In Situ Generation and Screening of a Dynamic Combinatorial Carbohydrate Library against Concanavalin A

Abstract

Dynamic combinatorial chemistry (DCC) is a recently introduced approach that is based on the generation of combinatorial libraries by reversible interconversion of the library constituents. In this study, the implementation of such libraries on carbohydrate-lectin interactions was examined. The dynamic carbohydrate libraries were generated from a small set (four or six compounds) of initial carbohydrate dimers through mild disulfide interchange, and selection was performed under two conditions defining either adaptive or pre-equilibrated libraries. Upon initiation, libraries were formed that contained comparable amounts of 10 or 21 individual dimeric species, dynamically interchanging during the scrambling process. They were probed with respect to binding to the plant lectin concanavalin A, either present during library generation or added after equilibration. The libraries could be generated easily both in the presence and absence of the receptor, and a bis-mannose structure was preferentially bound and selected from the mixture. Scrambling of the library in the presence of the receptor resulted in slightly higher yields than when the receptor was added after scrambling, indicating that the receptor to some extent acts as a thermodynamic trap during library generation. The present results illustrate the extention of the DCC approach to carbohydrate recognition groups, the generation of isoenergetic dynamic libraries, and the implementation of either adaptive or pre-equilibrated procedures.

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

“…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acids, peptoids (18), carbohydrates (19,20), nucleic acid components (D. T. Hickman, N. Sreenivasachary, and J.-M.L., unpublished data)], we synthesized the guanosine-5Ј-hydrazide derivative 1 by treatment of the corresponding methylester (17) with hydrazine.…”

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

“…25,33 DCL of disulfide carbohydrate dimers (Table 1) was generated by incubating disulfide dimers with an initiating reagent dithiothreitol (DTT) capable of reducing some disulfides to thiols. DTT is oxidized to a stable 6-membered cyclic disulfide that should not take part in the interconversion of the library disulfides.…”

“…When a receptor Con A was present during the interconversion, a significant amount of the bis-mannoside (Man/Man) and the mannose-containing heterodimers (Man/Gal, Man/Ara, Man/Xyl) was found to be bound to the receptor. 25 Moreover, receptor-induced shifts in equilibrium resulted in the amplification of mannose-containing dimers, which is in accordance with concepts of the DCC approach.…”

“…They are very stable to both metabolic and chemical degradation, being inert to hydrolytic, oxidizing, and reducing conditions, even at higher temperatures. 25 Due to resemblance with amide moiety in size, dipolar moment, and H-bond acceptor capacity, the 1,2,3-triazole ring can serve as its non-classic bioisostere. 44,45,87,88 Since 1,2,3-triazoles are basic aromatic heterocyclic compounds, they are bioisosteres of aromatic rings and double bonds.…”

Supramolecular templating in thermodynamically controlled synthesis

“…Disulfide exchange is mediated by a catalytic amount of thiolate anion attacking the existing disulfide bonds. Exchange proceeds readily under neutral to mildly basic conditions, whereas acidifying the medium causes protonation of the thiolate anion and turns off exchange (2,3).…”