosis protein tyrosine phosphatase B. Detailed structure–activity relationship (SAR) studies revealed that a nitro-substituted 2-oxoindole core together with a dihalogenated anilide and a halogenated
N-benzyl moiety are essential for strong inhibitory activity against MptpB (
M. tuberculosis protein tyrosine phosphatase B). Small structural modification of the identified compounds led to significant improvement of compound solubility and cell permeability retaining inhibitory activity in the micromolar range. The configuration of the spiro-center was found to be crucial for the inhibitory activity and the separation of the racemate revealed the
R-(−)-enantiomers as the biologically active component. The reported MptpB inhibitors show excellent selectivity against a selected panel of protein tyrosine phosphatases, including MptpA (
M. tuberculosis protein tyrosine phosphatase A), PTP1B (protein tyrosine phosphatase 1B), SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase), PTPN2, h-PTPβ (human protein tyrosine phosphatase β), and VHR (
Vaccinia virus VH1-related dual-specific protein phosphatase) and further highlight the identified thiazolidinones spiro-fused to indolin-2-ones as a promising class of new compounds that might prove useful for chemical biology research to dissect MptpB function and eventually foster the development of next generation antibiotics.
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Chemical modulators are powerful tools to investigate biological processes. To identify circadian clock effectors, we screened a natural product library in the model plant Arabidopsis thaliana. Two ...compounds, prieurianin (Pri) and prieurianin acetate, were identified as causing a shorter circadian period. Recently, Pri was independently identified as a vesicle trafficking inhibitor and re‐named endosidin 1 (ES1). Here we show that Pri primarily affects actin filament flexibility in vivo, later resulting in reduced severing and filament depolymerization. This stabilization of the actin cytoskeleton subsequently causes changes in vesicle trafficking. Pri also affected microfilaments in mammalian cells, indicating that its target is highly conserved; however, it did not alter actin dynamics in vitro, suggesting that its activity requires the presence of actin‐associated proteins. Furthermore, well‐characterized actin inhibitors shortened the period length of the Arabidopsis clock in a similar way to Pri, supporting the idea that Pri affects rhythms by altering the actin network. We conclude that actin‐associated processes influence the circadian system in a light‐dependent manner, but their disruption does not abolish rhythmicity. In summary, we propose that the primary effect of Pri is to stabilize the actin cytoskeleton system, thereby affecting endosome trafficking. Pri appears to stabilize actin filaments by a different mechanism from previously described inhibitors, and will be a useful tool to study actin‐related cellular processes.
► We developed a new screening system for the discovery of CYP11B2 inhibitors. ► The new screening system can be used to screen up to 600 compounds per week. ► Old drugs disclosed new applications ...for the therapy of hypertension-related diseases. ► 5 selective inhibitors of CYP11B2 have been discovered. ► Reinvestigation of existing drugs can lead to the discovery of new indications.
Cytochrome P450 enzymes play an important role in steroid hormone biosynthesis of the human adrenal gland, e.g., the production of cortisol and aldosterone. Aldosterone, the most important human mineralocorticoid, is involved in the regulation of the salt and water homeostasis of the body and thus in the regulation of blood pressure, whereas cortisol is the most important glucocorticoid of the human body. CYP11B-dependent steroid hydroxylases are drug development targets, and since they are very closely related enzymes, the discovery of selective inhibitors has been subject to intense investigations for several years. Here we report the development of a whole-cell medium throughput screening technology for the discovery of CYP11B2 inhibitors. The new screening system displayed high reproducibility and was applied to investigate a library of pharmacologically active compounds. 1268 compounds were investigated during this study which revealed 5 selective inhibitors of CYP11B2 (after validation against CYP11B1). The new inhibitors of CYP11B2 are already existing drugs that could be used either in the treatment of hyperaldosteronism-related diseases or as lead compounds that could further be optimised to achieve safer and selective inhibitors of aldosterone synthase.
Article from the Special issue on ‘Targeted Inhibitors’
Natural causes: A combination of organic synthesis, chemical proteomics, biophysics, and cell and molecular biology investigations reveals that the natural product melophlin A (purple) influences ...signal propagation through the Ras network by interfering with the function of dynamins (green) in endocytosis.
The microRNA pathway has been implicated in the regulation of synaptic protein synthesis and ultimately in dendritic spine morphogenesis, a phenomenon associated with long-lasting forms of memory. ...However, the particular microRNAs (miRNAs) involved are largely unknown. Here we identify specific miRNAs that function at synapses to control dendritic spine structure by performing a functional screen. One of the identified miRNAs, miR-138, is highly enriched in the brain, localized within dendrites and negatively regulates the size of dendritic spines in rat hippocampal neurons. miR-138 controls the expression of acyl protein thioesterase 1 (APT1), an enzyme regulating the palmitoylation status of proteins that are known to function at the synapse, including the alpha(13) subunits of G proteins (Galpha(13)). RNA-interference-mediated knockdown of APT1 and the expression of membrane-localized Galpha(13) both suppress spine enlargement caused by inhibition of miR-138, suggesting that APT1-regulated depalmitoylation of Galpha(13) might be an important downstream event of miR-138 function. Our results uncover a previously unknown miRNA-dependent mechanism in neurons and demonstrate a previously unrecognized complexity of miRNA-dependent control of dendritic spine morphogenesis.
New inhibitors for
d-alanine–
d-alanine ligase can be found based on the similarity of the ATP binding site of kinases and
d-alanine–
d-alanine ligase.
d-Alanine–
d-alanine ligase (DDl) is an ...essential enzyme in bacterial cell wall biosynthesis and an important target for developing new antibiotics. Here, we describe a new approach to identify new inhibitor scaffolds for DDl based on similarity in the ATP binding region of different kinases and DDl. After an initial screening of several protein kinase inhibitors, we found that the Brutons’s tyrosine kinase inhibitor LFM-A13, an analog of the Leflunomide metabolite A771726, inhibits DDl with a
K
i of 185
μM. A series of malononitrilamide and salicylamide derivatives of LFM-A13 has been synthesized to confirm the validity of this scaffold as an inhibitor of DDl.
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