We present a detailed investigation of the coordination chemistry toward [Cu/Cu]copper of a series of HDEDPA derivatives (HDEDPA = 6,6'-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid) containing cyclohexyl (HCHXDEDPA), cyclopentyl (HCpDEDPA) or cyclobutyl (HCBuDEDPA) spacers. Furthermore, we also developed a strategy that allowed the synthesis of a HCBuDEDPA analogue containing an additional NHBoc group at the cyclobutyl ring, which can be used for conjugation to targeting units. The X-ray structures of the Cu(II) complexes evidence distorted octahedral coordination around the metal ion in all cases.
View Article and Find Full Text PDFTwo new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.
View Article and Find Full Text PDFThe enantioselective preparation of the two isomers of 4-hydroxy-2-cyclohexanone derivatives , was achieved, starting from a common cyclohexenone, through asymmetric transfer hydrogenation (ATH) reactions using bifunctional ruthenium catalysts. From these versatile intermediates, a stereoselective route to a cytosine analogue built on a bicyclo [4.1.
View Article and Find Full Text PDFFour cationic chiral amino acid-based surfactants, - and - and - and -, have been studied as DNA-condensing agents with enhanced properties and the absence of cell toxicity. The polar head of the surfactant is made of a cyclobutane β-amino acid in which the amino group is a hydrochloride salt and the carboxyl group is involved in an amide bond, allowing the link with hydrophobic C (surfactant ) or C (surfactant ) chains. The ability of these surfactants to condense DNA was investigated using a dye exclusion assay, gel electrophoresis, and circular dichroism and compared with the well-studied dodecyltrimethylammonium bromide (DTAB) and cetyltrimethylammonium bromide (CTAB).
View Article and Find Full Text PDFA new family of hybrid β,γ-peptidomimetics consisting of a repetitive unit formed by a chiral cyclobutane-containing -β-amino acid plus a -functionalized -γ-amino-l-proline joined in alternation were synthesized and evaluated as cell penetrating peptides (CPP). They lack toxicity on the human tumoral cell line HeLa, with an almost negligible cell uptake. The dodecapeptide showed a substantial microbicidal activity on parasites at 50 µM but with a modest intracellular accumulation.
View Article and Find Full Text PDFThe stability constants of Mn complexes with ligands containing a trans-1,2-cyclobutanediamine spacer functionalized with picolinate and/or carboxylate functions were determined using potentiometric titrations (25 °C, 0.1 M KCl). The stability constant of the complex with a hexadentate ligand containing four acetate groups (L1, log K = 10.
View Article and Find Full Text PDFTwo series of new hybrid γ/γ-peptides, γ-CC and γ-CT, formed by (1,2)-3-amino-2,2,dimethylcyclobutane-1-carboxylic acid joined in alternation to a -functionalized - or -γ-amino-l-proline derivative, respectively, have been synthesized and evaluated as cell penetrating peptides (CPP) and as selective vectors for anti- drug delivery systems (DDS). They lacked cytotoxicity on the tumoral human cell line HeLa with a moderate cell-uptake on these cells. In contrast, both γ-CC and γ-CT tetradecamers were microbicidal on the protozoan parasite beyond 25 μM, with significant intracellular accumulation.
View Article and Find Full Text PDFIn an effort to explore novel ligand scaffolds for stable and inert lanthanide complexation in magnetic resonance imaging contrast agent research, three chiral ligands containing a highly rigid (1,2)-1,2-cyclobutanediamine spacer and different number of acetate and picolinate groups were efficiently synthesized. Potentiometric studies show comparable thermodynamic stability for the Gd complexes formed with either the octadentate (L3) bearing two acetate or two picolinate groups or the heptadentate (L2) analogue bearing one picolinate and three acetate groups (log = 17.41 and 18.
View Article and Find Full Text PDFEfficient and versatile synthetic methodologies are reported for the preparation of products that are suitable candidates to be used as surfactants, gelators for hydroxylic solvents or metal cation ligands, with potential use in several fields including biomedical applications. The common structural feature of all the synthesized products is the presence of a or -1,2- or -1,3-difunctionalized cyclobutane ring. In the two first cases, the key intermediates including enantiomerically pure 1,3-diamines and 1,3-amino alcohols have been prepared from β-amino acid derivatives obtained, in turn, from a chiral half-ester.
