Ketones as Building Blocks for Dynamic Combinatorial Libraries:  Highly Active Neuraminidase Inhibitors Generated via Selection Pressure of the Biological Target

Hochgürtel, Matthias; Biesinger, Ralf; Kroth, Heiko; Piecha, Dorothea; Hofmann, Michael; Krause, Sonja; Schaaf, Otmar; Nicolau, Claude; Елисеев, А. В.

doi:10.1021/jm025589m

Cited by 100 publications

(76 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Until now, mainly imines, [7,10,16] acyl hydrazones, [12,17,18] and disulfides [9,13,19,20] have been used for DCLs since these formats have proven to be the most efficient in the systems studied. This is especially the case when biological systems are targeted, since these require reactions that are stable under mild conditions in the aqueous phase.…”

mentioning

confidence: 99%

Catalytic Self‐Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library

2004

View full text Add to dashboard Cite

Simply the best: Dynamic combinatorial chemistry coupled to enzyme catalysis was used to identify enzyme substrates in a library constructed from a series of thioesters and thiols by transesterification. The library was directly coupled to the catalytic action of acetylcholinesterase, which selectively hydrolyzed the best substrate candidates (see schematic representation). The process allowed rapid identification of discrete substrates.

show abstract

mentioning

confidence: 99%

Catalytic Self‐Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library

2004

View full text Add to dashboard Cite

show abstract

“…Additionally, the use of organic solvents in DCC is limited by the strong tendency of solvents to denature the target (enzyme, receptor, etc.). Examples of DCC applications for the discovery of high affinity ligands for biological receptors have been reported, including formation of DCLs of imines, 19,20 …”

Section: Dynamic Combinatorial Chemistry Methodsmentioning

confidence: 99%

“…1). 20 After reduction of imines, LC/MS analysis identified several hits (1-4). The negative control experiment included library synthesis in the presence of the bovine serum albumin (BSA).…”

Section: Reversible Imine Formationmentioning

confidence: 99%

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Maraković

Šinko

2017

ACSi

View full text Add to dashboard Cite

Modern drug discovery is mainly based on the de novo synthesis of a large number of compounds with a diversity of chemical functionalities. Though the introduction of combinatorial chemistry enabled the preparation of large libraries of compounds from so-called building blocks, the problem of successfully identifying leads remains. The introduction of a dynamic combinatorial chemistry method served as a step forward due to the involvement of biological macromolecular targets (receptors) in the synthesis of high affinity products. The major breakthrough was a synthetic method in which building blocks are irreversibly combined due to the presence of a receptor. Here we present various receptor-based combinatorial chemistry approaches. Huisgen's cycloaddition (1,3-dipolar cycloaddition of azides and alkynes) forms stabile 1,2,3-triazoles with very high receptor affinity that can reach femtomolar levels, as the case with acetylcholinesterase inhibitors shows. Huisgen's cycloaddition can be applied to various receptors including acetylcholinesterase, acetylcholine binding protein, carbonic anhydrase-II, serine/threonine-protein kinase and minor groove of DNA.

show abstract

“…In an extension of their original work, Eliseev et al carried out similar DCC experiments with ketones rather than aldehydes. [48] COOH O NH 2 Scott et al probed the pantoate binding pocket of pantothenate synthetase using 5'-deoxy-5'-thioadenosine 3 as a noncovalent anchor fragment. [49] The DCL was composed of fragment 3 in addition to a number of other thiols, and the subsequent thiol-disulfide exchange monitored by HPLC.…”

Section: Protein-directed Dynamic Combinatorial Chemistrymentioning

confidence: 99%

“…Figure 48 DNA sequence for the catalytic domain of TS with sites for selected restriction enzymes highlighted. The insert was found to be cut at two consecutive NdeI sites (indicated by an asterix) rather than the desired NdeI and EcoRI sites.…”

Section: Figure 45mentioning

confidence: 99%

Kinetic Template‐Guided Tethering of Fragments

2012

View full text Add to dashboard Cite

This thesis is composed of two separate projects: Kinetic Template-Guided Tethering of Fragments and Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1 Degradation after DNA Damage. Kinetic Template-Guided Tethering of FragmentsThe development of a novel methodology for the site-directed discovery of small molecule, protein-binding ligands is described. The protein of interest, with a cysteine thiol (either native or engineered) adjacent to the desired binding pocket, is incubated with mixtures of low molecular weight compounds (fragments) modified with either an acrylamide or a vinyl sulfonamide capture group. Any ligand within the mixture that binds within the pocket brings the capture group into close proximity with the cysteine thiol, promoting a conjugate addition reaction at an increased rate over the background reaction. The capture reaction is designed to be slow, such that during the time course of an experiment, no adduct formation is observed unless the reaction is templated by the protein. By this method, binding ligands are rapidly identified by mass spectrometry analysis of the crude reaction mixtures. The methodology has been termed 'kinetic template-guided tethering'. Design and Synthesis of a Chemical Probe to Dissect the Cellular Signalling Cascade leading to Cyclin D1Degradation after DNA Damage An inhibitor described within the literature was found to attenuate the reduction of cyclin D1 after DNA damage to cells. In order to implement a two-step chemical proteomics strategy to find the molecular target of this inhibitor, a synthesis of the compound with an alkyne appendage was required. The alkyne acts as a functional handle for attachment of a reporter molecule in cells via the Huisgen cycloaddition ('Click') reaction. The design and synthesis of this inhibitor with the alkyne appendage is described.

show abstract

Ketones as Building Blocks for Dynamic Combinatorial Libraries: Highly Active Neuraminidase Inhibitors Generated via Selection Pressure of the Biological Target

Cited by 100 publications

References 30 publications

Catalytic Self‐Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library

Catalytic Self‐Screening of Cholinesterase Substrates from a Dynamic Combinatorial Thioester Library

The Lock is the Key: Development of Novel Drugs through Receptor Based Combinatorial Chemistry

Kinetic Template‐Guided Tethering of Fragments

Contact Info

Product

Resources

About