Macrocyclic Molecules Research Articles

Kinetic and Thermodynamic Behaviors of Pseudorotaxane Formation with C3v Macrocyclic BODIPY Trimers and the Remarkable Substituent Effect on Ring-Face Selectivity.

The thermodynamic and kinetic behaviors of the pseudorotaxane formation between the C3v macrocyclic BODIPY trimers and unsymmetrical secondary ammonium guests are investigated. We find a remarkable substituent effect of the BODIPY trimer on the ring-face selectivity during the threading. The difference in the small substituents (H or CH3) in the macrocyclic host molecules significantly modulated the thermodynamic and kinetic selectivity of the threading direction of the unsymmetrical ammonium ions.

Stability, Aromaticity, and Photophysical Behaviors of Macrocyclic Molecules: A Theoretical Analysis.

The macrocyclic molecules with terthiophene (TTH) isomers unit exhibit intriguing properties in terms of aromaticity, stability, and absorption. In this work, we theoretically designed a series of macrocyclic molecules featured with TTH and dithienothiophene (DTT) π-conjugated building units, which are used to permute pyrrole unit in porphyrin skeleton. Density functional theory and time-dependent DFT methods are used to evaluate the performance of the designed molecules. Our simulations show that molecules 1–3 exhibit excellent optoelectronic performance. Specifically, the molecule with the DTT unit is more stable than the one with TTH unit in terms of aromaticity and aromatic stabilization energy. This is because DTT unit enhances the coplanarity of the molecular material, facilitating electronic communication. Calculation of vertical electronic excitations suggests the absorption feature of these molecules is mainly contributed by the electronic excitations of higher occupied molecular orbital (HOMO) → lowest unoccupied molecular orbital (LUMO)+1 and HOMO-1 → LUMO. Judging from the key parameters determining the overall performance, 3 stands out because of its good planarity, large HOMO–LUMO gap, and strong aromaticity among all molecules. Interestingly, molecule 1 has the current density flow distributes around the outer section of TTH unit; in contrast, molecule 3 with DTT unit has the current density flow located at the inner section of DTT, which is beneficial for stability and aromaticity. Second-order perturbation energies are calculated to rationalize this observation. We expect that these research results can provide valuable insights into the rational design of novel molecular materials for a variety of applications.

Shifting the absorption to the near-infrared region and inducing a strong photothermal effect by encapsulating zinc(II) phthalocyanine in poly(lactic-co-glycolic acid)-hyaluronic acid nanoparticles

By using an oil-in-water single emulsion method, a series of multifunctional hybrid nanoparticles (NPs) were prepared which consisted of a core of poly(lactic-co-glycolic acid) (PLGA) with a lipoid shell of n-hexadecylamine-substituted hyaluronic acid (HA), encapsulating a zinc(II) phthalocyanine-based photosensitizer (ZnPc). As determined by laser light scattering, these hybrid NPs labeled as ZnPc@PLGA-HA NPs possessed a hydrodynamic diameter of 280nm and a surface charge of -30mV, showing high stability in serum. The Q-band absorption of ZnPc exhibited a large red-shift from 674nm for free ZnPc in dimethylsulfoxide to 832nm for this nanosystem in water. Upon light irradiation at 808nm, the encapsulated ZnPc induced a strong photothermal effect instead of photodynamic action, which is usually observed for ZnPc-containing NPs. The tumor-targeting effect of these NPs due to the HA coating was investigated against the human colorectal adenocarcinoma HT29 cells and human lung carcinoma A549 cells, both of which overexpress cluster determinant 44 (CD44) receptors, using the CD44-negative human normal hepatic LO2 cells as a negative control. The photothermal cell-killing effect of these NPs was significantly higher for the two CD44-positive cell lines than that for the negative control. Their in vivo photothermal efficacy was also examined on HT29 tumor-bearing nude mice. Upon irradiation, the NPs caused significant temperature increase at the tumor site and ablation of the tumor. The results showed that these multifunctional NPs could serve as an effective photothermal agent for targeted photothermal therapy. Statement of significance Phthalocyanines are well-known photosensitizers for photodynamic therapy. By encapsulating these molecules into various nanoplatforms, a range of multifunctional photosensitizing systems have been developed for cancer therapy. In this study, we have demonstrated that by careful selection of phthalocyanines and the nanocarriers, as well as the self-assembly and encapsulation methods, the encapsulated phthalocyanine molecules could switch the photoinduced action from photodynamic therapy to photothermal therapy as a result of the enhanced aggregation of the macrocyclic molecules in the nanoparticles. The unique packing of the molecules also resulted in a large red-shift of the Q-band absorption to 832nm, facilitating the in vitro and in vivo photothermal treatment.

