Total Synthesis of an Epothilone Analogue Based on the Amide-Triazole Bioisosterism.

Epothilones are 16-membered macrolides that act as microtubule-targeting agents to tackle cancer. Many synthetic analogues have been investigated for their activity, yet often based on macrolide structures. A notable exception is Ixabepilone, an azalide whose metabolic stability and pharmacokinetics are significantly improved. Exploiting the amide-triazole bioisosterism, in this work we report the synthesis of the first generation of epothilones lacking the macrolide or azalide structure, with the ester or amide linkage replaced by a triazole unit. Together with the synthesis of this new analogue, computational and biological evaluations have been performed too.

Smart Electrospun Nanofibers from Short Peptidomimetics Based on Pyrrolo-pyrazole Scaffold.

We prepared a small library of short peptidomimetics based on 3-pyrrolo-pyrazole carboxylate, a non-coded γ-amino acid, and glycine or alanine. The robust and eco-friendly synthetic approach adopted allows to obtain the dipeptides in two steps from commercial starting materials. This gives the possibility to shape these materials by electrospinning into micro- and nanofibers, in amounts required to be useful for coating surfaces of biomedical relevance. To promote high quality of electrospun fibers, different substitution patterns were evaluated, all for pure peptide fibers, free of any polymer or additive. The best candidate, which affords a homogeneous fibrous matrix, was prepared in larger amounts, and its biocompatibility was verified. This successful work is the first step to develop a new biomaterial able to produce pristine peptide-based nanofibers to be used as helpful component or stand-alone scaffolds for tissue engineering or for the surface modification of medical devices.

Amine-Carbamate Self-Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads.

Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.

Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2-(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives.

A phosphine-catalyzed domino assembly of six units of 2-bromomethyl acrylates afforded polyalkenyl adducts containing two cyclohexenyl rings. This reaction occurs under mild conditions providing the final product by formation of seven carbon-carbon bonds and four stereocenters. Experimental and computational studies support an initial dimerization of the substrate, which in turn trimerizes involving two totally regio- and stereocontrolled Diels-Alder cycloadditions. The yield of the hexamerization of the 2-bromomethyl acrylates depends on the size of the ester function. The protocol has also proved to be practicable on a gram scale.

Highly efficient morpholine-based organocatalysts for the 1,4-addition reaction between aldehydes and nitroolefins: an unexploited class of catalysts.

Many studies have demonstrated how the pyrrolidine nucleus is more efficient than the corresponding piperidine or morpholine as organocatalysts in the condensation of aldehydes with electrophiles via enamine. Focussing on morpholine-enamines, their low reactivity is ascribed to the presence of oxygen on the ring and to the pronounced pyramidalisation of nitrogen, decreasing the nucleophilicity of the enamine. Thus, the selection of efficient morpholine organocatalysts appears to be a difficult challenge. Herein, we reported on the synthesis of new organocatalysts belonging to the class of ß-morpholine amino acids that were tested in a model reaction, i.e., the 1,4-addition reaction of aldehydes to nitroolefins. Starting from commercially available amino acids and epichlorohydrin, we designed an efficient synthesis for the aforementioned catalysts, controlling the configuration and the substitution pattern. Computational studies indeed disclosed the transition state of the reaction, explaining why, despite all the limitations of the morpholine ring for enamine catalysis, our best catalyst works efficiently, affording condensation products with excellent yields, diastereoselection and good-to-exquisite enantioselectivity.

Non-Conventional Peptide Self-Assembly into a Conductive Supramolecular Rope.

Structures composed of alternating α and ß amino acids can give rise to peculiar secondary structural motifs, which could self-assemble into complex structures of controlled geometries. This work describes the self-assembly properties of an α,ß-peptide, containing three units of syn H2-(2-F-Phe)-h-PheGly-OH, able to self-organize on surfaces into a fascinating supramolecular rope. This material was characterized by AFM, electronic conduction and fluorescence measurements. Molecular dynamics simulations showed that this hexapeptide can self-assemble into an antiparallel ß-sheet layer, stabilized by intermolecular H-bonds, which, in turn, can self-assemble into many side-by-side layers, due to π-π interactions. As a matter of fact, we demonstrated that in this system, the presence of aromatic residues at the intramolecular interface promoted by the alternation of α,ß-amino-acids in the primary sequence, endorses the formation of a super-secondary structure where the aromatic groups are close to each other, conferring to the system good electron conduction properties. This work demonstrates the capability and future potential of designing and fabricating distinctive nanostructures and efficient bioelectronic interfaces based on an α,ß-peptide, by controlling structure and interaction processes beyond those obtained with α- or ß-peptides alone.

