Impact of Indole Inclusion in the Design of Multi-Tactical Metal-Binding Tetra-Aza Macrocycles that Target the Molecular Features of Neurodegeneration.

Numerous small molecules have been studied for their ability to counteract oxidative stress, a key contributor to neurodegenerative diseases such as Alzheimer's. Despite these efforts, the pharmacological properties and structure-activity relationships of these compounds remain insufficiently understood, yet they are critical in evaluating a drug molecule's therapeutic potential. A modified tetra-aza macrocycle has demonstrated strong antioxidant activity through various mechanisms; however, its limited permeability presents challenges for advanced formulation studies. To enhance permeability while preserving the beneficial reactivity of the parent molecule, two synthetic modifications involving indole functionality were explored and compared to modifications using methyl groups alone. New synthetic strategies were developed to produce the indole-containing molecules, which were characterized by 1D/2D NMR techniques. Isoelectric points, metal binding, and radical scavenging activity were determined to validate that the reactivity of the parent molecules was retained. The permeability of all molecules explored was improved. Protection against oxidative stress through activation of the Nrf2 pathway was demonstrated for molecules containing indoles in cellular models by measuring ROS levels upon treatment and mRNA levels of HO-1 and Nrf2. In contrast, no protection or Nrf2 activation was observed with the methylation of the O- or N atom. These results suggest that while alkylation improves permeability overall, concomitant antioxidant protection and positive permeability are achieved with the indole congeners alone.

Preferential Formation of Three-layered Host-Guest Complexes of a Planar Dinuclear Metallohost with Alkali Metal Ions.

We synthesized a planar macrocyclic dinuclear nickel(II) metallohost from the corresponding macrocyclic imine ligand containing two N2O2 chelate coordination sites and an O6 cation binding site like 18-crown-6 as well as peripheral hexyl groups. Due to the lipophilic nature of the hexyl groups, the metallohost was soluble in less polar media where its interaction with alkali metal ions was enhanced. The binding studies by NMR spectroscopy clearly showed its strong tendency to form multi-layered structures. The metallohost formed 2:1 and 1:1 (host/guest) complexes with Na+ with the two-step binding constants of logK1 = 6.6 and logK2 = 3.0. In contrast, its complexation with larger alkali metal ions (K+, Rb+, Cs+) preferentially gave 3:2 (host/guest) complexes when 2/3 equiv of the guest was present. The three-layered structures of these 3:2 complexes were well characterized by mass spectrometry and 2D COSY/ROESY experiments as well as DFT calculations, elucidating their unique structural feature with three chemically different environments due to the oppositely curved two [Ni(saloph)] moieties of the metallohost. Therefore, the three-layered structures were preferentially formed when larger alkali metal ions (K+, Rb+, Cs+) were complexed with the metallohost.

Cyclization by Intramolecular Suzuki-Miyaura Cross-Coupling - A Review.

Ring systems of all sizes are frequent core or substructures in natural products and they are important elements of many drug molecules, as they often confer high binding affinity to and selectivity for disease-relevant biological targets. A uniform key transformation in the synthesis of such structures is the cyclization step. Among the various approaches that have been developed for ring closure, the intramolecular Suzuki-Miyaura reaction has emerged as a powerful option for the construction of normal- and medium-sized rings as well as macrocycles, due to its stereospecificity, the mild reaction conditions, and the non-toxic nature of the boron by-products. In this review, we summarize the state-of-the-art of the application of intramolecular Suzuki-Miyaura cross-coupling reactions in the construction of (macro)cyclic frameworks of natural products and bioactive molecules of synthetic origin, covering (mostly) examples that have been reported since 2015. Target molecules prepared via intramolecular Suzuki-Miyaura cross-coupling as a key step range from natural products / natural product analogs to synthetic drug candidates, featuring ring sizes from 4 to >>12. We highlight the utility, scope, and limitations of the reaction for different ring sizes and arrays of functional groups. Where possible, comparisons with other methods of cyclization are provided.

Catalytic Enantioselective Synthesis of Planar Chiral Pillar[5]arenes via Asymmetric Sonogashira Coupling.

As a novel type of macrocycles with attractive planar chirality, pillar[5]arenes have gained increasing research interest over the past decades, enabling their widespread applications in diverse fields such as porous materials, molecular machines, and chiral luminescence materials. However, the catalytic methodology towards the enantioselective synthesis of planar chiral pillar[5]arenes remains elusive. Here we report a novel method for the enantioselective synthesis of planar chiral pillar[5]arenes via asymmetric Sonogashira coupling, giving access to a wide range of highly functionalized planar chiral pillar[5]arenes, including both homo- and hetero-rimmed ones, with excellent enantioselectivities. Attractively, the resultant planar chiral pillar[5]arenes show great potential for widespread use in many areas such as chiral luminescent materials. This work not only enables the successful synthesis of planar chiral pillar[5]arenes with abundant structural and functional diversity as key building blocks for practical applications but also enriches the asymmetric cross-coupling methodologies in organic synthetic chemistry.

