Flexible and Convergent Enantioselective Total Synthesis of (R)-Juglanaloids A and B: Two Phthalide Spiro Alkaloids with Potential Alzheimer's Disease Inhibitory Activity.

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.

1,2,3-Triazole-containing azamacrocycles from chiral triazolopeptoids: synthesis and solid-state studies.

Two new chiral 1,2,3-triazole-containing macrocyclic oligoamides (i.e.: triazolopeptoid 4 and 5) were obtained through solid-phase synthesis of linear precursors followed by high dilution macrocyclization reaction. Theoretical (DFT) and spectroscopic (NMR) studies revealed the intricate interplay between the Na-chiral side chains and their conformational attitudes. BH3-mediated reduction of the tertiary amide groups of known 1-3 and newly synthesized 4 gave novel azamacrocycles 6-9. Detection of borane complexes of azamacrocycles 6 and 9 (i.e.: 10 and 11), corroborated by X-ray diffraction studies, demonstrated the peculiar properties of 1,2,3-triazole-containing macrorings.

Deconstructing Best-in-Class Neoglycoclusters as a Tool for Dissecting Key Multivalent Processes in Glycosidase Inhibition.

Multivalency represents an appealing option to modulate selectivity in enzyme inhibition and transform moderate glycosidase inhibitors into highly potent ones. The rational design of multivalent inhibitors is however challenging because global affinity enhancement relies on several interconnected local mechanistic events, whose relative impact is unknown. So far, the largest multivalent effects ever reported for a non-polymeric glycosidase inhibitor have been obtained with cyclopeptoid-based inhibitors of Jack bean α-mannosidase (JBα-man). Here, we report a structure-activity relationship (SAR) study based on the top-down deconstruction of best-in-class multivalent inhibitors. This approach provides a valuable tool to understand the complex interdependent mechanisms underpinning the inhibitory multivalent effect. Combining SAR experiments, binding stoichiometry assessments, thermodynamic modelling and atomistic simulations allowed us to establish the significant contribution of statistical rebinding mechanisms and the importance of several key parameters, including inhitope accessibility, topological restrictions, and electrostatic interactions. Our findings indicate that strong chelate-binding, resulting from the formation of a cross-linked complex between a multivalent inhibitor and two dimeric JBα-man molecules, is not a sufficient condition to reach high levels of affinity enhancements. The deconstruction approach thus offers unique opportunities to better understand multivalent binding and provides important guidelines for the design of potent and selective multiheaded inhibitors.

The Antimicrobial, Antibiofilm and Anti-Inflammatory Activities of P13#1, a Cathelicidin-like Achiral Peptoid.

Cationic antimicrobial peptides (CAMPs) are powerful molecules with antimicrobial, antibiofilm and endotoxin-scavenging activities. These properties make CAMPs very attractive drugs in the face of the rapid increase in multidrug-resistant (MDR) pathogens, but they are limited by their susceptibility to proteolytic degradation. An intriguing solution to this issue could be the development of functional mimics of CAMPs with structures that enable the evasion of proteases. Peptoids (N-substituted glycine oligomers) are an important class of peptidomimetics with interesting benefits: easy synthetic access, intrinsic proteolytic stability and promising bioactivities. Here, we report the characterization of P13#1, a 13-residue peptoid specifically designed to mimic cathelicidins, the best-known and most widespread family of CAMPs. P13#1 showed all the biological activities typically associated with cathelicidins: bactericidal activity over a wide spectrum of strains, including several ESKAPE pathogens; the ability to act in combination with different classes of conventional antibiotics; antibiofilm activity against preformed biofilms of Pseudomonas aeruginosa, comparable to that of human cathelicidin LL-37; limited toxicity; and an ability to inhibit LPS-induced proinflammatory effects which is comparable to that of "the last resource" antibiotic colistin. We further studied the interaction of P13#1 with SDS, LPSs and bacterial cells by using a fluorescent version of P13#1. Finally, in a subcutaneous infection mouse model, it showed antimicrobial and anti-inflammatory activities comparable to ampicillin and gentamicin without apparent toxicity. The collected data indicate that P13#1 is an excellent candidate for the formulation of new antimicrobial therapies.