Fatty Acids/Tetraphenylethylene Conjugates: Hybrid AIEgens for the Preparation of Peptide-Based Supramolecular Gels.

Aggregation-induced emissive materials are gaining particular attention in the last decades due to their wide application in different fields, from optical devices to biomedicine. In this work, compounds having these kinds of properties, composed of tetraphenylethylene scaffold combined with fatty acids of different lengths, were synthesized and characterized. These molecules were found able to self-assemble into different supramolecular emissive structures depending on the chemical composition and water content. Furthermore, they were used as N-terminus capping agents in the development of peptide-based materials. The functionalization of a 5-mer laminin-derived peptide led to the obtainment of luminescent fibrillary materials that were not cytotoxic and were able to form supramolecular gels in aqueous environment.

Advanced Pyrrolidine-Carbamate Self-Immolative Spacer with Tertiary Amine Handle Induces Superfast Cyclative Drug Release.

Amine-carbamate self-immolative (SI) spacers represent practical and versatile tools in targeted prodrugs, but their slow degradation mechanism limits drug activation at the site of disease. We engineered a pyrrolidine-carbamate SI spacer with a tertiary amine handle which strongly accelerates the spacer cyclization to give a bicyclic urea and the free hydroxy groups of either cytotoxic (Camptothecin) or immunostimulatory (Resiquimod) drugs. In silico conformational analysis and pKa calculations suggest a plausible mechanism for the superior efficacy of the advanced SI spacer compared to state-of-art analogues.

Ultrashort Peptides and Gold Nanoparticles: Influence of Constrained Amino Acids on Colloidal Stability.

Poor colloidal stability of gold nanoparticles (AuNPs) in physiological environments remains one of the major limitations that contribute to their difficult translation from bench to clinic. For this reason, an active research field is the development of molecules able to hamper AuNPs aggregation tendency in physiological environments. In this context, synthetic peptides are gaining an increased interest as an alternative to the use of biomacromolecules and polymers, due to their easiness of synthesis and their profitable pharmacokinetic profile. In this work, we reported on the use of ultrashort peptides containing conformationally constrained amino acids (AAs) for the stabilization of AuNPs. A small library of non-natural self-assembled oligopeptides were synthesized and used to functionalize spherical AuNPs of 20 nm diameter, via the ligand exchange method. The aim was to investigate the role of the constrained AA, the anchor point (at C- or N-terminus) and the peptide length on their potential use as gold binding motif. Ultrashort Aib containing peptides were identified as effective tools for AuNPs colloidal stabilization. Furthermore, peptide coated AuNPs were found to be storable as powders without losing the stabilization properties once re-dispersed in water. Finally, the possibility to exploit the developed systems for binding proteins via molecular recognition was also evaluated using biotin as model.

Exploiting Ultrashort α,ß-Peptides in the Colloidal Stabilization of Gold Nanoparticles.

Colloidal gold nanoparticles (GNPs) have found wide-ranging applications in nanomedicine due to their unique optical properties, ease of preparation, and functionalization. To avoid the formation of GNP aggregates in the physiological environment, molecules such as lipids, polysaccharides, or polymers are employed as GNP coatings. Here, we present the colloidal stabilization of GNPs using ultrashort α,ß-peptides containing the repeating unit of a diaryl ß2,3-amino acid and characterized by an extended conformation. Differently functionalized GNPs have been characterized by ultraviolet, dynamic light scattering, and transmission electron microscopy analysis, allowing us to define the best candidate that inhibits the aggregation of GNPs not only in water but also in mouse serum. In particular, a short tripeptide was found to be able to stabilize GNPs in physiological media over 3 months. This new system has been further capped with albumin, obtaining a material with even more colloidal stability and ability to prevent the formation of a thick protein corona in physiological media.

Peptide-Based Electrospun Fibers: Current Status and Emerging Developments.