Supramolecular Vesicles Based on Amphiphilic Pillar[n]arenes for Smart Nano-Drug Delivery.

Supramolecular vesicles are the most popular smart nano-drug delivery systems (SDDs) because of their unique cavities, which have high loading carrying capacity and controlled-release action in response to specific stimuli. These vesicles are constructed from amphiphilic molecules via host-guest complexation, typically with targeted stimuli-responsive units, which are particularly important in biotechnology and biomedicine applications. Amphiphilic pillar[n]arenes, which are novel and functional macrocyclic host molecules, have been widely used to construct supramolecular vesicles because of their intrinsic rigid and symmetrical structure, electron-rich cavities and excellent properties. In this review, we first explain the synthesis of three types of amphiphilic pillar[n]arenes: neutral, anionic and cationic pillar[n]arenes. Second, we examine supramolecular vesicles composed of amphiphilic pillar[n]arenes recently used for the construction of SDDs. In addition, we describe the prospects for multifunctional amphiphilic pillar[n]arenes, particularly their potential in novel applications.

Reorganization of a photosensitive carbo-benzene layer in a triptych nanocatalyst with enhancement of the photocatalytic hydrogen production from water

The preparation of a triptych nanomaterial made of TiO2 nanoparticles as semiconductor, Ag plasmonic nanoparticles and a carbo-benzene macrocyclic molecule as photosensitizer is described, and used to produce hydrogen by photo-reduction of pure deionized water under 2.2 bar argon pressure without any electrical input. Silver nanoparticles (~5 nm) are grafted onto the surface of commercial TiO2 nanoparticles (~23 nm) by a photo-deposition process using an original silver amidinate precursor. The thickness of the photosensitive layer (2 nm), which completes the assembly, plays a crucial role in the efficiency and robustness of the triptych nanocatalyst. Thanks to the organic layer reorganization during the first ~24 h of irradiation, it leads to an enhancement of the hydrogen production rate up to 5 times. The amount of silver and carbo-benzene are optimized, along with the mass concentration of nanocatalyst in water and the pH of the aqueous medium, to allow reaching a hydrogen production rate of 22.1 μmol·h−1·gphotocatalyst−1.

Spectroscopic studies of the excited-state intramolecular proton and electron transfer processes of methyl benzoate derivatives in cucurbit[7]uril nanocage

