Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED.

ABSTRACT: Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute stereochemistry assigned by dynamical refinement of continuous rotation electron diffraction data, confirming dynamical refinement as a promising tool for the absolute stereochemistry determination of pharmaceutically relevant compounds.

SUBMITTER: de Moraes LS

PROVIDER: S-EPMC11348424 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Structural Elucidation and Absolute Stereochemistry for Pharma Compounds Using MicroED.

de Moraes Lygia Silva LS Burch Jessica E JE Delgadillo David A DA Rodriguez Isabel Hernandez IH Mai Huanghao H Smith Austin G AG Caille Seb S Walker Shawn D SD Wurz Ryan P RP Cee Victor J VJ Rodriguez Jose A JA Gostovic Dan D Quasdorf Kyle K Nelson Hosea M HM

Organic letters 20240808 33

Microcrystal electron diffraction (microED) is an emerging technique for rapid crystallographic analysis of small molecule micro- and nanocrystals. In this report, we evaluate the applicability of microED to pharmaceutical compounds through the analysis of 30 samples obtained from the process and medicinal chemistry groups at Amgen Inc. Using only 40 h of microscope time, 15 of 30 crystal structures were elucidated. From these crystal structures, all chiral compounds had the correct absolute ste ...[more]

PMID: 39116344

Similar Datasets

Elucidation of the relative and absolute stereochemistry of the kalimantacin/batumin antibiotics.

Project description:Kalimantacin A and batumin exhibit potent and selective antibiotic activity against Staphylococcus species including MRSA. Both compounds are formed via a hybrid polyketide synthase/non-ribosomal peptide synthetase (PKS-NRPS) biosynthetic pathway and from comparison of the gene clusters it is apparent that batumin from Pseudomonas batumici and kalimantacin from P. fluorescens are the same compound. The linear structure of this unsaturated acid was assigned by spectroscopic methods, but the relative and absolute stereochemistry of the five stereocentres remained unknown. Herein we describe isolation of kalimantacin A and two further metabolites 17,19-diol 2 and 27-descarbomyl hydroxyketone 3 from cultures of P. fluorescens. Their absolute and relative stereochemistries are rigorously determined using a multidisciplinary approach combining natural product degradation and fragment synthesis with bioinformatics and NMR spectroscopy. Diol 2 has the 5R, 15S, 17S, 19R, 26R, 27R configuration and is the immediate biosynthetic precursor of the bioactive kalimantacin A formed by oxidation of the 17-alcohol to the ketone.

| S-EPMC5628338 | biostudies-literature

Progressive-convergent elucidation of stereochemistry in complex polyols. The absolute configuration of (-)-sagittamide A.

Project description:The absolute stereostructure of sagittamide A (1), a O-hexacetyl long-chain hexahydroxy-alpha,omega-dicarboxylic acid, was assigned using a progressive-convergent approach that integrates three powerful regimens for stereochemical analysis of acyclic natural products: J-based analysis, 13C NMR universal database comparisons, and exciton coupling circular dichroism.

| S-EPMC3340292 | biostudies-literature

Isolation, structural elucidation, and absolute stereochemistry of enigmazole A, a cytotoxic phosphomacrolide from the Papua New Guinea marine sponge Cinachyrella enigmatica.

Project description:Enigmazole A (1), a novel phosphate-containing macrolide, was isolated from a Papua New Guinea collection of the marine sponge Cinachyrella enigmatica. The structure of 1, including the absolute stereochemistry at all eight chiral centers, was determined by a combination of spectroscopic analyses and a series of microscale chemical derivatization studies. Compound 1 is comprised of an 18-membered phosphomacrolide that contains an embedded exomethylene-substituted tetrahydropyran ring and an acyclic portion that spans an embedded oxazole moiety. Two additional analogues, 15-O-methylenigmazole A and 13-hydroxy-15-O-methylenigmazole A, were also isolated and assigned. The enigmazoles are the first phosphomacrolides from a marine source and 1 exhibited significant cytotoxicity in the NCI 60-cell line antitumor screen, with a mean GI(50) of 1.7 microM.

| S-EPMC3850515 | biostudies-literature

Structural Elucidation of Cryptic Algaecides in Marine Algal-Bacterial Symbioses by NMR Spectroscopy and MicroED.

Project description:Microbial secondary metabolite discovery is often conducted in pure monocultures. In a natural setting, however, where metabolites are constantly exchanged, biosynthetic precursors are likely provided by symbionts or hosts. In the current work, we report eight novel and architecturally unusual secondary metabolites synthesized by the bacterial symbiont Phaeobacter inhibens from precursors that, in a native context, would be provided by their algal hosts. Three of these were produced at low titres and their structures were determined de novo using the emerging microcrystal electron diffraction method. Some of the new metabolites exhibited potent algaecidal activity suggesting that the bacterial symbiont can convert algal precursors, tryptophan and sinapic acid, into complex cytotoxins. Our results have important implications for the parasitic phase of algal-bacterial symbiotic interactions.

| S-EPMC9056321 | biostudies-literature

Total synthesis, assignment of the relative and absolute stereochemistry, and structural reassignment of phostriecin (aka Sultriecin).