Electrospinning is a well-known, straightforward, and versatile technique, widely used for the preparation of fibers by electrifying a polymer solution. However, a high molecular weight is not essential for obtaining uniform electrospun fibers; in fact, the primary criterion to succeed is the presence of sufficient intermolecular interactions, which function similar to chain entanglements. Some small molecules able to self-assemble have been electrospun from solution into fibers and, among them, peptides containing both natural and non-natural amino acids are of particular relevance. Nowadays, the use of peptides for this purpose is at an early stage, but it is gaining more and more interest, and we are now witnessing the transition from basic research towards applications. Considering the novelty in the relevant processing, the aim of this review is to analyze the state of the art from the early 2000s on. Moreover, advantages and drawbacks in using peptides as the main or sole component for generating electrospun nanofibers will be discussed. Characterization techniques that are specifically targeted to the produced peptide fibers are presented.

Alternative Strategy to Obtain Artificial Imine Reductase by Exploiting Vancomycin/D-Ala-D-Ala Interactions with an Iridium Metal Complex.

Based on the supramolecular interaction between vancomycin (Van), an antibiotic glycopeptide, and D-Ala-D-Ala (DADA) dipeptides, a novel class of artificial metalloenzymes was synthesized and characterized. The presence of an iridium(III) ligand at the N-terminus of DADA allowed the use of the metalloenzyme as a catalyst in the asymmetric transfer hydrogenation of cyclic imines. In particular, the type of link between DADA and the metal-chelating moiety was found to be fundamental for inducing asymmetry in the reaction outcome, as highlighted by both computational studies and catalytic results. Using the [IrCp*(m-I)Cl]Cl ⊂ Van complex in 0.1 M CH3COONa buffer at pH 5, a significant 70% (S) e.e. was obtained in the reduction of quinaldine B.

Exploring the copper binding ability of Mets7 hCtr-1 protein domain and His7 derivative: An insight in Michael addition catalysis.

Mets7 is a methionine-rich motif present in hCtr-1 transporter that is involved in copper cellular trafficking. Its ability to bind Cu(I) was recently exploited to develop metallopeptide catalysts for Henry condensation. Here, the catalytic activity of Mets7-Cu(I) complex in Michael addition reactions has been evaluated. Furthermore, His7 peptide, in which Met residues have been substituted with His ones, was also prepared. This substitution allowed His7 to coordinate Cu (II), with the obtainment of a stable turn conformation as evicted by CD experiments. His7-Cu (II) proved also to be a better catalyst than Mets7-Cu(I) in the addition reaction. In particular, when the substrate was the (E)-1-phenyl-3-(pyridin-2-yl)prop-2-en-1-one, a conversion of 71% and a significative 58% of e.e. was observed.

Peptide grafting strategies before and after electrospinning of nanofibers.

Nanofiber films produced by electrospinning currently provide a promising platform for different applications. Although nonfunctionalized nanofiber films from natural or synthetic polymers are extensively used, electrospun materials combined with peptides are gaining more interest. In fact, the selection of specific peptides improves the performance of the material for biological applications and mainly for tissue engineering, mostly by maintaining similar mechanical properties with respect to the simple polymer. The main drawback in using peptides blended with a polymer is the quick release of the peptides. To avoid this problem, covalent linking of the peptide is more beneficial. Here, we reviewed synthetic protocols that enable covalent grafting of peptides to polymers before or after the electrospinning procedures to obtain more robust electrospun materials. Applications and the performance of the new material compared to that of the starting polymer are discussed.

Nucleobase morpholino ß amino acids as molecular chimeras for the preparation of photoluminescent materials from ribonucleosides.

Bioinspired smart materials represent a tremendously growing research field and the obtainment of new building blocks is at the molecular basis of this technology progress. In this work, colloidal materials have been prepared in few steps starting from ribonucleosides. Nucleobase morpholino ß-amino acids are the chimera key intermediates allowing Phe-Phe dipeptides' functionalization with adenine and thymine. The obtained compounds self-aggregate showing enhanced photoluminescent features, such as deep blue fluorescence and phosphorescence emissions.

Non-natural 3-Arylmorpholino-ß-amino Acid as a PPII Helix Inducer.

A new non-natural ß-amino acid, named 3-Ar-ß-Morph, was designed and synthesized via a regio- and diastereoselective Pd-catalyzed C(sp3)H-arylation of the corresponding 2S,6S-(6-methoxymorpholin-2-yl)carboxylic acid, readily available from glucose. According to the computational prevision and confirmed by IR and NMR data, the insertion of 3-Ar-ß-Morph in a model foldamer represents a way to stabilize a PPII-like helix through the presence of two γ-turns, secondary structure motifs induced by the morpholine ring, and the trans-tertiary amide bond.