The encapsulation of four methyl benzoate derivatives (I-IV) in aqueous solution in the presence of the macrocyclic host molecule cucurbit[7]uril (CB[7]) was studied using steady-state, time-resolved and 1H NMR spectroscopic techniques. The significant changes in the steady-state and time-resolved fluorescence spectra (and calculated from them fluorescence decay times) were attributed to the formation of a well-defined, stable 1:1 inclusion complex. To understand the mechanism of supramolecular solvation dynamics, the time-dependent fluorescence Stokes' shifts, represented by the normalized spectral response function c(t), were studied. Our studies have shown that solvation dynamics of water are significantly inhibited inside a cucurbit cavity. The experimental results were also used to calculate, according to Benesi-Hildebrand plot and nonlinear least-squares regression analysis, equilibrium constants of the formed inclusion complex. For all investigated dyes, the K1 value is significantly larger than this previously calculated for I-IV inclusion into cyclodextrins (CDs), indicating the superior host abilities of CB[7] as compared to CDs. The position of the guest molecule inside the host cavity was investigated by 1H NMR experiment. The nature of the 1H NMR shifts for different protons is qualitatively different for methoxy derivative-CB[7] complex (I-CB[7] and III-CB[7] systems) and hydroxy derivative-CB[7] complex (II-CB[7] and IV-CB[7] systems), which indicates that the inclusion complexes of hydroxy and methoxy derivatives with CB[7] are of a difference in nature. The CB[7]-induced chemical shifts clearly demonstrate that for II-CB[7] and IV-CB[7] complexes, benzene ring is fully embedded in the interior of CB[7], while for I-CB[7] and III-CB[7] complexes, only the part of the benzene ring is located within the CB[7] cavity. Finally, 1H NMR chemical shifts and evolution of the steady-state and time-resolved emission spectra clearly indicate that -NMe2 group attached to the III and IV is located outside of the CB[7] portal.

An Aminopyridine Bearing Pillar[5]arene-Based QCM Sensor for Chemical Sensing Applications: Design, Experimental Characterization, Data Modeling, and Prediction

This study presented that deca pyridin-2-amine bearing Pillar[5]arene (P5-PA) was designed in an appropriate cavity, which acts a part significant role in host–guest interactions of the macrocyclic molecules. P5-PA monolayer was deposited onto suitable substrates as an active layer by using Langmuir-Blodgett (LB) coating technique to examine its vapor sensing capabilities against vapor of some aliphatic hydrocarbons through Quartz Crystal Microbalance (QCM) technique. The kinetic vapor studies were occurred by exposing the P5-PA/LB thin film to different percentage of organic VOCs vapors such as dichloromethane, chloroform and carbon tetrachloride in air-VOCs mixture. The early-time Fick’s diffusion law was handled to extract the diffusion coefficients by utilizing QCM data depending real time. It is observed that there were two different regions with two slopes indicating that one belongs to slow surface diffusion and another fast for bulk diffusion into LB thin film. The collected experimental data with 1 Hz sampling frequency was modelled with deep learning models (NARNET and LSTM) which could get satisfactory results on small datasets. The models were trained with 83% samples of data; the remaining 17% data is used to evaluate the developed models prediction performance. The predicted values of models were compared with the original (measured) data in the results section. It is observed from the results; the developed deep learning models have higher than 0.98 correlation coefficient for each vapor, which is satisfactory for prediction applications.

Physico-chemical study of complexation of silver ion (Ag+) by macrocyclic molecules (hexa-Helicenes) based on statistical physics theory: new description of a cancer drug

In recent papers, it is found that the silver-[6]Helicene complex can be used as a cancer drug but the interaction silver-hexaHelicene has not yet proven. The idea of this paper is to investigate the complexation process of the [6]Helicene by the silver metal (Ag+) using three types of adsorbates. Indeed, the adsorption of silver chloride, silver nitrate and silver sulfide into the sensor films deposited on the QCM electrode are measured at three temperatures (293–333 K). Films of the [6]Helicene were deposited on the QCM resonators using spin coating method in order to obtain uniform and homogenous sensor surface. Experimental results indicated that the [6]Helicene can form a stable complex with the silver ion and that the AgCl is the appropriate adsorbate for the complexation achievement. Actually, an advanced modeling analysis by means of statistical physics adsorption models is applied to explore the new vision of the complextion system. The values of the models parameters are deduced from fitting the experimental data with the developed models. They result in confirming the experimental findings by comparing the complexation energies of the three examined systems. In particular, for the silver nitrate, the Van-der-Waals parameters explained the isotherms drop at high concentration through the lateral interactions between the adsorbates. The adsorption energies analysis showed the highest interaction AgCl-[6]Helicene. Density functional theory (DFT) simulations showed that chemical bonds take place during the adsorption of silver chloride on hexaHelicene which confirms that the [6]Helicene can function as a chiral molecular tweezer of the univalent cationic silver.

