Synthetic Multivalent Ligands Are Effective Inhibitors of Concanavalin A

A number of natural multidentate ligands, including oligosaccharides and glycoproteins [73,77,80,81], serve as highly effective ligands for tetrameric ConA. While these ligands provide useful information about ConA binding, the structures are so difficult to vary systematically that it is difficult to analyze binding data from such substrates. Synthetic ligands have been used, therefore, to address fundamental issues with regard to multivalent recognition by ConA. Major ligand classes that have been employed include low molecular weight derivatives, dendrimeric ligands, and linear polymers.

Some of the most potent inhibitors of ConA are multidentate ligands synthesized by the ring-opening metathesis polymerization (ROMP). ROMP has emerged as an attractive approach to the synthesis of functional polymers [82]. The advent of defined, functionalized group tolerant, metal alkylidine initiators has offered new opportunities for the creation of tailored materials with significant biological properties. A generalized mechanism for the polymerization involves an initiation through coordination of the metal alkylidine with a strained cyclic alkene monomer (Fig. 11). A [2 + 2] cycloaddition between the initiator (2) and a monomer (1) unit generates a metallocyclobutane intermediate (3) that undergoes a ring opening to relieve strain, thereby generating a new metal alkylidene. This intermediate metal-locarbene (4) can react with another monomer, and the sequence of events can continue until the monomer is consumed. The reaction can be terminated by the addition of an electron-rich enol ether (5), which results in the production of an unreactive metal carbene (7) and a terminated polymer chain (6). Because ROMP can be a living process and because the rate of initiation exceeds that of propagation, oligomers of controlled length and narrow molecular mass distribution can be generated. In addition, both the catalyst and the electron-rich enol ether afford an opportunity to attach unique end labels to either polymer terminus. Thus, ROMP offers advantages for the production of biologically active polymers [83].

To explore interactions of multivalent ligands with ConA, polymers with pendant mannose or glucose residues have been generated by ROMP. The saccharide epitopes were attached to norbornene monomers through C-glycoside linker units

Figure 11 General scheme for ring-opening metathesis polymerization (ROMP). Monomer 1 and catalyst 2 continue to react until the monomer has been consumed yielding polymer 4, which can be end-capped with functionalized allyl ether 5.

and polymers of high molecular mass were produced. These materials were highly effective inhibitors of ConA-facilitated red blood cell agglutination: they were up to 105-fold more potent than a-methyl glucopyranoside [31]. Other nonnatural saccha-ride-substituted polymers have also been found to be effective inhibitors of ConA [84,85]. In addition, dendrimers [86-88] and low molecular weight ligands [44,8993] show levels of activity that exceed those of mannose, although they do not approach those of the ROMP-generated polymers. Together, these results highlight the range of inhibitory activities that can be manifested by synthetic multidentate ligands.

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