Water-Soluble Chiral Cyclic Peptoids and Their Sodium and Gadolinium Complexes: Study of Conformational and Relaxometric Properties.

Cyclic peptoids are macrocyclic oligomers of N-substituted glycines with specific folding abilities and excellent metal binding properties. In this work, we show how strategic positioning of chiral (S)- and (R)-(1-carboxyethyl)glycine units influences the conformational stability of water-soluble macrocyclic peptoids as sodium complexes. The reported results are based on nuclear magnetic resonance spectroscopy, extensive computational studies, and X-ray diffraction analysis using single crystals grown from aqueous solutions. The studies include 1H relaxometric investigations of hexameric cyclic peptoids in the presence of the Gd3+ ion to assess their thermodynamic stabilities and relaxivities.

Macrocyclic Triazolopeptoids: A Promising Class of Extended Cyclic Peptoids.

Head-to-tail cyclization of linear oligoamides containing 4-benzylaminomethyl-1H-1,2,3-triazol-1-yl acetic acid monomers afforded a novel class of "extended macrocyclic peptoids". The identification of the conformation in solution for a cyclodimer and the X-ray crystal structure of a cyclic tetraamide are reported.

Right- and left-handed PPI helices in cyclic dodecapeptoids.

Enantiomorphic right- and left-handed polyproline type I helices in four cyclic dodecapeptoids with methoxyethyl and propargyl side chains are observed for the first time by single crystal X-ray diffraction. The peculiar absence of NH⋯OC hydrogen bonds in peptoids unveils the role of intramolecular backbone-to-backbone CO⋯CO interactions and CH⋯OC hydrogen bonds in the stabilization of the macrocycle conformation. Moreover, intramolecular backbone-side chain C5 CH⋯OC hydrogen bonds emerge as a stabilizing factor.

Structural dynamism of chiral sodium peraza-macrocycle complexes derived from cyclic peptoids.

A variety of cyclen and hexacyclen derivatives decorated with (S)-1-phenylethyl side chains or (S)-pyrrolidine units have been prepared via a reductive approach from the corresponding cyclic peptoids containing N-(S)-(1-phenylethyl)glycine and l-proline residues. Spectroscopic and DFT studies on their Na+ complexes show that point chirality and ring size play a crucial role in controlling the structural dynamism of 1,2-diaminoethylene units and pendant arms. The detection of highly symmetric C4- and C3-symmetric metalated species demonstrates that a full understanding of the relationship between the structure and conformational properties of peraza-macrocyclic metal complexes is possible.

Propyne Gas Adsorption in a Cyclic Hexapeptoid: A Combined In Situ XRPD and DFTB Study*.

Cyclic peptoids are macrocyclic N-substituted oligoglycines, with remarkable structural, chemical and physical properties. The gas adsorption properties of a permanently porous hexameric cyclopeptoid decorated with four propargyl and two methoxyethyl side chains were monitored by in situ X-ray powder diffraction (XRPD). High-resolution XRPD data together with Rietveld and density functional based tight binding (DFTB) method allowed us to locate propyne guest molecules inside the host channels, even though the powder sample contains more than one phase. We were able to characterize the host-guest interactions, providing useful information on the host recognition sites and discuss host adaptiveness and host-guest chemical affinity in comparison with analogous compounds.

An Entry to Enantioenriched 3,3-Disubstituted Phthalides through Asymmetric Phase-Transfer-Catalyzed γ-Alkylation.