An account of the first hours of the Covid-19 epidemic at the Nephrology Unit in Lodi (Lombardy).

Marco Farina and colleagues give us their account of the first days of the Covid-19 epidemic in the Nephrology Unit of the Ospedale Maggiore in Lodi. From the news trickling through from Codogno on the 20th of February to the hospitalization, the following day, of the first dialytic patient with signs of pneumonia, who later tested positive to the virus. They tell us of how the hospital has been completely restructured in the wake of the epidemic, at remarkable speed and providing an example for others to follow, and the great sense self-sacrifice displayed by all medical personnel. After an overview of the clinical conditions of the 7 patients positive to the virus hospitalised in the following few days, they describe in some detail how symptomatic Covid+ patients are currently managed at the Ospedale Maggiore in Lodi.

On-resin multicomponent 1,3-dipolar cycloaddition of cyclopentanone-proline enamines and sulfonylazides as an efficient tool for the synthesis of amidino depsipeptide mimics.

Depsipeptides are biologically active peptide derivatives that possess a high therapeutic interest. The development of depsipeptide mimics characterized by a chemical diversity could lead to compounds with enhanced features and activity. In this work, an on-resin multicomponent procedure for the synthesis of amidino depsipeptide mimics is described. This approach exploits a metal-free 1,3-dipolar cycloaddition of cyclopentanone-proline enamines and sulfonylazides. In this reaction, the obtained primary cycloadduct undergoes a ring opening and molecular rearrangement giving access to a linear sulfonyl amidine functionalized with both a peptide chain and a diazoalkane. The so-obtained diazo function "one pot" reacts with the carboxylic group of N-Fmoc-protected amino acids leading to amidino depsipeptide mimics possessing a C4 aliphatic chain. An important advantage of this procedure is the possibility to easily obtain amidino-functionalized derivatives that are proteolytically stable peptide bond bioisosteres. Moreover, the conformational freedom given by the alkyl chain could promote the obtainment of cyclic depsipeptide with a stabilized secondary structure as demonstrated with both in silico calculations and experimental conformational studies. Finally, labeled depsipeptide mimics can be also synthesized using a fluorescent sulfonylazide in the multicomponent reaction.

Self-assembled hydrophobic Ala-Aib peptide encapsulating curcumin: a convenient system for water insoluble drugs.

The exploitation of self-assembled systems to improve the solubility of drugs is getting more and more attention. Among the different types of self-assembled biomaterials, peptides and in particular peptides containing non-coded amino acids (NCAPs) are promising because their use opens the door to more stable materials inducing increased stability to proteolysis. New classes of NCAP, Ac-Ala-X-Ala-Aib-AlaCONH2 (X = alpha-aminoisobutyric acid (Aib) or X = cyclopentane amino acid (Ac5c)) have been prepared and the correlation between the different secondary peptide structure and solvent (i.e. CD3CN, CD3OH, H2O/D2O) verified by NMR. Furthermore, the formation of a nanocolloidal system in water was deeply studied by DLS and the morphology of the obtained spherical aggregates with nanometric dimensions was assessed by TEM. Aib containing pentapeptide was selected for greater ease of synthesis. Its ability to encapsulate curcumin, as a model insoluble drug molecule, was investigated using fluorescence emission and confocal microscopy analyses. Two different approaches were used to study the interaction between curcumin and peptide aggregates. In the first approach peptide aggregates were formed in the presence of curcumin, while in the second approach curcumin was added to the already formed peptide aggregates. We succeeded in our challenge by using the second approach and 53.8% of added curcumin had been encapsulated.

Vancomycin-Iridium (III) Interaction: An Unexplored Route for Enantioselective Imine Reduction.

The chiral structure of antibiotic vancomycin (Van) was exploited as an innovative coordination sphere for the preparation of an IrCp* based hybrid catalysts. We found that Van is able to coordinate iridium (Ir(III)) and the complexation was demonstrated by several analytical techniques such as MALDI-TOF, UV, Circular dichroism (CD), Raman IR, and NMR. The hybrid system so obtained was employed in the Asymmetric Transfer Hydrogenation (ATH) of cyclic imines allowing to obtain a valuable 61% e.e. (R) in the asymmetric reduction of quinaldine 2. The catalytic system exhibited a saturation kinetics with a calculated efficiency of Kcat/KM = 0.688 h-1mM-1.