Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Artificial Macrocycles.

ABSTRACT: Artificial macrocycles recently became popular as a novel research field in drug discovery. As opposed to their natural twins, artificial macrocycles promise to have better control on synthesizability and control over their physicochemical properties resulting in druglike properties. Very few synthetic methods allow for the convergent, fast but diverse access to large macrocycles chemical space. One synthetic technology to access artificial macrocycles with potential biological activity, multicomponent reactions, is reviewed here, with a focus on our own work. We believe that synthetic chemists have to acquaint themselves more with structure and activity to leverage the design aspect of their daily work.

SUBMITTER: Abdelraheem EMM

PROVIDER: S-EPMC6660156 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Artificial Macrocycles.

Abdelraheem Eman M M EMM Shaabani Shabnam S Dömling Alexander A

Synlett : accounts and rapid communications in synthetic organic chemistry 20180507 9

Artificial macrocycles recently became popular as a novel research field in drug discovery. As opposed to their natural twins, artificial macrocycles promise to have better control on synthesizability and control over their physicochemical properties resulting in druglike properties. Very few synthetic methods allow for the convergent, fast but diverse access to large macrocycles chemical space. One synthetic technology to access artificial macrocycles with potential biological activity, multico ...[more]

PMID: 31354188

Similar Datasets

Artificial Macrocycles by Ugi Reaction and Passerini Ring Closure.

Project description:Artificial macrocycles can be convergently synthesized by a sequence of an Ugi multicomponent reaction (MCR) followed by an intramolecular Passerini MCR used to close the macrocycle. Significantly, in this work, the first intramolecular macrocyclization through a Passerini reaction is described. We describe 21 macrocycles of a size of 15-20. The resulting macrocyclic depsipeptides are model compounds for natural products and could find applications in drug discovery.

| S-EPMC6280654 | biostudies-other

Artificial Macrocycles as Potent p53-MDM2 Inhibitors.

Project description:Based on a combination of an Ugi four component reaction and a ring closing metathesis, a library of novel artificial macrocyclic inhibitors of the p53-MDM2 interaction was designed and synthesized. These macrocycles, alternatively to stapled peptides, target for the first time the large hydrophobic surface area formed by Tyr67, Gln72, His73, Val93, and Lys94 yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using fluorescence polarization (FP) assay and 1H-15N two-dimensional HSQC nuclear magnetic resonance experiments.

| S-EPMC5641952 | biostudies-literature

Artificial Macrocycles as IL-17A/IL-17RA Antagonists.

Project description:Interleukin 17(A) is a pro-inflammatory cytokine involved in several auto-immune and inflammatory diseases. Current antagonists against IL17(A) or its receptor (IL17R) that show efficacy in clinical trials are monoclonal-antibodies (mAbs). However, recently designed artificial macrocyles are potent IL17-IL17R antagonists. Based on Co-crystal structures, a better understanding the biological activity and SAR of the macrocycles has been elucidated, demonstrating that macrocycles can compete with mAbs for difficult targets such as PPIs.

| S-EPMC5937545 | biostudies-literature

How proteins bind macrocycles.

Project description:The potential utility of synthetic macrocycles (MCs) as drugs, particularly against low-druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.

| S-EPMC4417626 | biostudies-literature

Strain visualization for strained macrocycles.

Project description:Strain has a unique and sometimes unpredictable impact on the properties and reactivity of molecules. To thoroughly describe strain in molecules, a computational tool that relates strain energy to reactivity by localizing and quantifying strain was developed. Strain energy is calculated local to every coordinate in the molecule and areas of higher strain are shown experimentally to be more reactive. Not only does this tool directly compare strain energy in parts of the same molecule, but it also computes total strain to give a full picture of molecular strain energy. It is freely available to the public on GitHub under the name StrainViz and much of the workflow is automated to simplify use for non-experts. Unique insight into the reactivity of curved aromatic molecules and strained alkyne bioorthogonal reagents is described within.

| S-EPMC8152662 | biostudies-literature

Molecular motor-functionalized porphyrin macrocycles.

