Difosfani binaftilici P,P'-eterotopici privi di simmetria C². Sintesi e applicazioni in catalisi asimmetrica

Recentemente abbiamo portato a compimento con successo la sintesi dei primi difosfani a scheletro binaftilico privi di simmetria C2 (BINAPP') 3 a partire dal ditriflato del binaftolo enantiopuro 1. Questi leganti sono stati preparati con una procedura a più stadi che prevede la sostituzione in sequenza dei due gruppi triflato

Lipopeptides as anti-infectives: a practical perspective

AbstractLipopeptide antibiotics represent an old class of antibiotics that were discovered over 50 years ago, which includes the old polymyxins but also new entries, such as the recently approved daptomycin. They generally consist of a hydrophilic cyclic peptide portion attached to a fatty acid chain which facilitates insertion into the lipid bilayer of bacterial membranes. This review presents an overview of this class of antibiotics, focusing on their therapeutic applications and putting particular emphasis on chemical modifications introduced to improve their activity

Enhanced Amphiphilic Profile of a Short β-Stranded Peptide Improves Its Antimicrobial Activity

SB056 is a novel semi-synthetic antimicrobial peptide with a dimeric dendrimer scaffold. Active against both Gram-negative and -positive bacteria, its mechanism has been attributed to a disruption of bacterial membranes. The branched peptide was shown to assume a β- stranded conformation in a lipidic environment. Here, we report on a rational modification of the original, empirically derived linear peptide sequence [WKKIRVRLSA-NH$_{2}$, SB056-lin]. We interchanged the first two residues [KWKIRVRLSA-NH$_{2}$, β-SB056-lin] to enhance the amphipathic profile, in the hope that a more regular β-strand would lead to a better antimicrobial performance. MIC values confirmed that an enhanced amphiphilic profile indeed significantly increases activity against both Gram-positive and -negative strains. The membrane binding affinity of both peptides, measured by tryptophan fluorescence, increased with an increasing ratio of negatively charged/zwitterionic lipids. Remarkably, β- SB056-lin showed considerable binding even to purely zwitterionic membranes, unlike the original sequence, indicating that besides electrostatic attraction also the amphipathicity of the peptide structure plays a fundamental role in binding, by stabilizing the bound state. Synchrotron radiation circular dichroism and solid-state $^{19}$F-NMR were used to characterize and compare the conformation and mobility of the membrane bound peptides. Both SB056- lin and β-SB056-lin adopt a β-stranded conformation upon binding POPC vesicles, but the former maintains an intrinsic structural disorder that also affects its aggregation tendency. Upon introducing some anionic POPG into the POPC matrix, the sequence-optimized β- SB056-lin forms well-ordered β-strands once electro-neutrality is approached, and it aggregates into more extended β-sheets as the concentration of anionic lipids in the bilayer is raised. The enhanced antimicrobial activity of the analogue correlates with the formation of these extended β-sheets, which also leads to a dramatic alteration of membrane integrity as shown by $^{31}$P-NMR. These findings are generally relevant for the design and optimization of other membrane-active antimicrobial peptides that can fold into amphipathic β-strands

Antimicrobial peptides: an overview of a promising class of therapeutics DOI: 10.2478/s11535-007-0010-5 Review article

Abstract: Antibiotic resistance is increasing at a rate that far exceeds the pace of new development of drugs. Antimicrobial peptides, both synthetic and from natural sources, have raised interest as pathogens become resistant against conventional antibiotics. Indeed, one of the major strengths of this class of molecules is their ability to kill multidrug-resistant bacteria. Antimicrobial peptides are relatively small (6 to 100 aminoacids), amphipathic molecules of variable length, sequence and structure with activity against a wide range of microorganisms including bacteria, protozoa, yeast, fungi, viruses and even tumor cells. They usually act through relatively non-specific mechanisms resulting in membranolytic activity but they can also stimulate the innate immune response. Several peptides have already entered pre-clinical and clinical trials for the treatment of catheter site infections, cystic fibrosis, acne, wound healing and patients undergoing stem cell transplantation. We review the advantages of these molecules in clinical applications, their disadvantages including their low in vivo stability, high costs of production and the strategies for their discovery and optimization

BINAPS: an axially chiral <i>P</i>,<i>S</i>-heterodonor ligand for asymmetric catalysis based on binaphthalene backbone

The chelating P,S-heterodonor ligand 2-diphenylphosphanyl-1,1¢-binaphthalene-2'-thiol (11) (BINAPS), which features a chiral axis as the unique stereogenic element, has been prepared in both racemic and enantiopure form through a multistep reaction sequence using 2,2'-dihydroxy-1,1'-binaphthalene (BINOL) as the starting material. The reaction sequence is completely stereoconservative and (S)-11 is obtained with no loss of enantiopurity from pure (S)- BINOL. (R)-11 can be alternatively obtained by resolution of racemic 11 using the chiral (S)-benzylaminato Pd(II)- complex 19 as the resolving agent. The S-methyl or the S-i-propyl derivatives 14 have been used as chiral ligands in the Rh(I)-catalyzed asymmetric hydroformylation of styrene and in the hydrogen transfer reduction of acetophenone with modest success (up to 20% ee). In the presence of suitable Pd-complexes the same ligands provide higher ees in the hydrosilylation of styrene (50% ee) and in the allylic alkylation of 1,3-diphenylprop-2-enyl acetate (60% ee)