Nonlinear optical properties of peripheral symmetrically and non-symmetrically 4-(trifluoromethoxy)phenoxy substituted zinc phthalocyanines

In this work, new non-symmetrical, peripherally substituted metallophthalocyanines, namely 2(3)-[(4-nitrophenyl)ethynyl]-{9,10,16,17,23,24-hexakis-(4-(trifluoromethoxy)phenoxy)-phthalocyaninato}zinc (1b) and 2(3)-[(4-nitrophenyl)ethynyl]-{9(10),16(17),23(24)-tris-(4-(trifluoromethoxy)phenoxy)-phthalocyaninato}zinc (2b) were prepared. Structural elucidation of the novel zinc phthalocyanines was carried out with well-known spectroscopic methods. The solubility of the phthalocyanines was investigated in organic solvents like tetrahydrofuran, dichloromethane, and dimethyl sulfoxide. The effect of concentration on aggregation behavior of the resulting phthalocyanines (1b and 2b) was examined in a wide area ranging from 4 × 10−6 to 14 × 10−6 M in tetrahydrofuran. Aggregation properties of the macrocyclic molecules (1b and 2b) were also investigated in many organic solvents. Based on the data existing in the literature, peripherally octa- and tetra-substituted zinc phthalocyanines (1a and 2a) with 4-(trifluoromethoxy)phenoxy moieties were synthesized. Optical limiting and the third-order nonlinear properties of symmetrically and non-symmetrically substituted phthalocyanines were determined and compared with each other.

Accurate Regulating of Visible-Light Absorption in Polyoxotitanate-Calix[8]arene Systems by Ligand Modification.

With use of a macrocyclic polyphenol, tert-butylcalix[8]arene (TBC[8]), as ligands, a series of TBC[8]-stabilized {Ti4O2}clusters, containing penta- and hexacoordinated Ti centers, were synthesized. Such complexes are "core-shell" shaped containing a {Ti4O2} core arranged in a zigzag fashion. While outer walls of the clusters are decorated by deprotonated TBC[8], their upper and lower surfaces can be modified by various O- or N-donor ligands, and the ratio of the penta- and hexacoordinated Ti(IV) centers in the {Ti4O2} core can be precisely regulated from 4:0, to 3:1, to 2:2, to 1:3, and finally to 0:4. The combined coordination of different ligands in the axial direction shows significant influence on the adsorption of the TBC[8]-Ti4 system in the visible-light region, and their absorption edge can be precisely regulated from 600 to 700 nm. The above structural functionalization in the TBC[8]-Ti4 system also tunes their photocatalytic H2 production activities and oxidative desulfurization ability. Thus, for the first time, by confining the polyoxotitanium cluster in macrocyclic molecules, we provide an example of understanding the structure-property relationship of titanium-oxygen materials by ligand modification.

Scope of 3D Shape-Based Approaches in Predicting the Macromolecular Targets of Structurally Complex Small Molecules Including Natural Products and Macrocyclic Ligands.

