Josep Farrera-Sinfreu

Undesired removal of the Fmoc group by the free ε-amino function of a lysine residue

Abstract In solid-phase peptide synthesis, a side-reaction consisting of the premature and undesired removal of the Fmoc group has been detected. This can be caused by a primary amine of sufficient basicity, such as the e-amino of the Lys, present in the peptide resin. This side-reaction, which is not promoted by either the β-amino side-chain of the Dapa residue or the α-amino group, can be prevented by a coupling/neutralization protocol in the case of Mtt protection or by a tandem deprotection–coupling reaction in the case of Alloc protection. The same kind of side-reaction has been detected when amino side-chain functions of Orn or Daba are free in the peptide resin.

Lamellarin D Bioconjugates II: Synthesis and Cellular Internalization of Dendrimer and Nuclear Location Signal Derivatives

The design and synthesis of Lamellarin D conjugates with a nuclear localization signal peptide and a poly(ethylene glycol)-based dendrimer are described. Conjugates 1-4 were obtained in 8-84% overall yields from the corresponding protected Lamellarin D. Conjugates 1 and 4 are 1.4- to 3.3-fold more cytotoxic than the parent compound against three human tumor cell lines (MDA-MB-231 breast, A-549 lung, and HT-29 colon). Besides, conjugates 3 and 4 showed a decrease in activity potency in BJ skin fibroblasts, a normal cell culture. Cellular internalization was analyzed, and a nuclear distribution pattern was observed for 4, which contains a nuclear localization signaling sequence.

Four-dimensional orthogonal solid-phase synthesis of new scaffolds based on cyclic tetra-β-peptides ☆

A four-dimensional orthogonal protecting scheme that involves the acid-labile BAL linker in conjunction with Fmoc, Alloc and pNb protecting groups, which can be removed by β-elimination, allyl transfer, and reductive hydrolysis, respectively, allows the solid-phase preparation of scaffolds based on a cyclic tetra-β-peptide with free amino side chains ready for further elaboration.

Design, synthesis and antiproliferative properties of oligomers with chromophore units linked by amide backbones

The preparation of oligomers made up of several chromophore units as compounds with potential fluorescent and antiproliferative properties is described. Specifically, chromophore units with protected-amino groups and one carboxylic group are described, together with methods to assemble these units using peptide chemistry. Some of these compounds have antiproliferative activity.

Solid-phase synthesis of oligomers carrying several chromophore units linked by phosphodiester backbones.

A method for the preparation of oligomers by linking chromophore units is described. Specifically, the synthesis of chromophore units having a protected-hydroxyl group and a phosphoramidite function is described, along with a method to link several units using solid-phase phosphite-triester protocols.

Acridine and quindoline oligomers linked through a 4-aminoproline backbone prefer G-quadruplex structures

BACKGROUND DNA-intercalating drugs are planar molecules with several fused aromatic rings that form stacks between DNA base pairs, reducing the opening and unwinding of the double helix. Recently, interest on intercalating agents has moved in the search for new ligands to G-quadruplex structures. METHODS The DNA binding properties of 4-aminoproline oligomers functionalized with one, two or three units of acridine and/or quindoline have been analyzed by competitive dialysis. A NMR/molecular dynamics study was performed on G-quadruplex telomeric sequence and the 4-aminoproline dimer carrying two quindolines. A model of the complex with the telomeric DNA quadruplex is described. RESULTS AND CONCLUSIONS A selectivity of quindoline 4-aminoproline oligomers for G-quadruplex and triplex structures was observed, especially for those quadruplex sequences found in telomeres and in the promoter regions of c-myc and bcl-2 oncogenes. In this model the quindoline dimer is stabilized by π-π stacking interactions between the aromatic rings of the ligand and the nucleobases of the telomeric sequence that are located above and below the molecule. GENERAL SIGNIFICANCE The results of this work can be used for the design of new molecules with high affinity to telomeres which may have anticancer properties.

Solid-Phase Combinatorial Synthesis of a Lysyl-tRNA Synthetase (LysRS) Inhibitory Library

The solid-phase combinatorial synthesis of a new library with potential inhibitory activity against the cytoplasmic lysyl-tRNA synthetase (LysRS) isoform of Trypanosoma brucei is described. The library has been specifically designed to mimic the lysyl adenylate complex. The design was carried out by dividing the complex into four modular parts. Proline derivatives (cis-gamma-amino-L-proline or trans-gamma-hydroxy-L-proline) were chosen as central scaffolds. After primary screening, three compounds of the library caused in vitro inhibition of the tRNA aminoacylation reaction in the low micromolar range.

Cell-Penetrating Proline-Rich Peptidomimetics

Cell-penetrating peptides (CPPs) offer potential as delivery agents for the cellular administration of drugs. However, the pharmacological utility of CPPs that are derived from natural amino acids is limited by their rapid metabolic degradation, low membrane permeability, and toxicity. Various peptidomimetics able to overcome these problems have been described, including peptides formed by D-amino acids and beta-peptides. This chapter summarizes the synthesis of gamma-proline-derived peptides and polyproline dendrimers for drug delivery applications, and includes descriptions of several modifications in the gamma-peptides (mimicking the side chains of the alpha-amino acids) or modulating the dendrimer surface. 5(6)-Carboxyfluorescein labeling of the aforementioned peptidomimetics for use in cell translocation studies is also described. Furthermore, different protocols for the study of the drug delivery capabilities of these compounds are reviewed, including enzymatic stability studies, cellular uptake measurements by plate fluorimetry and flow cytometry, confocal laser scanning microscopy, and cytotoxicity assays.