scholarly journals Tunable aziridinium ylide reactivity: non-covalent interactions enable divergent product outcomes

2021 ◽  
Author(s):  
Kate Nicastri ◽  
Soren Zappia ◽  
Jared Pratt ◽  
Julia Duncan ◽  
Ilia Guzei ◽  
...  
Keyword(s):  
Chemical Space ◽  
Steric Effects ◽  
Computational Studies ◽  
Rapid Preparation ◽  
Rotational Barriers ◽  
Wide Range ◽  
Non Covalent Interactions ◽  
Further Development ◽  
Covalent Interactions

Methods for rapid preparation of densely functionalized and stereochemically complex N-heterocyclic scaffolds are in demand for exploring potential new bioactive chemical space. This work describes experimental and computational studies to better understand the features of aziridinium ylides as intermediates for the synthesis of highly substituted dehydromorpholines. The development of this chemistry has enabled the extension of aziridinium ylide chemistry to the concomitant formation of both a C–N and a C–O bond in a manner that preserves the stereochemical information embedded in the substrate. The chemistry is tolerant of a wide range of functionalities that can be employed for DNA-encoded library (DEL) synthesis to prepare diverse libraries of heterocycles with potential bioactivity. In addition, we have uncovered several key insights that describe the importance of steric effects, rotational barriers around the C–N bond of the aziridinium ylide, and non-covalent interactions (NCIs) on the ultimate reaction outcome. These critical insights will assist in the further development of this chemistry to generate novel and complex N-heterocycles that will further expand complex amine chemical space.

scholarly journals A IMPORTÂNCIA DAS CUMARINAS PARA A QUÍMICA MEDICINAL E O DESENVOLVIMENTO DE COMPOSTOS BIOATIVOS NOS ÚLTIMOS ANOS

Química Nova ◽  
2020 ◽  
Author(s):  
Daiana Franco ◽  
Thiago Pereira ◽  
Felipe Vitorio ◽  
Nathalia Nadur ◽  
Renata Lacerda ◽  
...  
Keyword(s):  
Chemical Space ◽  
Biological Activities ◽  
Research Projects ◽  
Wide Range ◽  
Non Covalent Interactions ◽  
Iupac Nomenclature ◽  
Living Organisms ◽  
Coumarin Compounds ◽  
New Treatments ◽  
Covalent Interactions

Coumarins are natural products characterized as 2H-chromen-2-one, according to IUPAC nomenclature, largely distributed in plants, as well as, in species of fungi and bacteria. Nowadays, many synthetic procedures allow the discovery of coumarins with expanded chemical space. The ability to exert non-covalent interactions with many enzymes an receptors in living organisms lead the coumarins to exhibit a wide range of biological activities and applications. Then, this manuscript provides an overview of the use of coumarin compounds in medicinal chemistry in treating many diseases. Important examples of the last years have been selected concerning the activities of coumarins as anticoagulant, anticancer, antioxidant, antiviral, antidiabetics, anti-inflammatory, antibacterial, antifungal, and anti-neurodegenerative agents. Thus, this work aims at contributing to the development of new rational research projects searching for new treatments and bioactive compounds for many pathologies using coumarin derivatives.

scholarly journals Molecular interactions of amyloid nanofibrils with biological aggregation modifiers: implications for cytotoxicity mechanisms and biomaterial design

2017 ◽  
Vol 7 (4) ◽  
pp. 20160160 ◽  
Author(s):  
Durga Dharmadana ◽  
Nicholas P. Reynolds ◽  
Charlotte E. Conn ◽  
Céline Valéry
Keyword(s):  
Molecular Interactions ◽  
Lipid Membranes ◽  
Reaction Pathway ◽  
Third Party ◽  
Final Word ◽  
Nucleated Polymerization ◽  
Wide Range ◽  
Non Covalent Interactions ◽  
Functional Amyloids ◽  
Covalent Interactions

