Search results for "chemical space"
showing 10 items of 11 documents
8-Iodonaphthalene-1-carbaldehyde: A Versatile Building Block for Diversity-Oriented Synthesis.
2016
The scarcely studied 8-halonaphthalene-1-carbaldehyde structure has been converted into the corresponding Ellman’s imine and subjected to several transformations, thus achieving an assorted library of polycyclic carbo- and heterocycles. The potential of this scaffold for Diversity-Oriented Synthesis has been shown. Most of these skeletons are unprecedented and, therefore, cover unexplored regions of the chemical space.
New insights into the mechanism of action of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives endowed with anticancer potential
2018
Due to the scarce biological profile, the pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one scaffold (PBT) has been recently explored as promising core for potential anticancer candidates. Several suitably decorated derivatives (PBTs) exhibited antiproliferative activity in the low-micromolar range associated with apoptosis induction and cell cycle arrest on S phase. Herein, we selected the most active derivatives and submitted them to further biological explorations to deepen the mechanism of action. At first, a DNA targeting is approached by means of flow Linear Dichroism experiments so as to evaluate how small planar molecules might interact with DNA, including the interference with the catal…
A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure
2018
International audience; Recently discovered new chemical entities in RNA modifications have involved surprising functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over 100 signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds that are new structures of RNA modifications. One structure was elucidated by deuterium exchange and high-resolution mass spectrometry. The structure of msms2 i6 A (2-methylthiomethylenethio-N6-isopentenyl-adenosine) was confirmed by methione-D3 feeding experiments and by synthesis of the nucleobase. The msms2 i6 A contai…
Increasing the Coverage of Medicinal Chemistry-Relevant Space in Commercial Fragments Screening
2014
Analyzing the chemical space coverage in commercial fragment screening collections revealed the overlap between bioactive medicinal chemistry substructures and rule-of-three compliant fragments is only ∼25%. We recommend including these fragments in fragment screening libraries to maximize confidence in discovering hit matter within known bioactive chemical space, while incorporation of nonoverlapping substructures could offer novel hits in screening libraries. Using principal component analysis, polar and three-dimensional substructures display a higher-than-average enrichment of bioactive compounds, indicating increasing representation of these substructures may be beneficial in fragment …
ProteoPlex: stability optimization of macromolecular complexes by sparse-matrix screening of chemical space.
2015
Molecular machines or macromolecular complexes are supramolecular assemblies of biomolecules that ensure cellular homeostasis. Structure determination of those complexes in a purified state is often a tedious undertaking due to the compositional complexity and the related relative structural instability. To improve the stability of macromolecular complexes in vitro, we present here a generic method that optimizes the stability, homogeneity and solubility of macromolecular complexes by sparse-matrix screening of their thermal unfolding behaviour in the presence of various buffers and small molecules. The method includes the automated analysis of thermal unfolding curves based on a newly deve…
CheS-Mapper - Chemical Space Mapping and Visualization in 3D
2012
Abstract Analyzing chemical datasets is a challenging task for scientific researchers in the field of chemoinformatics. It is important, yet difficult to understand the relationship between the structure of chemical compounds, their physico-chemical properties, and biological or toxic effects. To that respect, visualization tools can help to better comprehend the underlying correlations. Our recently developed 3D molecular viewer CheS-Mapper (Chemical Space Mapper) divides large datasets into clusters of similar compounds and consequently arranges them in 3D space, such that their spatial proximity reflects their similarity. The user can indirectly determine similarity, by selecting which f…
Novel scaffold of natural compound eliciting sweet taste revealed by machine learning
2020
Abstract Sugar replacement is still an active issue in the food industry. The use of structure-taste relationships remains one of the most rational strategy to expand the chemical space associated to sweet taste. A new machine learning model has been setup based on an update of the SweetenersDB and on open-source molecular features. It has been implemented on a freely accessible webserver. Cellular functional assays show that the sweet taste receptor is activated in vitro by a new scaffold of natural compounds identified by the in silico protocol. The newly identified sweetener belongs to the lignan chemical family and opens a new chemical space to explore.
Beyond Pseudo‐natural Products: Sequential Ugi/Pictet‐Spengler Reactions Leading to Steroidal Pyrazinoisoquinolines That Trigger Caspase‐Independent …
2021
In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are…
Translocation Biosensors – Cellular System Integrators to Dissect CRM1-Dependent Nuclear Export by Chemicogenomics
2009
Fluorescent protein biosensors are powerful cellular systems biology tools for dissecting the complexity of cellular processes with high spatial and temporal resolution. As regulated nucleo-cytoplasmic transport is crucial for the modulation of numerous (patho)physiological cellular responses, a detailed understanding of its molecular mechanism would open up novel options for a rational manipulation of the cell. In contrast to genetic approaches, we here established and employed high-content cellular translocation biosensors applicable for dissecting nuclear export by chemicogenomics. A431 cell lines, stably expressing a translocation biosensor composed of glutathione S-transferase, GFP and…
The Chardonnay wine olfactory concept revisited: A stable core of volatile compounds, and fuzzy boundaries
2011
Abstract An earlier study by the same team showed that Chardonnay wines have common olfactory properties by which wine experts can recognize them. The specific Chardonnay olfactory space was also tentatively linked to the relative concentrations of 29 volatile compounds, regarded as possible aroma-impact compounds. The question now is whether or not those initial results hold independently of the sample under consideration, that is, whether these sensory and chemical spaces are vintage-specific. A series of investigations was conducted on a new set of 46 wines (23 Chardonnay wines and 23 non Chardonnay wines) using the same sensory (wine typicality level) and physico-chemical (Gas Chromatog…