A plethora of similarity-based, network-based, machine learning, docking and hybrid approaches for predicting the macromolecular targets of small molecules are available today and recognized as valuable tools for providing guidance in early drug discovery. With the increasing maturity of target prediction methods, researchers have started to explore ways to expand their scope to more challenging molecules such as structurally complex natural products and macrocyclic small molecules. In this work, we systematically explore the capacity of an alignment-based approach to identify the targets of structurally complex small molecules (including large and flexible natural products and macrocyclic compounds) based on the similarity of their 3D molecular shape to noncomplex molecules (i.e., more conventional, “drug-like”, synthetic compounds). For this analysis, query sets of 10 representative, structurally complex molecules were compiled for each of the 28 pharmaceutically relevant proteins. Subsequently, ROCS, a leading shape-based screening engine, was utilized to generate rank-ordered lists of the potential targets of the 28 × 10 queries according to the similarity of their 3D molecular shapes with those of compounds from a knowledge base of 272 640 noncomplex small molecules active on a total of 3642 different proteins. Four of the scores implemented in ROCS were explored for target ranking, with the TanimotoCombo score consistently outperforming all others. The score successfully recovered the targets of 30% and 41% of the 280 queries among the top-5 and top-20 positions, respectively. For 24 out of the 28 investigated targets (86%), the method correctly assigned the first rank (out of 3642) to the target of interest for at least one of the 10 queries. The shape-based target prediction approach showed remarkable robustness, with good success rates obtained even for compounds that are clearly distinct from any of the ligands present in the knowledge base. However, complex natural products and macrocyclic compounds proved to be challenging even with this approach, although cases of complete failure were recorded only for a small number of targets.

Supramolecular nano drug delivery systems mediated via host-guest chemistry of cucurbit[n]uril (n = 6 and 7)

As a novel family of macrocyclic molecules, cucurbit[n]urils (CB[n]s) have emerged as promising building blocks of supramolecular nano drug delivery systems (SNDDS) in recent years. Direct encapsulation of amphiphilic guests by CB[6] and CB[7] can modulate their amphiphilicity, resulting in formation of supramolecular amphiphiles that self-assemble into supramolecular nanoparticles for drug delivery. Additionally, CB[n]’s host-guest chemistry on the surface of mesoporous nanoparticles makes CB[n] an ideal blocking agent to control drug release from delivery vehicles. These SNDDS possess intrinsic stimuli responsiveness towards external guest or host, which can further incorporate responsiveness to a variety of other stimuli including pH, thermal, redox, photo and enzyme, to realize multiple stimuli-responsive drug release. Moreover, the recent breakthrough in direct functionalization of CB[n]s has provided a feasible method for preparing superior CB[6] and CB[7] derivatives that can be employed to build multifunctional SNDDS with unoccupied macrocycles located on surface, which could be decorated with various functional “tags” through host-guest chemistry. In this review, we summarized the recent progress of CB[6] and CB[7] based SNDDS through formation of supramolecular amphiphiles, supramolecular nanovalves as well as supramolecularly tailorable surface, which we hope to further promote the development of CB[n]s family as building blocks for advanced SNDDS.

Recent Development of Supramolecular Sensors Constructed by Hybridization of Organic Macrocycles with Nanomaterials

Macrocyclic compounds have attracted tremendous attention for their superior performance in supramolecular recognition, catalysis, and host-guest interaction. With these admirable properties, macrocyclic compounds were used as modifiers for enhancing the sensitivity and selectivity of electrodes and optical sensors. The classic macrocyclic compounds, including crown ethers, cyclodextrins, calixarenes, cucurbiturils, and pillararenes, were employed as receptors for electrochemical and optical sensors to develop new analytical methods with the wilder detection range, lower detection limit, and better tolerance of interference. Macrocyclic molecules functionalized with nanomaterials, the small entities with dimensions in the nanoscale, realized the versatility and diversification of the nano-hybrid materials, which improved the capabilities of recognition and response with the combining characteristics of two components. Herein, this review focused on the development in the research field of hybridization of organic macrocycles with nanoparticles and their applications for chemosensors, aiming at both existing researchers in the field and who would like to enter into the research.

Review on synthetic advances in porphyrins and metalloporphyrins

Due to extensive applications of porphyrin-based materials today, this paper aims to present review on the synthesis of the first and principal methodologies along with recent synthetic developments in this macrocyclic molecule.