A novel asymmetric phase-transfer-catalyzed γ-alkylation of phthalide 3-carboxylic esters has been developed, giving access to 3,3-disubstituted phthalide derivatives, which present a chiral quaternary γ-carbon in good to excellent yields and good enantioselectivities (74-88% ee). The enantiomeric purity could be substantially enhanced to 94-95% ee by recrystallization. Both electron-withdrawing and electron-releasing substituents are well tolerated on the phthalide core as well as on the aromatic moiety of the alkylating agent. This methodology, enabling the introduction of an unfunctionalized group at the phthalide γ-position, fully complements previously reported organocatalytic strategies involving functionalized electrophiles, thus expanding the scope of accessible 3,3-disubstituted products. The high synthetic value of this asymmetric reaction has been proven by the formal synthesis of the naturally occurring alkaloid (+)-(9S,13R)-13-hydroxyisocyclocelabenzine.

Peptoid-based siderophore mimics as dinuclear Fe3+ chelators.

A practical synthesis of preorganized tripodal enterobactin/corynebactin-type ligands (consisting of a C3-symmetric macrocyclic peptoid core, three catecholamide coordinating units, and C2, C4, and C6 spacers) is reported. The formation of complexes with Fe3+ was investigated by spectrophotometric (UV-Vis) and spectrometric (ESI, negative ionization mode) methods and corroborated by theoretical (DFT) calculations. Preliminary studies revealed the intricate interplay between the conformational chirality of cyclic trimeric peptoids and metal coordination geometry of mononuclear species similar to that of natural catechol-based siderophores. Experimental results demonstrated the unexpected formation of unique dinuclear Fe3+ complexes.

From Cyclic Peptoids to Peraza-macrocycles: A General Reductive Approach.

Peraza-macrocycles form chelates of high thermodynamic and kinetic stability useful in diagnostic imaging (MRI, SPECT, PET), in coordination chemistry, and as catalysts. In this letter, we report an advantageous method to prepare these compounds via BH3-induced reduction of cyclic peptoids. Using this procedure, 10 homo- and heterosubstituted aza-coronands, with different sizes and side chains, have been synthesized from the corresponding cyclic oligoamides. Solid structures of free, protonated, and Na+ coordinated polyaza-derivatives have been disclosed by single-crystal X-ray diffraction analysis.

Reverse Turn and Loop Secondary Structures in Stereodefined Cyclic Peptoid Scaffolds.

Controlling the network of intramolecular interactions encoded by Nα-chiral side chains and the equilibria between cis- and trans-amide junctions in cyclic peptoid architectures constitutes a significant challenge for the construction of stable reverse turn and loop structures. In this contribution, we reveal, with the support of NMR spectroscopy, single-crystal X-ray crystallography and density functional theory calculations, the relevant noncovalent interactions stabilizing tri-, tetra-, hexa-, and octameric cyclic peptoids (as free hosts and host-guest complexes) with strategically positioned N-(S)-(1-phenylethyl)/N-benzyl side chains, and how these interactions influence the backbone topological order. With the help of theoretical models and spectroscopic/diffractometric studies, we disclose new γ-/ß-turn and loop structures present in α-peptoid-based macrocycles and classify them according ϕ, ψ, and ω torsion angles. In our endeavor to characterize emergent secondary structures, we solved the solid-state structure of the largest metallated cyclic peptoid ever reported, characterized by an unprecedented alternated cis/trans amide bond linkage. Overall, our results indicate that molecules endowed with different elements of asymmetry (central and conformational) provide new architectural elements of facile atroposelective construction and broad conformational stability as the minimalist scaffold for novel stereodefined peptidomimetic foldamers and topologically biased libraries necessary for future application of peptoids in all fields of science.

Unprecedented Diastereoselective Arylogous Michael Addition of Unactivated Phthalides.

The first highly enantioselective arylogous Michael reaction (AMR) of 3-unsubstituted phthalides has been described. This phase-transfer methodology, which uses catalytic amounts of KOH/18-crown-6 catalyst in mesitylene in the presence of N,O-bis(trimethylsilyl)acetamide (BSA), gives access to a broad range of 3-monosubstituted phthalides with high levels of syn diastereoselectivity and good yields, starting from 3-unsubstituted derivatives and diverse α,ß-unsaturated carbonyl compounds. The reaction also applies to unactivated 3-alkyl phthalides to afford 3,3-dialkyl derivatives. A plausible mechanism has been suggested. DFT analysis of possible transition states gives a rationale of the high syn diastereoselectivity observed and its correlation with the solvent's dielectric constant.

