Judit Tulla-Puche

Polymers and drug delivery systems.

In the treatment of health related dysfunctions, it is desirable that the drug reaches its site of action at a particular concentration and that this therapeutic dose range remains constant over a sufficiently long period of time to alter the process. However, the action of pharmaceutical agents is limited by various factors, including their degradation, their interaction with other cells, and their incapacity to penetrate tissues as a result of their chemical nature. For these reasons, new formulations are being studied to achieve a greater pharmacological response; among these, polymeric systems of drug carriers are of high interest. These systems are an appropriate tool for time- and distribution-controlled drug delivery. The mechanisms involved in controlled release require polymers with a variety of physicochemical properties. Thus, several types of polymers have been tested as potential drug delivery systems, including nano- and micro-particles, dendrimers, nano- and micro-spheres, capsosomes, and micelles. In all these systems, drugs can be encapsulated or conjugated in polymer matrices. These polymeric systems have been used for a range of treatments for antineoplastic activity, bacterial infections and inflammatory processes, in addition to vaccines.

The first total synthesis of the cyclodepsipeptide pipecolidepsin A

Pipecolidepsin A is a head-to-side-chain cyclodepsipeptide isolated from the marine sponge Homophymia lamellosa. This compound shows relevant cytotoxic activity in three human tumour cell lines and has unique structural features, with an abundance of non-proteinogenic residues, including several intriguing amino acids. Although the moieties present in the structure show high synthetic difficulty, the cornerstone is constituted by the unprecedented and highly hindered γ-branched β-hydroxy-α-amino acid D-allo-(2R,3R,4R)-2-amino-3-hydroxy-4,5-dimethylhexanoic acid (AHDMHA) residue, placed at the branching ester position and surrounded by the four demanding residues L-(2S,3S,4R)-3,4-dimethylglutamine, (2R,3R,4S)-4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, D-allo-Thr and L-pipecolic acid. Here we describe the first total synthesis of a D-allo-AHDMHA-containing peptide, pipecolidepsin A, thus allowing chemical structure validation of the natural product and providing a robust synthetic strategy to access other members of the relevant head-to-side-chain family in a straightforward manner.

Handles for Fmoc Solid-Phase Synthesis of Protected Peptides

Protected peptide fragments are valuable building blocks for the assembly of large peptide sequences through fragment condensation approaches, whereas protected peptides are typically synthesized for the preparation of amide-bridge cyclic peptides in solution. Efficient synthesis of both protected peptides and protected peptide fragments by solid-phase peptide synthesis methodology requires handles that attach the growing peptides to the polymeric support and can be cleaved under appropriate conditions, while maintaining intact the side-chain protecting groups. Here, we provide an overview of attachment methods described in the literature for the preparation of protected peptides using Fmoc/tBu chemistry, including the most commonly used acid-labile linkers along with the most recent and sophisticated.

ChemMatrix® for complex peptides and combinatorial chemistry

CM resin is a totally PEG‐based resin, made exclusively from primary ether bonds and therefore highly chemically stable. Compared to other PEG resins, it exhibits good loading and is user friendly because of its free‐flowing form upon drying. It shows improved performance over PS resins for the preparation of hydrophobic, highly structured poly‐Arg peptides. In combination with ψPros, it allows the synthesis of small proteins such as the chemokine RANTES. Like other PEG‐based resins, CM resin swells well in biocompatible solvents such as water, thereby allowing on‐bead screening. Furthermore, the high loading of this resin permits the use of a tiny quarter of a bead as a microreactor for HPLC and MALDI‐TOF analysis, thus further extending its applications in the field of combinatorial chemistry. Copyright

The power of functional resins in organic synthesis

INTRODUCTION The (Classic Concept of) Solid Support Molecularly Imprinted Polymers Nanoparticles Functionalized with Bioactive Molecules: Biomedical Applications SOLID-SUPPORTED REAGENTS AND SCAVENGERS Oxidizing and Reducing Reagents Base and Acid Reagents Nucleophilic, Electrophilic, and Radical Reactions Coupling and Introducing Building Block Reagents Supported/Tagged Scavengers for Facilitating High-Throughput Chemistry Metal Scavengers RESIN-BOUND CATALYSTS Polymer-Supported Organocatalysts Transition Metal Catalysts Chiral Auxiliaries on Solid Support Immobilized Enyzmes in Organic Synthesis RESINS FOR SOLID-PHASE SYNTHESIS Acid-Labile Resins Base/Nucleophile-Labile Resins Safety-Catch and Traceless Linkers/Resins in SPOS Photolabile and Miscellaneous Linkers/Resins SOLID-PHASE SYNTHESIS OF BIOMOLECULES. THE STATE OF THE ART (FROM THE RESIN POINT OF VIEW) Peptides Oligonucleotides and their Derivatives Oligosacharides High Throughput Synthesis of Natural Products