Project description:A total synthesis of phostriecin (2), previously known as sultriecin (1), its structural reassignment as a phosphate versus sulfate monoester, and the assignment of its relative and absolute stereochemistry are disclosed herein. Key elements of the work, which provided first the originally assigned sulfate monoester 1 and then the reassigned and renamed phosphate monoester 2, relied on diagnostic (1)H NMR spectroscopic properties of the natural product for the assignment of relative and absolute stereochemistry as well as the subsequent structural reassignment, and a convergent asymmetric total synthesis to provide the unequivocal authentic materials. Key steps of the synthetic approach include a Brown allylation for diastereoselective introduction of the C9 stereochemistry, an asymmetric CBS reduction to establish the lactone C5-stereochemistry, diastereoselective oxidative ring expansion of an alpha-hydroxyfuran to access the pyran lactone precursor, and single-step installation of the sensitive Z,Z,E-triene unit through a chelation-controlled cuprate addition with installation of the C11 stereochemistry. The approach allows ready access to analogues that can now be used to probe important structural features required for protein phosphatase 2A inhibition, the mechanism of action defined herein.

| S-EPMC2824046 | biostudies-literature

Structural Reassignment and Absolute Stereochemistry of Madurastatin C1 (MBJ-0034) and the Related Aziridine Siderophores: Madurastatins A1, B1, and MBJ-0035.

Project description:The madurastatins are pentapeptide siderophores originally described as containing an unusual salicylate-capped N-terminal aziridine ring. Isolation of madurastatin C1 (1) (also designated MBJ-0034), from Actinomadura sp. DEM31376 (itself isolated from a deep sea sediment), prompted structural reevaluation of the madurastatin siderophores, in line with the recent work of Thorson and Shaaban. NMR spectroscopy in combination with partial synthesis allowed confirmation of the structure of madurastatin C1 (1) as containing an N-terminal 2-(2-hydroxyphenyl)oxazoline in place of the originally postulated aziridine, while absolute stereochemistry was determined via Harada's advanced Marfey's method. Therefore, this work further supports Thorson and Shaaban's proposed structural revision of the madurastatin class of siderophores (madurastatins A1 (2), B1 (3), C1 (1), and MBJ-0036 (4)) as N-terminal 2-(2-hydroxyphenyl)oxazolines.

| S-EPMC6544507 | biostudies-literature

Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole.

Project description:Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a-1h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans- stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the anti-angiogenic and anti-fungal activities of itraconazole.

| S-EPMC3165044 | biostudies-literature

MicroED: Unveiling the Structural Chemistry of Plant Biomineralisation.

Project description:Plants are able to produce various types of crystals through metabolic processes, serving functions ranging from herbivore deterrence to photosynthetic efficiency. However, the structural analysis of these crystals has remained challenging due to their small and often imperfect nature, which renders traditional X-ray diffraction techniques unsuitable. This study explores the use of Microcrystal Electron Diffraction (microED) as a novel method for the structural analysis of plant-derived microcrystals, focusing on Armeria maritima (Milld.), a halophytic plant known for its biomineralisation capabilities. In this study, A. maritima plants were cultivated under controlled laboratory conditions with exposure to cadmium and thallium to induce the formation of crystalline deposits on their leaf surfaces. These deposits were analysed using microED, revealing the presence of sodium chloride (halite), sodium sulphate (thénardite), and calcium sulphate dihydrate (gypsum). Our findings highlight the potential of microED as a versatile tool in plant science, capable of providing detailed structural insights into biomineralisation processes, even from minimal and imperfect crystalline samples. The application of microED in this context not only advances the present understanding of A. maritima's adaptation to saline environments but also opens new avenues for exploring the structural chemistry of biomineralisation in other plant species. Our study advocates for the broader adoption of microED in botanical research, especially when dealing with challenging crystallographic problems.

| S-EPMC11510860 | biostudies-literature

Absolute configuration determination of pharmaceutical crystalline powders by MicroED <i>via</i> chiral salt formation.

Project description:Microcrystal electron diffraction (MicroED) has established its complementary role alongside X-ray diffraction in crystal structure elucidation. Unfortunately, kinematical refinement of MicroED data lacks the differentiation power to assign the absolute structure solely based on the measured intensities. Here we report a method for absolute configuration determination via MicroED by employing salt formation with chiral counterions.

| S-EPMC9004345 | biostudies-literature

Asymmetric total synthesis and absolute stereochemistry of the neuroactive marine macrolide palmyrolide A.

Project description:The first asymmetric total synthesis and determination of the absolute configuration for the neuroactive marine macrolide palmyrolide A is described. The highlight of the synthesis is macrocyclization via trans-enamide formation catalyzed by copper(I) iodide and cesium carbonate. Comparison with the authentic spectral data confirms the synthesis of (+)-ent-palmyrolide A.

| S-EPMC3352666 | 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