The Preparation and Crystal Structures of Octaoxoketocalix[8]arene Derivatives: The Ketocalixarene Counterparts of the Largest "Major" Calixarene.

The purpose of this study was to synthesize and structurally characterize ketocalixarenes (i.e., calixarenes where the bridging methylene bridges are replaced by carbonyl groups) derived from the largest "major" calixarene, namely p-tert-butylcalix[8]arene 3a. Ketocalix[8]arenes were synthesized by the oxidation of protected p-tert-butylcalix[8]arene derivatives. Octamethoxy-p-tert-butylketocalix[8]arene 6b was prepared by the photochemical reaction of the calixarene 3b with NBS in a CHCl3/H2O mixture. The oxidation of the methylene groups of octaacetoxy-p-tert-butylcalix[8]arene 3c was conducted by a reaction with CrO3 in Ac2O/AcOH. The basic hydrolysis of the acetate groups of the oxidation product yielded octahydroxy-p-tert-butylketocalix[8]arene 6a. In the crystal, the molecule adopts a saddle-like conformation of crystallographic C2 and idealized S4 symmetry. Strikingly, the array of OH/OH intramolecular hydrogen bonds present in the parent 3a is completely disrupted in 6a.

Deep-Cavity Calix[4]naphth[4]arene Macrocycles: Synthesis, Conformational Features, and Solid-State Structures.

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C4N4) and its permethylated analog (C4N4-Me), thereby expanding the calix[n]naphth[m]arene family. C4N4 was synthesized through a 2 + 2 fragment coupling macrocyclization under acidic conditions, where the solvent played a crucial role in selectively forming the C4N4 derivative. The X-ray structure of C4N4 reveals a chair-like 1,2,3,4-alternate conformation characterized by two opposing 3/4-cone moieties stabilized by intramolecular hydrogen bonds. In contrast, the X-ray structure of C4N4-Me exhibits a 1,3,5,7-alternate conformation.

Adsorption and separation technologies based on supramolecular macrocycles for water treatment.

The escalating challenges in water treatment, exacerbated by climate change, have catalyzed the emergence of innovative solutions. Novel adsorption separation and membrane filtration methodologies, achieved through molecular structure manipulation, are gaining traction in the environmental and energy sectors. Separation technologies, integral to both the chemical industry and everyday life, encompass concentration and purification processes. Macrocycles, recognized as porous materials, have been prevalent in water treatment due to their inherent benefits: stability, adaptability, and facile modification. These structures typically exhibit high selectivity and reversibility for specific ions or molecules, enhancing their efficacy in water purification processes. The progression of purification methods utilizing macrocyclic frameworks holds promise for improved adsorption separations, membrane filtrations, resource utilization, and broader water treatment applications. This review encapsulates the latest breakthroughs in macrocyclic host-guest chemistry, with a focus on adsorptive and membrane separations. The aim is to spotlight strategies for optimizing macrocycle designs and their subsequent implementation in environmental and energy endeavors, including desalination, elemental extraction, seawater energy harnessing, and sustainable extraction. Hopefully, this review can guide the design and functionality of macrocycles, offering a significantly promising pathway for pollutant removal and resource utilization.

Highly Twisted Fenestrindane-Based Porous Nanographenes.

Two fenestrindane-based porous nanographenes containing four polyaromatic macrocycles in a highly twisted, basically S4-symmetric conformation were synthesized and characterized by NMR spectroscopy and mass spectrometry. Stepwise π-extension at the periphery of the fenestrindane core by a sequence of eightfold Suzuki-Miyaura cross-coupling, fourfold Scholl cyclodehydrogenation and another eightfold Suzuki-Miyaura reaction affords the porous nanographene precursors in good yields. In the last step, fourfold intramolecular Yamamoto coupling generates the porous nanographenes in 17-18% yield. Their optical and electronic properties were studied by UV/Vis and fluorescence spectroscopy and cyclic voltammetry. DFT calculations revealed structural details of the macrocycles. The surprisingly weak binding of these porous structures with chloride ions (K ≈ 10 M-1) is attributed to their highly twisted conformation. The title compounds represent the first porous nanographenes based on the [5.5.5.5]fenestrane motif and, at the same time, they consist of a fenestrane-like polyarylene network.