Amyloid nanofibrils are ubiquitous biological protein fibrous aggregates, with a wide range of either toxic or beneficial activities that are relevant to human disease and normal biology. Protein amyloid fibrillization occurs via nucleated polymerization, through non-covalent interactions. As such, protein nanofibril formation is based on a complex interplay between kinetic and thermodynamic factors. The process entails metastable oligomeric species and a highly thermodynamically favoured end state. The kinetics, and the reaction pathway itself, can be influenced by third party moieties, either molecules or surfaces. Specifically, in the biological context, different classes of biomolecules are known to act as catalysts, inhibitors or modifiers of the generic protein fibrillization process. The biological aggregation modifiers reviewed here include lipid membranes of varying composition, glycosaminoglycans and metal ions, with a final word on xenobiotic compounds. The corresponding molecular interactions are critically analysed and placed in the context of the mechanisms of cytotoxicity of the amyloids involved in diverse pathologies and the non-toxicity of functional amyloids (at least towards their biological host). Finally, the utilization of this knowledge towards the design of bio-inspired and biocompatible nanomaterials is explored.

Non-Covalent Interactions Atlas Benchmark Data Sets: Hydrogen Bonding

2019 ◽  
Author(s):  
Jan Řezáč
Keyword(s):  
Hydrogen Bonding ◽  
Basis Sets ◽  
Data Sets ◽  
Neutral Systems ◽  
Benchmark Data ◽  
Wide Range ◽  
Non Covalent Interactions ◽  
Dissociation Curves ◽  
New Generation ◽  
Covalent Interactions

The Non-Covalent Interactions Atlas project (www.nciatlas.org) aims to cover a wide range of non-covalent interactions with a new generation of benchmark data sets. This paper presents the first two data sets focused on hydrogen bonding: HB375, featuring neutral systems, and IHB100 for ionic H-bonds. Both data sets are complemented by ten-point dissociation curves (HB375x10, IHB100x10). The interaction energies are extrapolated to the CCSD(T)/CBS limit from calculations in large basis sets. The paper also summarizes the design principles that will be used to construct the subsequent data sets in the series. The testing of DFT-D methods on the HB375 set has revealed interesting, previously unnoticed issues. The application of the new data to the testing and parameterization of semiempirical QM methods is also discussed.

scholarly journals Non-Covalent Interactions Atlas Benchmark Data Sets 2: Hydrogen Bonding in an Extended Chemical Space

2020 ◽  
Author(s):  
Jan Řezáč
Keyword(s):  
Hydrogen Bonding ◽  
Organic Molecules ◽  
Chemical Space ◽  
Data Sets ◽  
Data Set ◽  
Benchmark Data ◽  
Non Covalent Interactions ◽  
Dissociation Curves ◽  
New Generation ◽  
Covalent Interactions

The Non-Covalent Interactions Atlas (www.nciatlas.org) aims to provide a new generation of benchmark data sets for non-covalent interactions. The HB300SPX data set presented here extends the coverage of hydrogen bonds to phosphorus, sulfur and halogens up to iodine. It is again complemented by a set of dissociation curves, HB300SPX×10. The new data make it possible to analyze the transferability of the parametrization of e.g. dispersion corrections for DFT from simple organic molecules to a broader chemical space. The HB300SPX×10 has also been used for the extension of the parametrization of hydrogen-bonding corrections in the semiempirical PM6-D3H4X and DFTB3-D3H5 methods to additional elements.<br>

scholarly journals Non-Covalent Interactions Atlas Benchmark Data Sets 5: London Dispersion in an Extended Chemical Space

2022 ◽  
Author(s):  
Jan Řezáč
Keyword(s):  
Chemical Space ◽  
Data Sets ◽  
Dft Methods ◽  
Data Set ◽  
Data Points ◽  
Comprehensive Test ◽  
Non Covalent Interactions ◽  
London Dispersion ◽  
Dissociation Curves ◽  
Covalent Interactions

