J Labelled Comp Radiopharm
November 2024
The rise of nucleic acid-based therapeutics continues apace. At the same time, the need for radiolabelled oligonucleotides for determination of spatial distribution is increasing. Complex molecular structures with mostly multiple charges and low solubility in organic solvents increase the challenge of integrating radionuclides.
View Article and Find Full Text PDFAn electrochemical desulfurization of 2-mercapto-imidazoles to the corresponding imidazole is established. This novel anodic transformation is bromide-mediated and easy to conduct in the simplest electrochemical setup, consisting of an undivided cell, carbon electrodes, and constant current electrolysis. The method proved successful in 14 diverse examples of imidazoles and triazoles with up to a 97% yield.
View Article and Find Full Text PDFChemical modification of DNA is a common strategy to improve the properties of oligonucleotides, particularly for therapeutics and nanotechnology. Existing synthetic methods essentially rely on phosphoramidite chemistry or the polymerization of nucleoside triphosphates but are limited in terms of size, scalability, and sustainability. Herein, we report a robust alternative method for the de novo synthesis of modified oligonucleotides using template-dependent DNA ligation of shortmer fragments.
View Article and Find Full Text PDFEnzymatic, XNA synthesis represents an alternative method for the production of long oligonucleotides containing chemical modifications at distinct locations. While such an approach is currently developed for DNA, controlled enzymatic synthesis of XNA remains at a relative state of infancy. In order to protect the masking groups of 3'--modified LNA and DNA nucleotides against removal caused by phosphatase and esterase activities of polymerases, we report the synthesis and biochemical characterization of nucleotides equipped with ether and robust ester moieties.
View Article and Find Full Text PDFWe conducted a biophysical study to investigate the self-assembling and albumin-binding propensities of a series of fatty acid-modified locked nucleic acid (LNA) antisense oligonucleotide (ASO) gapmers specific to the MALAT1 gene. To this end, a series of biophysical techniques were applied using label-free ASOs that were covalently modified with saturated fatty acids (FAs) of varying length, branching, and 5'/3' attachment. Using analytical ultracentrifugation (AUC), we demonstrate that ASOs conjugated with fatty acids longer than C16 exhibit an increasing tendency to form self-assembled vesicular structures.
View Article and Find Full Text PDFChemically modified oligonucleotides have advanced as important therapeutic tools as reflected by the recent advent of mRNA vaccines and the FDA-approval of various siRNA and antisense oligonucleotides. These sequences are typically accessed by solid-phase synthesis which despite numerous advantages is restricted to short sequences and displays a limited tolerance to functional groups. Controlled enzymatic synthesis is an emerging alternative synthetic methodology that circumvents the limitations of traditional solid-phase synthesis.
View Article and Find Full Text PDFPurpose: Exploration of the chemical, analytical and pharmacokinetic properties of the API, RO7304898, an allosteric EGFR inhibitor, intended to be developed as a mixture of two rapidly interconverting diastereoisomers with composition ratio of approximately 1:1.
Methods: Assessment of diastereoisomer stereochemistry, interconversion rates, binding to EGFR protein, metabolic stability and in vivo PK in Wistar-Han rats was conducted.
Results: The two diastereoisomers of the API undergo fast interconversion at physiologically relevant pH and direct EGFR binding studies revealed diastereoisomer B to be the active moiety.
Bioorg Med Chem Lett
September 2021
Therapeutic oligonucleotides require the addition of multiple chemical modifications to the nucleosidic scaffold in order to improve their drug delivery efficiency, cell penetration capacity, biological stability, and pharmacokinetic properties. This chemical modification pattern is often accompanied by a synthetic burden and by limitations in sequence length. Here, we have synthesized a nucleoside triphosphate analog bearing two simultaneous modifications at the level of the sugar (LNA) and the backbone (thiophosphate) and have tested its compatibility with enzymatic DNA synthesis which could abrogate some of these synthetic limitations.
View Article and Find Full Text PDFThe natural capacity of extracellular vesicles (EVs) to transport their payload to recipient cells has raised big interest to repurpose EVs as delivery vehicles for xenobiotics. In the present study, bovine milk-derived EVs (BMEVs) were investigated for their potential to shuttle locked nucleic acid-modified antisense oligonucleotides (LNA ASOs) into the systemic circulation after oral administration. To this end, a broad array of analytical methods including proteomics and lipidomics were used to thoroughly characterize BMEVs.
View Article and Find Full Text PDFA DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity.
View Article and Find Full Text PDFThe screening of encoded self-assembling chemical libraries allows the identification of fragment pairs that bind to adjacent pockets on target proteins of interest. For practical applications, it is necessary to link these ligand pairs into discrete organic molecules, devoid of any nucleic acid component. Here we describe the discovery of a synergistic binding pair for acid alpha-1 glycoprotein and a chemical strategy for the identification of optimal linkers, connecting the two fragments.
View Article and Find Full Text PDFSerotonin-gated ionotropic 5-HT receptors are the major pharmacological targets for antiemetic compounds. Furthermore, they have become a focus for the treatment of irritable bowel syndrome (IBS) and there is some evidence that pharmacological modulation of 5-HT receptors might alleviate symptoms of other neurological disorders. Highly selective, high-affinity antagonists, such as granisetron (Kytril) and palonosetron (Aloxi), belong to a family of drugs (the "setrons") that are well established for clinical use.