Total Synthesis of Tosyl-Samroiyotmycin A and Its Biological Profiling.

A total synthesis of the enantiopure syn,syn-tosyl-samroiyotmycin A, a C2-symmetric 20-membered antimalarial macrodiolide with syn,syn-configuration of the 8,24-dihydroxy-9,25-dimethyl units and it's enantiopure anti,anti-derivative is described. The synthesis was accomplished utilizing a linear approach in 7 steps and 3 % overall yield via a sequence of diastereoselective methylation of SuperQuat oxazolidinone auxiliary, cross metathesis and Yamaguchi macrolactonization of fully functionalized seco-acids. By a similar approach we gained access to several samroiyotmycin analogues and precursors. Antimalarial activity was tested on multi-resistant (K1) and sensitive (Nf54) P. falciparum strains providing insight into structure activity relationships. Both tosyl-oxazol unit as well as the syn-configuration of the two contiguous stereogenic centers turned out to be beneficial for antiplasmodial activity. For instance, syn,syn-tosyl-samroiyotmycin A showed 3.4 times higher activities than the "tosyl-free" natural product.

Macrocyclic-based strategy in drug design: From lab to the clinic.

Macrocyclic compounds have emerged as potent tools in the field of drug design, offering unique advantages for enhancing molecular recognition, improving pharmacokinetic properties, and expanding the chemical space accessible to medicinal chemists. This review delves into the evolutionary trajectory of macrocyclic-based strategies, tracing their journey from laboratory innovations to clinical applications. Beginning with an exploration of the defining structural features of macrocycles and their impact on drug-like characteristics, this discussion progresses to highlight key design principles that have facilitated the development of diverse macrocyclic drug candidates. Through a series of illustrative representative case studies from approved macrocyclic drugs and candidates spanning various therapeutic areas, particular emphasis is placed on their efficacy in targeting challenging protein-protein interactions, enzymes, and receptors. Additionally, this review thoroughly examines how macrocycles effectively address critical issues such as metabolic stability, oral bioavailability and selectivity. Valuable insights into optimization strategies employed during both approved and clinical phases underscore successful translation of promising leads into efficacious therapies while providing valuable perspectives on harnessing the full potential of macrocycles in drug discovery and development endeavors.

Size-Increased All-Phenylene Molecular Spoked Wheels - A Combined Theoretical and Experimental Approach.

A lateral expansion of molecular spoked wheels (MSWs) based on an all-phenylene backbone is described. The MSWs contain a central hub, six spokes, and a rim that is formed by a sixfold Yamamoto coupling of the respective non-cyclized dodecabromo precursor yielding MSWs with up to 30 phenylene rings in the perimeter. Attempts to prepare compounds of such size without flexible side groups at the spokes were unsuccessful, most probably due to an aggregation and accompanying oligomerization of the precursors during the cyclization. To overcome these problems, fluorene units are inserted into the spokes. These contain additional alkyl chains and lead to a curvature of the wheels. Quantum chemical calculations on the mechanism of the Yamamoto coupling lead to geometry and strain-related criteria for the successful rim closure to the respective MSW. Subsequently, MSWs are prepared with four and even six phenylene units at each edge of the hexagonal wheels. The resulting MSWs are characterized by spectroscopic methods, and additionally some of them are visualized via scanning tunneling microscopy (STM).

Recent Advances on Catalytic Atroposelective Synthesis of Planar-Chiral Macrocycles.

Planar-chiral skeletons widely exist in natural products, bioactive compounds, and other functional molecules. Although significant progress has been made in the field of asymmetric synthesis of centrally or axially chiral molecules over the past years, enantioselective constructing of planar chirality is still a big obstacle and numerous efforts have been made in this field. Previous works have mainly focused on the assembly of planar-chiral [2,2]-paracyclophanes and metallocenes. This Minireview describes recent advancements in asymmetric catalytic synthesis of planar-chiral macrocycles, including ansa chain construction, plane formation and asymmetric transformation strategies. It is anticipated that this Minireview will sever as a source of inspiration for developing new unconventional procedures for access to planar-chiral skeletons.

Pnictogen-Assisted Self-Assembly As A Means To Study Mediated Thiol/Disulfide Exchange in Supramolecular Dynamic Covalent Assemblies.

