Fmoc-N-(4-Boc-aminobutyl)glycine

Described herein is the design of a cell-adherent and degradable hydrogel. Our goal was to create a self-assembling, backbone ester-containing analogue of the cell adhesion motif, arginine-glycine-aspartic acid (RGD). Two depsipeptides containing Fmoc (N-(fluorenyl)-9-methoxycarbonyl), Fmoc-FR-Glc-D, and Fmoc-F-Glc-RGD (where "Glc" is glycolic acid) were designed based on the results of integrin-binding affinity and cell interaction analyses. Two candidate molecules were synthesized, and their gelation characteristics, degradation profiles, and ability to promote cell attachment were analyzed. We found that ester substitution within the RGD sequence significantly decreases the integrin-binding affinity and subsequent cell attachment, but when the ester moiety flanks the bioactive sequence, the molecule can maintain its integrin-binding function while permitting nonenzymatic hydrolytic degradation. A self-assembled Fmoc-F-Glc-RGD hydrogel showed steady, linear degradation over 60 days, and when mixed with Fmoc-diphenylalanine (Fmoc-FF) for improved mechanical stiffness, the depsipeptide gel exhibited improved cell attachment and viability. Though the currently designed depsipeptide has several inherent limitations, our results indicate the potential of depsipeptides as the basis for biologically functional and degradable self-assembling hydrogel materials.

We have studied the dynamic interaction of surfactants with carbon surfaces by using a series of Fmoc- (N-(fluorenyl-9-methoxycarbonyl)) terminated amino acid derivatives (Fmoc-X, where X is glycine, tyrosine, phenylalanine, tryptophan, or histidine) as a model system. In these systems, highly conjugated fluorenyl groups and aromatic amino acid side chains interact with the carbon surface, while carboxylate groups provide an overall negative charge. Ideal carbon surfaces were selected which possessed either predominantly macroscale (graphite) or nanoscale features (multiwalled carbon nanotube (MWNT) mats). The adsorption equilibrium for the Fmoc-X solutions with the graphitic surfaces was well-described by the Freundlich model. When a library containing various Fmoc-X compounds were exposed to a target graphite surface, Fmoc-tryptophan was found to bind preferentially at the expense of the other components present, leading to a substantial difference in the observed binding behavior compared to individual adsorption experiments. This approach therefore provides a straightforward means to identify good surfactants within a library of many candidates. Finally, the fully reversible nature of Fmoc-X binding was demonstrated by switching the surface chemistry of carbon substrate through sequential exposure to surfactants with increasing binding energies.

When administered in vivo, amylin (1-8) stimulates osteoblast proliferation increasing bone volume and bone strength. The native cyclic octapeptide amylin (1-8) is unstable, however, it provides an attractive framework for the creation of more stable, orally active synthetic analogues using various peptidomimetic techniques. On-resin ring closing metathesis (RCM) on the olefinic side chains of allylglycine residues and lysine moieties functionalized with an allyloxycarbonyl (Alloc) group, was used to prepare novel carba-bridged surrogates of the disulfide bridge between Cys/2 and Cys/7 in amylin-(1-8). Commercially available N(α)-Fmoc N(ε)-Alloc protected lysine was used as a convenient substrate for Grubbs' ring closing metathesis. Analogues of amylin-(1-8) prepared by cyclization of allylglycine residues that also contained proline residues at either position 4 or 6, or both, were also prepared to investigate the effect of proline as a 'kink-inducing' residue on the efficiency of the RCM reaction. Of the nine novel alkene-bridged analogues prepared, five showed promising biological activity in a proliferation study in primary foetal rat osteoblasts at physiological concentrations. Two of these analogues were chosen for further in vivo evaluation.