The Non-Covalent Interactions Atlas (www.nciatlas.org) has been extended with two data sets of benchmark interaction energies in complexes dominated by London dispersion. The D1200 data set of equilibrium geometries provides a thorough sampling of an extended chemical space, while the D442×10 set features dissociation curves for selected complexes. In total, they provide 5,178 new CCSD(T)/CBS data points of the highest quality. The new data have been combined with previous NCIA data sets in a comprehensive test of dispersion-corrected DFT methods, identifying the ones that achieve high accuracy in all types of non-covalent interactions in a broad chemical space. Additional tests of dispersion-corrected MP2 and semiempirical QM methods are also reported.

scholarly journals Stereodynamic tetrahydrobiisoindole “NU-BIPHEP(O)”s: functionalization, rotational barriers and non-covalent interactions

2016 ◽  
Vol 12 ◽  
pp. 1453-1458 ◽  
Author(s):  
Golo Storch ◽  
Sebastian Pallmann ◽  
Frank Rominger ◽  
Oliver Trapp
Keyword(s):  
Adduct Formation ◽  
Enantioselective Catalysis ◽  
Cellulose Derivatives ◽  
Diphosphine Ligands ◽  
Rotational Barriers ◽  
Covalent Adduct ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Stereodynamic ligands offer intriguing possibilities in enantioselective catalysis. “NU-BIPHEPs” are a class of stereodynamic diphosphine ligands which are easily accessible via rhodium-catalyzed double [2 + 2 + 2] cycloadditions. This study explores the preparation of differently functionalized “NU-BIPHEP(O)” compounds, the characterization of non-covalent adduct formation and the quantification of enantiomerization barriers. In order to explore the possibilities of functionalization, we studied modifications of the ligand backbone, e.g., with 3,5-dichlorobenzoyl chloride. Diastereomeric adducts with Okamoto-type cellulose derivatives and on-column deracemization were realized on the basis of non-covalent interactions. Enantioselective dynamic HPLC (DHPLC) allowed for the determination of rotational barriers of ΔG ‡ 298K = 92.2 ± 0.3 kJ mol−1 and 99.5 ± 0.1 kJ mol−1 underlining the stereodynamic properties of “NU-BIPHEPs” and “NU-BIPHEP(O)s”, respectively. These results make the preparation of tailor-made functionalized stereodynamic ligands possible and give an outline for possible applications in enantioselective catalysis.

scholarly journals The role of the nucleosome acidic patch in modulating higher order chromatin structure

2013 ◽  
Vol 10 (82) ◽  
pp. 20121022 ◽  
Author(s):  
Anna A. Kalashnikova ◽  
Mary E. Porter-Goff ◽  
Uma M. Muthurajan ◽  
Karolin Luger ◽  
Jeffrey C. Hansen
Keyword(s):  
Higher Order ◽  
Folding Pathway ◽  
Computational Studies ◽  
Biological Functions ◽  
Histone H4 ◽  
Chromatin Fibre ◽  
Chromatin Folding ◽  
Non Covalent Interactions ◽  
Covalent Interactions

Higher order folding of chromatin fibre is mediated by interactions of the histone H4 N-terminal tail domains with neighbouring nucleosomes. Mechanistically, the H4 tails of one nucleosome bind to the acidic patch region on the surface of adjacent nucleosomes, causing fibre compaction. The functionality of the chromatin fibre can be modified by proteins that interact with the nucleosome. The co-structures of five different proteins with the nucleosome (LANA, IL-33, RCC1, Sir3 and HMGN2) recently have been examined by experimental and computational studies. Interestingly, each of these proteins displays steric, ionic and hydrogen bond complementarity with the acidic patch, and therefore will compete with each other for binding to the nucleosome. We first review the molecular details of each interface, focusing on the key non-covalent interactions that stabilize the protein–acidic patch interactions. We then propose a model in which binding of proteins to the nucleosome disrupts interaction of the H4 tail domains with the acidic patch, preventing the intrinsic chromatin folding pathway and leading to assembly of alternative higher order chromatin structures with unique biological functions.

Sign in / Sign up

Export Citation Format

Share Document