Synthesis of <i>P</i>,<i>P</i>-heterotopic binaphthyldiphosphanes (BINAPP') devoid of <i>C</i>₂ symmetry from 2,2'-binaphthol

The introduction of two nonequivalent diarylphosphanyl substituents into the 2- and 2'-positions of 1,1'-binaphthalene has been successfully accomplished in four steps from 1,1'-binaphthalene-2,2'-diol (BINOL) through conversion into the ditriflate followed by sequential substitution of triflate groups mediated by palladium or nickel catalysts. The selective monosubstitution of the triflate has been achieved by introducing the first phosphorated substituent in the form of phosphane oxide through a Pd-catalyzed reaction. The otolyl- substituted diphosphane 4c is a chiral inducer that is more efficient than BINAP both in the Rh-catalyzed asymmetric hydrogenation of acetamido acrylic acid derivatives and in the Pd-catalyzed allylic alkylation of 1,3-diphenylprop- 2-enyl acetate (85% ee)

Identification of a Dendrimeric Heparan Sulfate-Binding Peptide That Inhibits Infectivity of Genital Types of Human Papillomaviruses▿

Peptide dendrimers consist of a peptidyl branching core and/or covalently attached surface functional units. They show a variety of biological properties, including antiviral activity. In this study, a minilibrary of linear, dimeric, and dendrimeric peptides containing clusters of basic amino acids was evaluated for in vitro activity against human papillomaviruses (HPVs). The peptide dendrimer SB105-A10 was found to be a potent inhibitor of genital HPV types (i.e., types 16, 18, and 6) in pseudovirus-based neutralization assays. The 50% inhibitory concentration was between 2.8 and 4.2 μg/ml (0.59 and 0.88 μM), and no evidence of cytotoxicity was observed. SB105-A10 interacts with immobilized heparin and with heparan sulfates exposed on the cell surface, most likely preventing virus attachment. The findings from this study indicate SB105-A10 to be a leading candidate compound for further development as an active ingredient of a topical microbicide against HPV and other sexually transmitted viral infections

Synthesis, characterization, antimicrobial activity and LPS-interaction properties of SB041, a novel dendrimeric peptide with antimicrobial properties

Multimeric peptides offer several advantages with respect to their monomeric counterparts, as increased activity and greater stability to peptidases and proteases. SB041 is a novel antimicrobial peptide with dendrimeric structure; it is a tetramer of pyrEKKIRVRLSA linked by a lysine core, with an amino valeric acid chain. Here, we report on its synthesis, NMR characterization, antimicrobial activity, and LPS-interaction properties. The peptide was especially active against Gram-negative strains, with a potency comparable (on molar basis) to that of lipopeptides colistin and polymixin B, but it also displayed some activity against selected Gram-positive strains. Following these indications, we investigated the efficacy of SB041 in binding Escherichia coli and Pseudomonas aeruginosa LPS in vitro and counteracting its biological effects in RAW-Blue cells, derived from RAW 264.7 macrophages. SB041 strongly bound purified LPS, especially that of E. coli, as proved by fluorescent displacement assay, and readily penetrated into LPS monolayers. However, the killing activity of SB041 against E. coli was not inhibited by increasing concentrations of LPS added to the medium. Checking the SB041 effect on LPS-induced activation of pattern recognition receptors (PRRs) in Raw-Blue cells revealed that while the peptide gave a statistically significant decrease in PRRs stimulation when RAW-Blue cells were challenged with P. aeruginosa LPS, the same was not seen when E. coli LPS was used to activate innate immune defense-like responses. Thus, as previously seen for other antimicrobial peptides, also for SB041 binding to LPS did not translate necessarily into LPS-neutralizing activity, suggesting that SB041-LPS interactions must be of complex nature

Investigation of the Faraday effect in tellurite glass optical fiber

The Faraday effect of a tellurite glass in the bulk and fibre form was investigated for magneto-optic applications. Polarization analysis showed that an optical beam linearly polarized at the multimode fibre input changed to elliptically polarized after propagating down the fibre and the result was compared with a standard silica optical fibre. However, the elliptical distribution remained unchanged with or without applied magnetic field, demonstrating that no circular dichroism occurs within the fibre. The Verdet constant values of the tellurite bulk glass diverged by less than 3% from the values measured on the fibre whose core had the same composition of the bulk glass. The results of the investigation demonstrate that tellurite glass fibres obtained by preform drawing are suitable for developing devices for magneto-optic application