Sesterterpenoids: sources, structural diversity, biological activity, and data management.

Reviewing the literature published up to October 2024.Sesterterpenoids are one of the most chemically diverse and biologically promising subgroup of terpenoids, the largest family of secondary metabolites. The present review article summarizes more than seven decades of studies on isolation and characterization of more than 1600 structurally novel sesterterpenoids, supplemented by biological, pharmacological, ecological, and geographic distribution data.

Flexible and Convergent Enantioselective Total Synthesis of ()-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.

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.

Macrocyclic Triazolopeptoids: A Promising Class of Extended Cyclic Peptoids.

Head-to-tail cyclization of linear oligoamides containing 4-benzylaminomethyl-1-1,2,3-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 C- and C-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.

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.

Peptoid-based siderophore mimics as dinuclear Fe chelators.

A practical synthesis of preorganized tripodal enterobactin/corynebactin-type ligands (consisting of a C-symmetric macrocyclic peptoid core, three catecholamide coordinating units, and C, C, and C spacers) is reported. The formation of complexes with Fe 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.

Asymmetric trifluoromethylthiolation of azlactones under chiral phase transfer catalysis.

The first enantioselective method for the installation of the SCF3 group at the C-4 position of azlactones is described in the present communication under quinidinium phase transfer catalysis. The higher performance of substrates containing electron-rich 2-aryl groups at the azlactone was rationalized using DFT calculations.

Antibacterial and ATP Synthesis Modulating Compounds from .

A surface extract of the aerial parts of afforded a nor-sesterterpenoid () and eight new sesterterpenoids (-̵), along with five known sesterterpenoids, five labdane and one abietane diterpenoid, one sesquiterpenoid, and four flavonoids. The structures of the new compounds were established by 1D and 2D NMR spectroscopy, HRESIMS, and VCD data and Mosher's esters analysis. The antimicrobial activity of compounds was evaluated against 30 human pathogens including 27 clinical strains and three isolates of marine origin for their possible implications on human health.

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 BH-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.

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

Controlling the network of intramolecular interactions encoded by α-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 -()-(1-phenylethyl)/-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-/β-turn and loop structures present in α-peptoid-based macrocycles and classify them according ϕ, ψ, and ω torsion angles.

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,β-unsaturated carbonyl compounds. The reaction also applies to unactivated 3-alkyl phthalides to afford 3,3-dialkyl derivatives.

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 H NMR data, theoretical models, and single-crystal X-ray diffraction analysis.

Tuning the biomimetic performances of 4-hydroxyproline-containing cyclic peptoids.

Five new cyclic peptoids containing (2S,4R)-4-hydroxyproline (Hyp) residues have been designed and synthesized using a mixed "submonomer/monomer" approach. Alkali metal cation affinities and ion transport activities were assessed by experimental (NMR and HPTS assay in liposomes) and computational methods. Easy functionalization of hydroxyproline residues afforded a bouquet of cyclic oligomers showing correlation between ion transport abilities and cytotoxic activities on selected human cancer cell lines.

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.

Chimeric XNA: An Unconventional Design for Orthogonal Informational Systems.

The paradigm of homogenous-sugar-backbone of RNA and DNA has reliably guided the construction of many functional and useful xeno nucleic acid (XNA) systems to date. Deviations from this monotonous and canonical design, in many cases, results in oligonucleotide systems that lack base pairing with themselves, or with RNA or DNA. Here we show that nucleotides of two such compromised XNA systems can be combined with RNA and DNA in specific patterns to produce chimeric-backbone oligonucleotides, which in certain cases demonstrate base pairing properties comparable to-or stronger than-canonical systems, while also altering the conventional Watson-Crick pairing behavior.

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.

Topologically Diverse Shapes Accessible by Modular Design of Arylopeptoid Macrocycles.

N-Substituted aromatic cyclooligoamides composed of different combinations of ortho-, meta-, and/or para-arylopeptoid residues carrying methoxyethyl side chains have been efficiently synthesized by macrocyclization of the corresponding linear oligomers. The study of the architectures of these macrocycles in solution and solid state has revealed that tetracyclic arylopeptoids adopt sequence-dependent shapes with different backbone amide conformations and side-chain orientations. Remarkably, despite the absence of intramolecular H-bonding ability, some of these arylopeptoid macrocycles show well-defined architectures in solution.

Conformational isomerism in cyclic peptoids and its specification.

Most of the structural studies made on the secondary structure of peptoids describe their geometric attributes in terms of the classic Ramachandran plot (based on the local analysis of ω, ψ, χ, φ dihedral angles). However, little intuitive understanding is available from internal coordinates when stereochemistry is involved. In this contribution we list all the conformationally stable cyclic peptoids reported up to the year 2017 and propose a simple method to define their geometric arrangement in terms of planar chirality.

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 KPO 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.