View Article and Find Full Text PDFDNA-encoded combinatorial libraries are increasingly being used as tools for the discovery of small organic binding molecules to proteins of biological or pharmaceutical interest. In the majority of cases, synthetic procedures for the formation of DNA-encoded combinatorial libraries incorporate at least one step of amide bond formation between amino-modified DNA and a carboxylic acid. We investigated reaction conditions and established a methodology by using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, 1-hydroxy-7-azabenzotriazole and N,N'-diisopropylethylamine (EDC/HOAt/DIPEA) in combination, which provided conversions greater than 75% for 423/543 (78%) of the carboxylic acids tested.
View Article and Find Full Text PDFWe report a novel prosthetic group based on a heterocyclic methylsulfone derivative for the rapid, stable, and chemoselective (18)F-labeling of thiol-containing (bio)molecules under mild aqueous reaction conditions. Compared to established maleimide approaches, the new methodology displays some clear advantages for imaging probe development.
View Article and Find Full Text PDFA family of practical, liquid trifluoromethylation and pentafluoroethylation reagents is described. We show how halogen bonding can be used to obtain easily handled liquid reagents from gaseous CF3I and CF3CF2I. The synthetic utility of the new reagents is exemplified by a novel direct arene trifluoromethylation reaction as well as adaptations of other perfluoroalkylation reactions.
View Article and Find Full Text PDFThe enantioselective Conia-ene cyclization of alkyne-tethered β-ketoesters is efficiently catalyzed by the combination of cinchona-derived amino-urea pre-catalysts and copper(I) salts. The reaction scope is broad and a series of substrates can be efficiently cyclized with high yields and enantioselectivities. Herein, we present a detailed mechanistic study based on experimental considerations and quantum mechanical calculations.
View Article and Find Full Text PDFAn operationally simple protocol for the selective deoxyfluorination of structurally complex alcohols is presented. Several fluorinated derivatives of natural products and pharmaceuticals have been prepared to showcase the potential of the method for late-stage diversification and its functional group compatibility. A series of simple guidelines for predicting the selectivity in substrates with multiple alcohols is given.
View Article and Find Full Text PDFA new family of bifunctional H-bond donor phase-transfer catalysts derived from cinchona alkaloids has been developed and evaluated in the enantio- and diastereoselective nitro-Mannich reaction of in situ generated N-Boc-protected imines of aliphatic, aromatic, and heteroaromatic aldehydes. Under optimal conditions, good reactivity and high diastereoselectivities (up to 24:1 dr) and enantioselectivities (up to 95% ee) were obtained using a 9-amino-9-deoxyepiquinidine-derived phase-transfer catalyst possessing a 3,5-bis(trifluoromethyl)phenylurea H-bond donor group at the 9-position.
View Article and Find Full Text PDFA synthetic strategy for the construction of the [7-5-5] all-carbon tricyclic core of numerous calyciphylline A-type Daphniphyllum alkaloids has been developed using a key intramolecular Pauson-Khand reaction. A subsequent base-mediated double-bond migration and a regio- and stereoselective radical late stage allylic oxygenation provide access to the substitution patterns of daphnilongeranin B and daphniyunnine D.
View Article and Find Full Text PDFA new cascade reaction involving an intramolecular Michael addition followed by an alkyne carbocyclization is presented. The reaction is promoted by a substoichiometric amount of KHMDS and represents one of the rare examples where the carbocyclization of an unactivated alkyne is mediated by an alkali metal base, under mild conditions. The reaction allows the generation of functionally dense, stereochemically defined, tricyclic structures possessing three adjacent stereocenters in good yields and with high stereoselectivity.
View Article and Find Full Text PDFAn efficient, robust, and scalable strategy to access the functionalized core of calyciphylline A-type alkaloids has been developed starting from commercially available 3-methylanisole. Key features of this approach are an intramolecular Michael addition/allylation sequence and a ring-closing metathesis step.
View Article and Find Full Text PDFA new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Brønsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained.
View Article and Find Full Text PDFFour peptides differing for the structure of the new morpholine-based heterocyclic compound acting as a turn inducer were synthesized in solution phase, and the conformational preferences were assessed by means of NMR analysis. All spectroscopic data revealed an adaptive behaviour of the turn peptides in generating turn conformations stabilized by intramolecular hydrogen-bonds, despite the conformational changes of the turn inducer. Thus, this study suggests the possibility of functionalizing morpholine-containing beta-turn peptides with no significant loss of the secondary framework.
View Article and Find Full Text PDFA mutually compatible and cooperative combination of copper(I) triflate and bifunctional 9-amino-9-deoxyepicinchona-derived urea compounds for the enantioselective Conia-ene cyclization of alkyne-tethered beta-ketoester substrates is reported. The reaction is efficient, broad in scope, and easy to perform and allows access to chiral methylenecyclopentane products with high enantiocontrol. The transformation illustrates the concept of combining inactive precatalysts with inactive transition-metal-ion complexes in situ to reversibly create a catalytically active combination of the two.
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