Computational Modeling of Boron Subphthalocyanines and Subnaphthalocyanines to Justify Their Development and to Predict and Confirm Their Electrochemical and Physical Properties

For some time, our group has been focused on the molecular design, synthesis and application of derivatives of boron subphthalocyanines (BsubPcs) and subnaphthalocyanines (BsubNcs), which are macrocyclic molecules with a chelated central boron atom. Our focal point has been and continues to be equally balanced between the basic and applied chemistry of BsubPcs/BsubNcs and their application as light absorbing and electronic conducting materials in organic photovoltaics (OPVs)/organic solar cells. Electrochemical properties being critical to this application. For OPVs, we selected a preferred approach to the development of BsubPcs/BsubNcs whereby their molecular design and their synthesis is justified through a development cycle which includes data accumulation of their basic physical chemistry properties, their immediate integration into OPVs and their stability evaluation when applied into OPVs/organic solar cells. Based on data acquisition, we then cycle back to consider alternative molecular designs of BsubPcs/BsubNcs. Recently we have re-Integrated into this cycle our computational modeling methodology which is used to screen potential BsubPcs/BsubNcs for their application in OPVs/organic solar cells and other organic electronic devices.For this presentation I will begin by outlining how we have re-adopted our past computational model to help develop these materials. I will start by showing how we calibrate several levels of computational modeling relative to firm experimental data. I will highlight how a low level and high level computational model can be calibrated and the difference between them. I will then move onto several examples of how we have developed BsubPcs/BsubNcs for application in OPVs and other organic electronic devices utilizing this method.An example I will show is that we have recently identified a pathway to BsubPcs whereby all carbons are bio-sourced. In order to justify their synthesis with the desired OPV application, I will highlight how the computational model justified the time and resource commitment to their synthesis and development. I will also show how the computational calibration model did accurately predict their relevant properties, the prediction being a level of justification for their development.I will outline several other BsubPc/BsubNc macrocycle structures that where either justified by the computational model to be developed or where not justified. I will also highlight to the community progress in avoiding bay-position halogenation of the BsubNc macrocycles during their formation.Additional co-authors/investigators will be identified during this presentation. Figure 1

A modular biomimetic strategy for the synthesis of macrolide P-glycoprotein inhibitors via Rh-catalyzed C-H activation

One of the key challenges to overcome multidrug resistance (MDR) in cancer is the development of more effective and general strategies to discover bioactive scaffolds. Inspired by natural products, we describe a strategy to achieve this goal by modular biomimetic synthesis of scaffolds of (Z)-allylic-supported macrolides. Herein, an Rh(III)-catalyzed native carboxylic acid-directed and solvent-free C−H activation allylation with high stereoselectivity and chemoselectivity is achieved. The generated poly-substituted allylic alcohol as a multifunctional and biomimetic building block is crucial for the synthesis of (Z)-allylic-supported macrolides. Moreover, the unique allylic-supported macrolides significantly potentiate the sensitivity of tumor cells to cytotoxic agents such as vinorelbine and doxetaxel by reversing p170-glycoprotein-mediated MDR. Our findings will inspire the evolution of synthetic chemistry and open avenues for expedient and diversified synthesis of bioactive macrocyclic molecules.

Host-Guest Chemistry of Porphyrins in Liquid Crystalline Macrocycles

Structurally well-defined macrocyclic molecules have great potential to accommodate specific guest molecules in the hollow. Recently, we have reported a series of macrocycles which are composed of four carbazoles connected with four salphen ligands1, four dibenzothiophenes connected with four salen ligands2, or four diindrocarbazoles connected with four salphen ligands3 (MC1, MC2 and MC3, respectively). The macrocycles with appropriate peripheral alkyl chains and their tetranuclear metal complexes with square planar metal ions showed thermotropic columnar liquid crystalline properties1,2. These macrocycles stacked to form columns inside the fluid materials. Especially, the giant macrocycle MC3 contained a square hollow with a diagonal of 2.5 nm. This giant macrocycle has the largest inner cavity among known discrete shape-persistent macrocycles that exhibit thermotropic LC properties. The size and shape of the hollow structure make it interesting for molecular inclusion applications. For example, MC3 molecule can accommodate a tetrapyridylporphyrin inside the hollow to afford a planar conjugate, and the conjugate showed liquid crystalline behavior. Reference: [1] S. Kawano, Y. Ishida, and K. Tanaka, J. Am. Chem. Soc. 2015, 137, 2295.[2] Kawano, S.; Hamazaki, T.; Suzuki, A.; Kurahashi, K.; Tanaka, K. Chem. Eur. J. 2016, 22, 15674-15683.[3] Kawano, S.; Kato, M.; Somiya, S.; Nakayama, M.; Onoe, J.; Tanaka, K. Angew. Chem. Int. Ed. 2018, 57, 167–171. Figure 1