Cation-Induced Molecular Switching Based on Reversible Modulation of Peptoid Conformational States.

Peptoids are oligomers of N-substituted glycines with predictable folding and strong potentials as guest-binding receptor molecules. In this contribution, we investigate the structural features of a series of designed symmetric cyclic octamer peptoids (with methoxyethyl/propargyl side chains) as free hosts and reveal their morphologic changes in the presence of sodium and alkylammonium guests as tetrakis[3,5-bis(trifluoromethyl)phenyl]borate salts, reporting the first case of reversible adaptive switching between defined conformational states induced by cationic guests (Na+ and benzylammonium ion) in the peptoid field. The reported results are based on 1H NMR data, theoretical models, and single-crystal X-ray diffraction analysis. They represent initial steps toward deciphering the unique conformational states of cyclic octamer peptoids as supramolecular hosts with the aim to fully disclose their functional and dynamic properties.

Cyclic Octamer Peptoids: Simplified Isosters of Bioactive Fungal Cyclodepsipeptides.

Cyclic peptoids have recently emerged as an important class of bioactive scaffolds with unique conformational properties and excellent metabolic stabilities. In this paper, we describe the design and synthesis of novel cyclic octamer peptoids as simplified isosters of mycotoxin depsipeptides bassianolide, verticilide A1, PF1022A and PF1022B. We also examine their complexing abilities in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) salt and explore their general insecticidal activity. Finally, we discuss the possible relationship between structural features of free and Na⁺-complexed cyclic octamer peptoids and bioactivities in light of conformational isomerism, a crucial factor affecting cyclic peptoids' biomimetic potentials.

Structural Basis of Outstanding Multivalent Effects in Jack Bean α-Mannosidase Inhibition.

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean α-mannosidase (JBα-man) in apo and inhibited states. The three-dimensional structure of JBα-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.

Cyclic Peptoids as Topological Templates: Synthesis via Central to Conformational Chirality Induction.

Chiral induction was utilized for the synthesis of diastereopure cyclic peptoids containing an N-benzyl alanine residue. Molecular modeling, NMR spectroscopy, single-crystal X-ray diffraction studies, and HPLC with chiral stationary phase demonstrated easy formation of free and sodium/benzylammonium complexed cyclic oligomers through strategic incorporation of a single stereogenic center in the oligomeric backbone. The synthesis of cyclic peptoids with defined conformational chirality and appropriate side chain topology is now possible.

Cyclic Peptoids as Mycotoxin Mimics: An Exploration of Their Structural and Biological Properties.

Cyclic peptoids have recently emerged as important examples of peptidomimetics for their interesting complexing properties and innate ability to permeate biological barriers. In the present contribution, experimental and theoretical data evidence the intricate conformational and stereochemical properties of five novel hexameric peptoids decorated with N-isopropyl, N-isobutyl, and N-benzyl substituents. Complexation studies by NMR, in the presence of sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaTFPB), theoretical calculations, and single-crystal X-ray analyses indicate that the conformationally stable host/guest metal adducts display architectural ordering comparable to that of the enniatins and beauvericin mycotoxins. Similarly to the natural depsipeptides, the synthetic oligolactam analogues show a correlation between ion transport abilities in artificial liposomes and cytotoxic activity on human cancer cell lines. The reported results demonstrate that the versatile cyclic peptoid scaffold, for its remarkable conformational and complexing properties, can morphologically mimic related natural products and elicit powerful biological activities.

Highly Diastereoselective Crown Ether Catalyzed Arylogous Michael Reaction of 3-Aryl Phthalides.

The first arylogous Michael reaction of 3-aryl phthalides has been developed. The reaction, promoted by catalytic amounts of KOH or K3PO4 and dibenzo-18-crown-6, affords the corresponding 3,3-disubstituted phthalides in good to high yields and as single diastereomers in nearly all studied cases.