View Article and Find Full Text PDFNew enantiomerically pure C-alkyl diamides derived from trihydroxy cyclohexane-1,2-dicarboxylic acid have been synthesized from (-)-shikimic acid. The hydroxyl groups in these compounds are free or, alternatively, they present full or partial protection. Their gelling abilities towards several solvents have been tested and rationalized by means of the combined use of Hansen solubility parameters, scanning electron microscopy (SEM), and circular dichroism (CD), as well as computational calculations.
View Article and Find Full Text PDFCationic bolaamphiphiles have been synthesized starting from meso cis- or chiral trans-1,2-difunctionalized cyclobutane derivatives. They include cis/trans pairs of diastereoisomers, of N- or C-centered bisamides. The goal of this work was to investigate the influence of stereochemistry and regiochemistry on their abilities as surfactants and self-assembly.
View Article and Find Full Text PDFSeveral α,β,α- or α,γ,α-tripeptides, consisting of a central cyclobutane β- or γ-amino acid being flanked by two d- or l-proline residues, have been synthesized and tested as organocatalysts in asymmetric aldol additions. High yields and enantioselectivities have been achieved with α,γ,α-tripeptides, being superior to peptides containing a cyclobutane β-amino acid residue. This is probably due to their high rigidity, which hinders some of the peptide catalysts to adopt the proper active conformation.
View Article and Find Full Text PDFEnantiomerically pure C -alkyl amides derived from cis and trans cycloalkane-1,2-dicarboxylic acids, respectively, have been synthesized and their behavior as organogelators has been investigated. These compounds include cis/trans diastereomeric cyclobutane and cyclohexane derivatives with the aim to explore the influence of the ring size as well as the relative configuration in their hierarchical self-assembly to form gels. High resolution H NMR spectroscopy studies allowed the determination of the dynamics of the gelation process in [D ]toluene and the sol-gel transition temperature.
View Article and Find Full Text PDFNew diastereomeric nonionic amphiphiles, cis- and trans-1, based on an optically pure cyclobutane β-amino ester moiety have been investigated to gain insight into the influence exerted by cis/trans stereochemistry and stereochemical constraints on the physicochemical behavior, molecular organization, and morphology of their Langmuir monolayers and dry solid states. All these features are relevant to the rational design of functional materials. trans-1 showed a higher thermal stability than cis-1.
View Article and Find Full Text PDFNovel diastereomeric anionic amphiphiles based on the rigid cyclobutane β-amino acid scaffold have been synthesized and deeply investigated with the aim of generating new functional supramolecular architectures on the basis of the rational design of original amphiphilic molecules and the control of their self-assembly. The main interest has been focused on the effect that cis/trans stereochemistry exerts on their molecular organization and recognition. In diluted solutions, the relative stereochemistry mainly influences the headgroup solvation and anionic-charge stabilization, i.
View Article and Find Full Text PDFNeuropeptide Y (NPY) and pancreatic polypeptide (PP) control central and peripheral processes by activating the G protein coupled receptors YxR (x = 1, 2, 4, 5). We present analogs of the C-terminal fragments 25-36 and 32-36 of NPY and PP containing (1R,2S)-cyclobutane (βCbu) or (1R,2S)-cyclopentane (βCpe) β-amino acids, which display exclusively Y4R affinity. In particular, [βCpe(34)]-NPY-(25-36) is a Y4R selective partial agonist (EC50 41 ± 6 nM, Emax 71%) that binds Y4R with a Ki of 10 ± 2 nM and a selectivity >100-fold relative to Y1R and Y2R and >50-fold relative to Y5R.
View Article and Find Full Text PDFThe chiral sulfide, isothiocineole, has been synthesized in one step from elemental sulfur, γ-terpinene, and limonene in 61% yield. A mechanism involving radical intermediates for this reaction is proposed based on experimental evidence. The application of isothiocineole to the asymmetric epoxidation of aldehydes and the aziridination of imines is described.