Thiol-disulfide interchange has been an active field of study for biochemists and physical organic chemists alike due to its prevalence within biological systems and fundamentally interesting dynamic nature. More recently, efforts have been made to harness the power of this reversible reaction to make self-assembling systems of macrocyclic and cage-like molecules. However, less effort has focused on the fundamental study of isolating these assemblies and analyzing the factors that control the assembly and sorting of these emerging cyclic systems. We have shown previously that pnictogen-assisted self-assembly enables formation of discrete disulfide macrocycles and cages without competition from polymer formation for a wide variety of alkyl thiols. Herein we report the expansion of these methods to form disulfide macrocycles from aryl thiol containing ligands, allowing access to previously unreported molecules. More importantly, the development of this new self-assembly chemistry allows for a comparison of aryl vs alkyl disulfide exchange and self-assembly. These studies complement classical physical organic and chemical biology studies on the kinetics and thermodynamics of aryl thiol oxidation to disulfides, and we show that this self-assembly method revises some prevailing wisdom from these key classical studies by providing new product distributions and new isolable products in cyclic disulfide formation.

Diphenylacetylene-Incorporating Octaphyrin: A Rigid Macrocycle with Readily Separable Conformational Isomers.

An expanded carbaporphyrinoid analogue, octaphyrin(2,1,1,1,2,1,1,1), containing two rigid diphenylacetylene moieties is reported. In contrast to traditional pyrrolic macrocycles where flexible conformers coexist in dynamic equilibrium, this macrocycle exists as two separable, conformationally stable stereoisomers, denoted as 1A and 1B. The conformational effect of both conformers, as well as their protonated forms, were thoroughly studied using NMR spectroscopy, UV-Vis, and single crystal X-ray diffraction analyses. Importantly, heating conformer 1B leads to its irreversible conversion to 1A, whereas in its protonated form, 1A·2MSA undergoes irreversible transformation to 1B·2MSA at lower temperatures. These temperature-dependent features establish a foundation for developing new accumulated heat sensors, as demonstrated by the use of the present octaphyrins as a customized thermochromic indicator in steam sterilization. The present study thus underscores how the conformational rigidity of these new polypyrrolic macrocycles imparts properties that are distinct from historically flexible expanded porphyrinoids.

Janus Reactivity of Crownphyrinoids: Alkali- vs. Transition Metal-Mediated Transformations of Crown Ether-Porphyrin Hybrids.

Crownphyrinogens and crownphyrins constitute a group of macrocycles that combine the structural facets of porphyrinoids and crown ethers. The dual-nature cavity embedded in their molecules enables reactivity involving two structurally distinct parts of the macrocyclic ligand. Upon Ni(II) and Pd(II) insertion, coordination compounds are produced wherein the metal is incorporated into the porphyrinoid-like pocket, resulting in monomeric or accordion-like dimeric products, depending on the oxidation level of the macrocycle and metal cation. The reactions with Na(I) and K(I) resulted in the formation of complexes where only the crown ether segment of the molecule is involved in metal binding, yielding remarkable dimeric species. The exploitation of a crownphyrin large enough to accommodate two metal cations allowed the synthesis of an alkali/transition metal binuclear complexes wherein the macrocycle demonstrated the Janus reactivity with one cavity acting as a porphyrinoid, and the other mimicking the crown ether.

Are peptidomimetics the compounds of choice for developing new modulators of the JAK-STAT pathway?

Protein-protein interactions (PPIs) play critical roles in a wide range of biological processes including the dysregulation of cellular pathways leading to the loss of cell function, which in turn leads to diseases. The dysfunction of several signaling pathways is linked to the insurgence of pathological processes such as inflammation, cancer development and neurodegeneration. Thus, there is an urgent need for novel chemical modulators of dysregulated PPIs to drive progress in targeted therapies. Several PPIs have been targeted by bioactive compounds, and, often, to properly cover interacting protein regions and improve the biological activities of modulators, a particular focus concerns the employment of macrocycles as proteomimetics. Indeed, for their physicochemical properties, they occupy an intermediate space between small organic molecules and macromolecular proteins and are prominent in the drug discovery process. Peptide macrocycles can modulate fundamental biological mechanisms and here we will focus on peptidomimetics active on the Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways.

Synthesis and crystal structures of 5,17-di-bromo-26,28-dihy-droxy-25,27-dipropynyloxycalix[4]arene, 5,17-di-bromo-26,28-dipropoxy-25,27-dipropynyloxycalix[4]arene and 25,27-bis-(2-azido-eth-oxy)-5,17-di-bromo-26,28-di-hydroxy-calix[4]arene.

