Dynamic Combinatorial Carbohydrate Libraries: Probing the Binding Site of the Concanavalin A Lectin

Ramström, Olof; Lohmann, Sophie; Bunyapaiboonsri, Taridaporn; Lehn, Jean‐Maríe

doi:10.1002/chem.200305551

Cited by 130 publications

(100 citation statements)

References 42 publications

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“…In an ongoing exploration of the dynamic combinational chemistry of derivatives of biological substances [amino acids, peptoids (18), carbohydrates (19,20), nucleic acid components (D. T. Hickman, N. Sreenivasachary, and J.-M.L., unpublished data)], we synthesized the guanosine-5Ј-hydrazide derivative 1 by treatment of the corresponding methylester (17) with hydrazine.…”

Section: Resultsmentioning

confidence: 99%

“…This feature offered the possibility of exploring the effect of side chains attached through reversible condensation with various aldehydes (in particular, of biological type) on the properties of the hydrogel. More specifically for the present purposes, 1 displays a hydrazide functionality that may engage into the formation of reversible acylhydrazones by condensation with various aldehyde (or ketone) compounds, thus generating dynamic libraries of acylhydrazones as documented (18,20,(26)(27)(28). As a result, reversible decoration of 1, its G 4 derivative Q 1 (Fig.…”

Section: Entry Hydrazidesmentioning

confidence: 99%

“…The dynamic library was generated at 15 mM concentration for each compound, at pD 6 in sodium acetate buffer (0.5 M). It consists of four acylhydrazones, each presenting two configurational isomers, undergoing interchange continuously by acylhydrazone bond formation and cleavage in aqueous medium (18,20,(26)(27)(28).…”

Section: Gelation-driven Component Selectionmentioning

confidence: 99%

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Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

Sreenivasachary

Lehn

2005

Proc. Natl. Acad. Sci. U.S.A.

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334

195

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The guanosine hydrazide 1 yields a stable supramolecular hydrogel based on the formation of a guanine quartet (G-quartet) in presence of metal cations. The effect of various parameters (concentration, nature of metal ion, and temperature) on the properties of this gel has been studied. Proton NMR spectroscopy is shown to allow a molecular characterization of the gelation process. Hydrazide 1 and its assemblies can be reversibly decorated by acylhydrazone formation with various aldehydes, resulting in formation of highly viscous dynamic hydrogels. When a mixture of aldehydes is used, the dynamic system selects the aldehyde that leads to the most stable gel. Mixing hydrazides 1, 9 and aldehydes 6, 8 in 1:1:1:1 ratio generated a constitutional dynamic library containing the four acylhydrazone derivatives A, B, C, and D. The library constitution displayed preferential formation of the acylhydrazone B that yields the strongest gel. Thus, gelation redirects the acylhydrazone distribution in the dynamic library as guanosine hydrazide 1 scavenges preferentially aldehyde 8, under the pressure of gelation because of the collective interactions in the assemblies of G-quartets B, despite the strong preference of the competing hydrazide 9 for 8. Gel formation and component selection are thermoreversible. The process amounts to gelation-driven selforganization with component selection and amplification in constitutional dynamic hydrogels based on G-quartet formation and reversible covalent connections. The observed self-organization and component selection occur by means of a multilevel selfassembly involving three dynamic processes, two of supramolecular and one of reversible covalent nature. They extend constitutional dynamic chemistry to phase-organization and phasetransition events.dynamic combinatorial chemistry ͉ component selection ͉ supramolecular chemistry S upramolecular entities present the ability to reversibly modify their constitution through exchange and rearrangement of their molecular components because of the lability of the noncovalent interactions that hold them together (1, 2). Similar features may be imported into molecular species if reversible covalent bonds are introduced into their structure, allowing cleavage and formation of interatomic connections with fragment exchange under specific conditions. Thus, entities, capable of reversible modification of their constitution, define a constitutional dynamic chemistry on both the supramolecular and the molecular levels (3). Because the constitutional changes may be expected to respond to external factors, constitutional dynamic chemistry is the basis for the design and development of adaptive chemical systems. It generates constitutional dynamic libraries (CDLs) whose constituents are in dynamic equilibrium, such that they can exchange their components and express all of the entities that are potentially accessible through recombination by means of reversible covalent bonds and noncovalent interactions. The CDL may then adapt to (internal or) external phy...

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Section: Resultsmentioning

confidence: 99%

Section: Entry Hydrazidesmentioning

confidence: 99%

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Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

Sreenivasachary

Lehn

2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

334

195

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“…21 Acylhydrazone libraries were generated from a series of oligohydrazide core building blocks A-I and a set of aldehyde counterparts 5-10 based on six common, naturally occurring carbohydrates, potentially capable of interacting with the binding site of Con A (Fig. 2).…”

Section: Reversible Acylhydrazone Formationmentioning

confidence: 99%

“…Also, 15 sub-libraries were formed by mixing all building blocks except one specific hydrazide or aldehyde building block under the same conditions. 21 Following equilibration libraries were subsequently subjected to the lectin assay in which the inhibitory potency of library constituents was monitored.…”

Section: Reversible Acylhydrazone Formationmentioning

confidence: 99%

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

Maraković

Šinko

2017

ACSi

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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.

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Dynamic Combinatorial Diversity in Drug Discovery

Hochgürtel¹,

Lehn

2006

Methods and Principles in Medicinal Chemistry

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IntroductionCombinatorial chemistry evolved as a key technology for the rapid generation of large populations of structurally distinct molecules that can be screened efficiently en masse for desirable properties. This approach, in combination with highthroughput screening, evolved into a powerful technique capable of significantly accelerating the drug discovery process [1]. Initially developed to produce peptide libraries for screening against antibodies or receptors, combinatorial synthesis and the screening of combinatorial arrays became an integral part in lead generation and optimization in drug discovery [2][3][4][5]. Furthermore, combinatorial methodologies also demonstrated their potential in other areas, such as the development and discovery of catalysts, and material science [6,7].Modern combinatorial libraries are characterized by the generation of numerous different, but structurally related compounds that exist discretely as static entities, under similar conditions, in a systematic manner. Currently, there are several distinct methodologies for the generation of combinatorial libraries [8,9]. These combinatorial arrays can be produced in a parallel fashion, either as a library of individual compounds or as pooled mixtures. In applying a parallel format, the compounds are handled individually in separated compartments. This removes difficulties associated with compound mixtures; and it allows for every individual compound a straightforward evaluation of chemical integrity and structure-activity relationship after biological testing. The library size handled with this methodology is more limited than in a pooling strategy. Pooled mixture formation is straightforward and less time-consuming than the synthesis of individual compounds. More difficult is the analysis and screening of mixtures of components. By the split and mix technology, very large libraries can be formed progressively over multiple synthetic steps. Also, several technological advances in solid phase automated synthesis, analysis, robotics and miniaturization allow the rapid parallel synthesis and characterization of very large arrays of individual compounds. The substances generated are then subsequently evaluated for biological activity by high-throughput screening, applying fully automated systems towards a chosen target protein. 341Fragment-based Approaches in Drug Discovery. Edited

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Dynamic Combinatorial Carbohydrate Libraries: Probing the Binding Site of the Concanavalin A Lectin

Cited by 130 publications

References 42 publications

Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

Gelation-driven component selection in the generation of constitutional dynamic hydrogels based on guanine-quartet formation

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

Dynamic Combinatorial Diversity in Drug Discovery

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