View Article and Find Full Text PDFSome hybrid tetrapeptides consisting of (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, β-alanine, or γ-aminobutyric acid (GABA) joined in alternation, compounds 1-3, respectively, have been investigated to gain information on the non-covalent interactions responsible for their self-assembly to form ordered aggregates, as well as on parameters such as their morphology and size. All three peptides formed nice gels in many organic solvents and significant difference in their behaviour was not observed. Scanning electron microscopy (SEM) and circular dichroism (CD) pointed out that peptide 1, which contains the shortest C2 linear residue, presented the most defined fibril network and afforded nanoscale helical aggregates.
View Article and Find Full Text PDFThe four stereoisomers of protected cyclobutane-1,2-diamine have been prepared in an enantio- and diastereocontrolled manner through stereodivergent synthetic routes starting from a half-ester as a common chiral precursor. Orthogonal protection allows the chemoselective manipulation of both amino groups as shown in this work.
View Article and Find Full Text PDFTwo generations of hybrid γ,γ-peptides containing cyclobutane amino acids and cis-γ-amino-L-proline joined in alternation have been synthesized and their capacity to cross the eukaryotic cell membrane has been evaluated. The first generation consists of di-, tetra- and hexapeptides, and their properties have been analyzed as well as the influence of peptide length and chirality of the cyclobutane residues. Results have shown that the absolute configuration of the cyclobutane amino acid does not have a relevant influence.
View Article and Find Full Text PDFSeveral oligomers constructed with (1R,2S)-2-aminocyclobutane-1-carboxylic acid and glycine, β-alanine, and γ-amino butyric acid (GABA), respectively, joined in alternation have been synthesized and studied by means of NMR and CD experiments as well as with computational calculations. Results account for the spacer length effect on folding and show that conformational preference for these hybrid peptides can be tuned from β-sheet-like folding for those containing a C(2) or C(4) linear segment to a helical folding for those with a C(3) spacer between cyclobutane residues. The introduction of cyclic spacers between these residues does not modify the extended ribbon-type structure previously manifested in poly(cis-cyclobutane) β-oligomers.
View Article and Find Full Text PDFTwo diastereomeric series of hybrid γ,γ-peptides derived from conveniently protected derivatives of (1R,2S)- and (1S,2R)-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid and cis-4-amino-L: -proline joined in alternation have efficiently been prepared through convergent synthesis. High-resolution NMR experiments show that these compounds present defined conformations in solution affording very compact structures as the result of intra and inter residue hydrogen-bonded ring formation. (R,S)-cyclobutane containing peptides adopt more twisted conformations than (S,R) diastereomers.
View Article and Find Full Text PDFFive new highly functionalized cyclobutane containing C(3)-symmetric peptide dendrimers have been synthesized through a convergent approach from 1,3,5-trisubstituted benzene and chiral gamma,epsilon-amino diacid derivatives as well as a gamma-tetrapeptide. The first example of the synthesis of N-centered amides by using 1,3,5-triaminobenzene and a carboxylic acid is reported.
View Article and Find Full Text PDFHeating one of the most abundant naturally occurring inorganic chemicals (elemental sulfur) with one of the most readily available homochiral molecules (limonene) gives a one-step synthesis of a chiral sulfide which exhibits outstanding selectivities in sulfur ylide mediated asymmetric epoxidations and aziridinations. In particular reactions of benzyl and allylic sulfonium salts with both aromatic and aliphatic aldehydes gave epoxides with perfect enantioselectivities and the highest diastereoselectivities reported to date. In addition reactions with imines gave aziridines again with the highest enantioselectivities and diastereoselectivities reported to date.
View Article and Find Full Text PDFChiral nonracemic thiomorpholines have been synthesized in four to six steps from limonene or achiral alkenes using alpha-methylbenzylamine to control absolute stereochemistry. These aminosulfides have been used to generate sulfur ylides, which have been applied in the asymmetric epoxidation of aldehydes as easily recoverable catalysts. Excellent yields (up to 98 %), enantioselectivities (up to 97:3 e.
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