Photophysics and visible light photodissociation of supramolecular meso-tetra(4-pyridyl) porphyrin/RuCl2(CO)(PPh3)2 structures.

In the last decades, supramolecular structures have been explored in many technological efforts. One example of such supramolecules is attained when ruthenium complexes are attached in the outer sites of a porphyrin. Ruthenium complexes act as modulators of the photophysical processes of macrocyclic molecules. Besides the investigation of the main changes introduced by the ruthenium complexes in the electronic and vibronic properties, and in the excited state deactivation processes of porphyrins, discussions concerning the photostability of these supramolecules are much needed. Here, we investigate the supramolecular free-base meso-tetra(4-pyridyl) porphyrin decorated with "RuCl2(CO)(PPh3)2" ruthenium species linked at each of its (4-pyridyl) moieties. The modifications in the photophysical processes introduced by the metallic outlying species are discussed and our results suggest an energy transfer process from the porphyrin B-band to the ruthenium complex MLCT-band. The demonstration of visible light photodissociation of the supramolecule, via both pulsed and continuous laser, is also addressed.

Substrate Recognition by the Class II Lanthipeptide Synthetase HalM2.

Class II lanthipeptides belong to a diverse group of natural products known as ribosomally synthesized and post-translationally modified peptides (RiPPs). Most RiPP precursor peptides contain an N-terminal recognition sequence known as the leader peptide, which is typically recognized by biosynthetic enzymes that catalyze modifications on the C-terminal core peptide. For class II lanthipeptides, these are carried out by a bifunctional lanthipeptide synthetase (LanM) that catalyzes dehydration and cyclization reactions on peptidic substrates to generate thioether-containing, macrocyclic molecules. Some lanthipeptide synthetases are extraordinarily substrate tolerant, making them promising candidates for biotechnological applications such as combinatorial biosynthesis and cyclic peptide library construction. In this study, we characterized the mode of leader peptide recognition by HalM2, the lanthipeptide synthetase responsible for the production of the antimicrobial peptide haloduracin β. Using NMR spectroscopic techniques, in vitro binding assays, and enzyme activity assays, we identified substrate residues that are important for binding to HalM2 and for post-translational modification of the peptide substrates. Additionally, we provide evidence of the binding site on the enzyme using binding assays with truncated enzyme variants, hydrogen-deuterium exchange mass spectrometry, and photoaffinity labeling. Understanding the mechanism by which lanthipeptide synthetases recognize their substrate will facilitate their use in biotechnology, as well as further our general understanding of how RiPP enzymes recognize their substrates.

Non‐Covalent Interactions Enable the Length‐Controlled Generation of Discrete Tubes Capable of Guest Exchange

AbstractSupramolecular chemistry in confined spaces constructed from macrocyclic molecules has attracted much attention because it can utilize the specific binding properties of macrocyclic cavities. Herein we report the preparation of length‐controlled discrete tubular structures by homo‐/co‐assembly of rim‐differentiated and peralkylamino‐substituted pillar[5]arenes via hydrogen bonds and salt bridges. By dimerization and trimerization, the expanded tubes show a fivefold helical structure and stepwise binding, respectively. We found that the exchange speed of guest molecules in the tubes could be controlled by varying the tube length.