The calixarenes, 5,17-di-bromo-26,28-dihy-droxy-25,27-dipropynyloxycalix[4]arene (C34H26Br2O4, 1), 5,17-di-bromo-26,28-dipropoxy-25,27-dipropynyloxycalix[4]arene (C40H38Br2O4, 2) and 25,27-bis-(2-azido-eth-oxy)-5,17-di-bromo-26,28-di-hydroxy-calix[4]arene (C32H28Br2N6O4, 3) possess a pinched cone mol-ecular shape for 1 and 3, and a 1,3-alternate shape for compound 2. In calixarenes 1 and 3, the cone conformations are additionally stabilized by intra-molecular O-H⋯O hydrogen bonds, while in calixarene 2 intra-molecular Br⋯Br inter-actions consolidate the 1,3-alternate mol-ecular conformation. The dense crystal packing of the cone dialkyne 1 is a consequence of π-π, C-H⋯π and C-H⋯O inter-actions. In the crystal of the diazide 3, there are large channels extending parallel to the c axis, which are filled by highly disordered CH2Cl2 solvent mol-ecules. Their contribution to the intensity data was removed by the SQUEEZE procedure that showed an accessible void volume of 585 Å3 where there is room for 4.5 CH2Cl2 solvent mol-ecules per unit cell. Rigid mol-ecules of the 1,3-alternate calixarene 2 form a columnar head-to-tail packing parallel to [010] via van der Waals inter-actions, and the resulting columns are held together by weak C-H⋯π contacts.

Cobalt(III)-Macrocyclic Scaffolds with Anti-Cancer Stem Cell Activity.

Cobalt(III) compounds with tetradentate ligands have been widely employed to deliver cytotoxic and imaging agents into cells. A large body of work has focused on using cobalt(III)-cyclam scaffolds for this purpose. Here, we investigate the cytotoxic properties of cobalt(III) complexes containing 14-membered macrocycles related to cyclam. A breast cancer stem cell (CSC) in vitro model was used to gauge efficacy. Specifically, [Co(1,4,7,11-tetraazacyclotetradecane)Cl2]+ (1) and [Co(1-oxa-4,8,12-triazacyclotetradecane)Cl2]+ (2) were synthesised and characterised, and their breast CSC activity was determined. The cobalt(III) complexes 1 and 2 displayed micromolar potency towards bulk breast cancer cells and breast CSCs grown in monolayers. Notably, 1 and 2 displayed selective potency towards breast CSCs over bulk breast cancer cells (up to 4.5-fold), which was similar to salinomycin (an established breast CSC-selective agent). The cobalt(III) complexes 1 and 2 were also able to inhibit mammosphere formation at low micromolar doses (with respect to size and number). The mammopshere inhibitory effect of 2 was similar to that of salinomycin. Our studies show that cobalt(III) complexes with 1,4,7,11-tetraazacyclotetradecane and 1-oxa-4,8,12-triazacyclotetradecane macrocycles could be useful starting points for the development of new cobalt-based delivery systems that can transport cytotoxic and imaging agents into breast CSCs.

A Review of Macrocycles Applied in Electrochemical Energy Storge and Conversion.

Macrocycles composed of diverse aromatic or nonaromatic structures, such as cyclodextrins (CDs), calixarenes (CAs), cucurbiturils (CBs), and pillararenes (PAs), have garnered significant attention due to their inherent advantages of possessing cavity structures, unique functional groups, and facile modification. Due to these distinctive features enabling them to facilitate ion insertion and extraction, form crosslinked porous structures, offer multiple redox-active sites, and engage in host-guest interactions, macrocycles have made huge contributions to electrochemical energy storage and conversion (EES/EEC). Here, we have summarized the recent advancements and challenges in the utilization of CDs, CAs, CBs, and PAs as well as other novel macrocycles applied in EES/EEC devices. The molecular structure, properties, and modification strategies are discussed along with the corresponding energy density, specific capacity, and cycling life properties in detail. Finally, crucial limitations and future research directions pertaining to these macrocycles in electrochemical energy storage and conversion are addressed. It is hoped that this review is able to inspire interest and enthusiasm in researchers to investigate macrocycles and promote their applications in EES/EEC.

Introduction of peripheral nitrogen atoms to cyclo-meta-phenylenes.

Cyclo-meta-phenylenes doped with nitrogen atoms at the periphery were designed and synthesized. The syntheses of the macrocyclic structures were achieved with one-pot Suzuki-Miyaura coupling to arrange phenylene rings and pyridinylene rings in an alternating fashion. Analyses with UV-vis spectroscopy showed changes in the photophysical properties with nitrogen doping, and X-ray crystallographic analyses experimentally revealed the presence of biased charges on the peripheral nitrogen atoms.