Self-Supporting Hydrogels Based on Fmoc-Derivatized Cationic Hexapeptides for Potential Biomedical Applications

Peptide-based hydrogels (PHGs) are biocompatible materials suitable for biological, biomedical, and biotechnological applications, such as drug delivery and diagnostic tools for imaging. Recently, a novel class of synthetic hydrogel-forming amphiphilic cationic peptides (referred to as series K), containing an aliphatic region and a Lys residue, was proposed as a scaffold for bioprinting applications. Here, we report the synthesis of six analogues of the series K, in which the acetyl group at the N-terminus is replaced by aromatic portions, such as the Fmoc protecting group or the Fmoc-FF hydrogelator. The tendency of all peptides to self-assemble and to gel in aqueous solution was investigated using a set of biophysical techniques. The structural characterization pointed out that only the Fmoc-derivatives of series K keep their capability to gel. Among them, Fmoc-K3 hydrogel, which is the more rigid one (G’ = 2526 Pa), acts as potential material for tissue engineering, fully supporting cell adhesion, survival, and duplication. These results describe a gelification process, allowed only by the correct balancing among aggregation forces within the peptide sequences (e.g., van der Waals, hydrogen bonding, and π–π stacking).

Scope and Limitations of γ-Valerolactone (GVL) as a Green Solvent to be Used with Base for Fmoc Removal in Solid Phase Peptide Synthesis

GVL is a green solvent used in Fmoc-based solid-phase peptide synthesis. It is susceptible to ring opening in the presence of bases such as piperidines, which are used to remove the Fmoc protecting group. Here we studied the formation of the corresponding acyl piperidides by time-dependent monitoring using NMR. The results, corroborated by theoretical calculations, indicate that a solution of piperidines in GVL should be prepared daily for a better Fmoc removal.

Reduction and Oxidation

Craig M. Williams of the University of Queensland and John Tsanaktsidis of CSIRO Victoria decarboxylated (Org. Lett. 2011, 13, 1944) the acid 1 to the hydrocarbon 2 by coupling the crude acid chloride, formed in CHCl3, with 3 while irradiating with a tungsten bulb. In a related development, David C. Harrowven of the University of Southampton showed (Chem. Commun. 2011, 46, 6335, not illustrated) that tin residues can be removed from a reaction mixture by passage through silica gel containing 10% K2CO3. Sangho Koo of Myong Ji University selectively removed (Org. Lett. 2011, 13, 2682) the allylic oxygen of 5, leaving the other protected alcohol. Donald Poirier of Laval University reduced (Synlett 2011, 2025) the nitrile of 7 to a methyl group. Kiyotomi Kaneda of Osaka University prepared (Chem. Eur. J. 2010, 16, 11818; Angew. Chem. Int. Ed. 2011, 50, 2986) supported Au nanoparticles that deoxygenated an epoxide 9 to the alkene 10. Epoxides of cyclic alkenes also worked well. Shahrokh Saba of Fordham University aminated (Tetrahedron Lett. 2011, 52, 129) the ketone 11 by heating it with an amine 12 in the presence of ammonium formate. Shuangfeng Yin and Li-Biao Han of Hunan University devised (J. Am. Chem. Soc. 2011, 133, 17037) catalyst systems that reduced the alkyne 14 selectively to either the Z or the E product. Professor Kaneda uncovered (Chem. Lett. 2011, 40, 405) a reliable Pd catalyst for the hydrogenation (not illustrated) of an alkyne to the Z alkene. David R. Spring of the University of Cambridge established (Synlett 2011, 1917) biphasic reaction conditions for the conversion of 16 to the azide 18 that were compatible with the base-sensitive Fmoc protecting group. Noritaka Mizuno of the University of Tokyo developed (J. Org. Chem. 2011, 76, 4606) a Ru catalyst for the transformation of an alkyl azide 19 to the nitrile 20. Chi-Ming Che of the University of Hong Kong (Synlett 2011, 1174) and Philip Wai Hong Chan of Nanyang Technological University (J. Org. Chem. 2011, 76, 4894) independently oxidized an aldehyde 21 to the amide 22.

Solid phase synthesis of α-amino squaric acid-containing peptides

A new method has been developed for the synthesis of 3-(1-aminoalkyl)-4-hydroxycyclobut-3-ene-1,2-dione [(α-amino squaric acid (α-Asq)]-containing peptides using solid phase peptide synthesis according to an Fmoc protecting group strategy.

Synthetic, structural and biological studies of the ubiquitin system: the total chemical synthesis of ubiquitin

The small protein ubiquitin (76 amino acids) has been synthesized under optimized conditions by Merrifield solid-phase methodology using the N alpha-Fmoc protecting group. The crude polypeptide mixture was purified to homogeneity by gel filtration, dialysis and a combination of cation- and anion-exchange chromatography to yield ubiquitin. Amino acid analysis, enzymic digestion and sequencing by automated Edman degradation were used to authenticate the primary structure. Isoelectric focusing and m.s. were used to demonstrate that the final product was greater than 98% pure with a final yield of 93 mg (4.3%) from a single synthesis on a 0.25 nmol scale.