Project description:Molecular motors and switches change conformation under the influence of an external stimulus, e.g. light. They can be incorporated into functional systems, allowing the construction of adaptive materials and switchable catalysts. Here, we present two molecular motor-functionalized porphyrin macrocycles for future photo-switchable catalysis. They display helical, planar and point chirality, and are diastereomers, which differ in the relative orientation of the motor and macrocyclic components. Fluorescence, UV-vis, and 1H NMR experiments reveal that the motor-functionalized macrocycles can bind and thread different variants of viologen guests, including a one-side blocked polymeric one of 30 repeat units. The latter feature indicates that the motor systems can find the open end of a polymer chain, thread on it, and move along the chain to eventually bind at the viologen trap, opening possibilities for catalytic writing on single polymer chains via chemical routes.

| S-EPMC7576194 | biostudies-literature

Synthesis of Tetrathia-Oligothiophene Macrocycles.

Project description:The synthesis of six tetrathia-oligothiophene macrocycles is described with modest ring-closing yields between 21 and 55%. Single-crystal X-ray studies of four of the macrocycles indicated that encapsulated solvent or guest molecules were possible. A variety of guest molecules were explored for inclusion complexes via NMR, absorption, emission, and X-ray techniques. The solution-phase inclusion complexes were uninformative; yet the solid-state experiments revealed that solvent exchangeable channels exist through the macrocyclic pores.

| S-EPMC6648883 | biostudies-literature

Olefinic-lactone cyclizations to macrocycles.

Project description:Olefinic-lactone cyclization reactions that result in the generation of macrocycles are described.

| S-EPMC2765781 | biostudies-literature

Squaraine rotaxanes with boat conformation macrocycles.

Project description:Mechanical encapsulation of fluorescent, deep-red bis(anilino)squaraine dyes inside Leigh-type tetralactam macrocycles produces interlocked squaraine rotaxanes. The surrounding macrocycles are flexible and undergo rapid exchange of chair and boat conformations in solution. A series of X-ray crystal structures show how the rotaxane co-conformational exchange process involves simultaneous lateral oscillation of the macrocycle about the center of the encapsulated squaraine thread. Rotaxane macrocycles with 1,4-phenylene sidewalls and 2,6-pyridine dicarboxamide bridging units are more likely to adopt boat conformations in the solid state than analogous squaraine rotaxane systems with isophthalamide-containing macrocycles. A truncated squaraine dye, with a secondary amine attached directly to the central C(4)O(2) core, is less electrophilic than the extended bis(anilino)squaraine analogue, but it is still susceptible to chemical and photochemical bleaching. Its stability is greatly enhanced when it is encapsulated as an interlocked squaraine rotaxane. An X-ray crystal structure of this truncated squaraine rotaxane shows the macrocycle in a boat conformation, and NMR studies indicate that the boat is maintained in solution. Encapsulation as a rotaxane increases the dye's brightness by a factor of 6. The encapsulation process appears to constrain the dye and reduce deformation of the chromophore from planarity. This study shows how mechanical encapsulation as a rotaxane can be used as a rational design parameter to fine-tune the chemical and photochemical properties of squaraine dyes.

| S-EPMC2847772 | biostudies-literature

Benchmark of Generic Shapes for Macrocycles.

Project description:Macrocycles target proteins that are otherwise considered undruggable because of a lack of hydrophobic cavities and the presence of extended featureless surfaces. Increasing efforts by computational chemists have developed effective software to overcome the restrictions of torsional and conformational freedom that arise as a consequence of macrocyclization. Moloc is an efficient algorithm, with an emphasis on high interactivity, and has been constantly updated since 1986 by drug designers and crystallographers of the Roche biostructural community. In this work, we have benchmarked the shape-guided algorithm using a dataset of 208 macrocycles, carefully selected on the basis of structural complexity. We have quantified the accuracy, diversity, speed, exhaustiveness, and sampling efficiency in an automated fashion and we compared them with four commercial (Prime, MacroModel, molecular operating environment, and molecular dynamics) and four open-access (experimental-torsion distance geometry with additional "basic knowledge" alone and with Merck molecular force field minimization or universal force field minimization, Cambridge Crystallographic Data Centre conformer generator, and conformator) packages. With three-quarters of the database processed below the threshold of high ring accuracy, Moloc was identified as having the highest sampling efficiency and exhaustiveness without producing thousands of conformations, random ring splitting into two half-loops, and possibility to interactively produce globular or flat conformations with diversity similar to Prime, MacroModel, and molecular dynamics. The algorithm and the Python scripts for full automatization of these parameters are freely available for academic use.

| S-EPMC7768607 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data