NMe Amide as a Synthetic Surrogate for the Thioester Moiety in Thiocoraline

Bridged N-methyl amides are used as isosteres for depsi and thiodepsi bonds in thiocoraline. The introduction of NMe-amides in bridges mimics the thioester bonds without imposing steric hindrance and allows conservation of the hydrogen bonding map of the natural product. NMe-azathiocoraline was constructed by solid-phase N-methylation of the side chain of diaminopropionic acid (Dap). The three consecutive N-methyl amino acids could be coupled in good yields by using HATU/HOAt/DIEA in DMF, and the final octapeptide was also obtained on solid phase following a 4 + 4 fragment coupling approach. NMe-azathiocoraline (NMA) displayed nanomolar activity in the same order as the natural product and the same mode of action. In fact, modeling of NMe-azathiocoraline bonded to a TCGA sequence showed how the methyl groups remained further away from the DNA strand without changing the recognition pattern of thiocoraline. Moreover, NMe-azathiocoraline displayed an increased stability in human serum as compared to the parent natural product. This approach could be used in other depsipeptides and side chain to side chain cyclic peptides.

“Head-to-Side-Chain” Cyclodepsipeptides of Marine Origin

Since the late 1980s, a large number of depsipeptides that contain a new topography, referred to as “head-to-side-chain” cyclodepsipeptides, have been isolated and characterized. These peptides present a unique structural arrangement that comprises a macrocyclic region closed through an ester bond between the C-terminus and a β-hydroxyl group, and terminated with a polyketide moiety or a more simple branched aliphatic acid. This structural pattern, the presence of unique and complex residues, and relevant bioactivity are the main features shared by all the members of this new class of depsipeptides, which are reviewed herein.

Solid-Phase Synthesis of NMe-IB-01212, a Highly N-Methylated Cyclic Peptide

N-Methylation of peptides is an important synthetic tool in peptide-based medicinal chemistry. Herein, an optimized strategy for solid-phase synthesis of small but highly N-methylated cyclic peptides is described. The proposed route addresses several problems associated with the synthesis of peptides containing several sequential N-methyl-amino acids, such as in situ N-methylation, difficulty of acylation, epimerization, diketopiperazine formation, and stability at the NMe sites under trifluoroacetic acid exposure. The resulting NMe-IB-01212 exhibits micromolar activity and considerable stability.

Acid-labile Cys-protecting groups for the Fmoc/tBu strategy: filling the gap.

To address the existing gap in the current set of acid-labile Cys-protecting groups for the Fmoc/tBu strategy, diverse Fmoc-Cys(PG)-OH derivatives were prepared and incorporated into a model tripeptide to study their stability against TFA. S-Dpm proved to be compatible with the commonly used S-Trt group and was applied for the regioselecive construction of disulfide bonds.

Stellatolides, a New Cyclodepsipeptide Family from the Sponge Ecionemia acervus: Isolation, Solid-Phase Total Synthesis, and Full Structural Assignment of Stellatolide A

The marine environment is a rich source of metabolites with potential therapeutic properties and applications for humans. Here we describe the first isolation, solid-phase total synthesis, and full structural assignment of a new class of cyclodepsipeptides from the Madagascan sponge Ecionemia acervus that shows in vitro cytotoxic activities at submicromolar concentrations. Seven structures belonging to a new family of compounds, given the general name stellatolides, were characterized. The sequence and stereochemistry of all the amino acids in these molecules were established by a combination of spectroscopic analysis, chemical degradation, and derivatization studies. Furthermore, the complete structure of stellatolide A was confirmed by an efficient solid-phase method for the first total synthesis and the full structural assignment of this molecule, including the asymmetric synthesis of the unique β-hydroxy acid moiety (Z)-3-hydroxy-6,8-dimethylnon-4-enoic acid.