Molecular Architecture Research Articles

A facile synthesis of α,β-unsaturated imines via palladium-catalyzed dehydrogenation

The dehydrogenation adjacent to an electron-withdrawing group provides an efficient access to α,β-unsaturated compounds that serving as versatile synthons in organic chemistry. However, the α,β-desaturation of aliphatic imines has hitherto proven to be challenging due to easy hydrolysis and preferential dimerization. Herein, by employing a pre-fluorination and palladium-catalyzed dehydrogenation reaction sequence, the abundant simple aliphatic amides are amendable to the rapid construction of complex molecular architectures to produce α,β-unsaturated imines. Mechanistic investigations reveal a Pd(0)/Pd(II) catalytic cycle involving oxidative H–F elimination of N-fluoroamide followed by a smooth α,β-desaturation of the in-situ generated aliphatic imine intermediate. This protocol exhibits excellent functional group tolerance, and even the carbonyl groups are compatible without any competing dehydrogenation, allowing for late-stage functionalization of complex bioactive molecules. The synthetic utility of this transformation has been further demonstrated by a diversity-oriented derivatization and a concise formal synthesis of (±)-alloyohimbane.

Quantifying CO-release from a photo-CORM using 19F NMR: An investigation into light-induced CO delivery

Carbon monoxide (CO) is an innate signaling molecule that can regulate immune responses and interact with crucial elements of the circadian clock. Moreover, pharmacologically, CO has been substantiated for its therapeutic advantages in animal models of diverse pathological conditions. Given that an excessive level of CO can be toxic, it is imperative to quantify the necessary amount for therapeutic use accurately. However, estimating gaseous CO is notably challenging. Therefore, novel techniques are essential to quantify CO in therapeutic applications and overcome this obstacle precisely. The classical Myoglobin (Mb) assay technique has been extensively used to determine the amount of CO-release from CO-releasing molecules (CORMs) within therapeutic contexts. Nevertheless, specific challenges arise when applying the Mb assay to evaluate CORMs featuring innovative molecular architectures. Here, we report a fluorinated photo-CORM (CORM-FBS) for the photo-induced CO-release. We employed the 19F NMR spectroscopy approach to monitor the release of CO as well as quantitative evaluation of CO release. This new 19F NMR approach opens immense opportunities for researchers to develop reliable techniques for identifying molecular structures, quantitative studies of drug metabolism, and monitoring the reaction process.

Multiplexed In Vivo Screening Using Barcoded Aptamer Technology to Identify Oligonucleotide-Based Targeting Reagents.

Recent FDA approvals of mRNA vaccines, short-interfering RNAs, and antisense oligonucleotides highlight the success of oligonucleotides as therapeutics. Aptamers are excellent affinity reagents that can selectively label protein biomarkers, but their clinical application has lagged. When formulating a given aptamer for invivo use, molecular design details can determine biostability and biodistribution; therefore, extensive postselection manipulation is often required for each new design to identify clinically useful reagents harboring improved pharmacokinetic properties. Few methods are available to comprehensively screen such aptamers, especially invivo, constituting a significant bottleneck in the field. In this study, we introduce barcoded aptamer technology (BApT) for multiplexed screening of predefined aptamer formulations in vitro and invivo. We demonstrate this technology by simultaneously investigating 20 aptamer formulations, each harboring different molecular designs, for targeting Non-Small Cell Lung Cancer cells and tumors. Screening in vitro identified a 45 kDa bispecific formulation as the best cancer cell targeting reagent, whereas screening invivo identified a 30 kDa monomeric formulation as the best tumor-specific targeting reagent. The multiplexed analysis pipeline also identified biodistribution phenotypes shared among formulations with similar molecular architectures. The BApT approach we describe here has the potential for broad application to fields where oligonucleotide-based targeting reagents are desired.

Enantioselective Nickel-Electrocatalyzed Reductive Propargylic Carboxylation with CO2.

The exploitation of carbon dioxide (CO2) as a sustainable, plentiful, and harmless C1 source for the catalytic synthesis of enantioenriched carboxylic acids has long been acknowledged as a pivotal task in synthetic chemistry. Herein, we present a current-driven nickel-catalyzed reductive carboxylation reaction with CO2 fixation, facilitating the formation of C(sp3)-C(sp2) bonds by circumventing the handling of moisture-sensitive organometallic reagents. This electroreductive protocol serves as a practical platform, paving the way for the synthesis of enantioenriched propargylic carboxylic acids (up to 98% enantiomeric excess) from racemic propargylic carbonates and CO2. The efficacy of this transformation is exemplified by its successful utilization in the asymmetric total synthesis of (S)-arundic acid, (R)-PIA, (S)-chizhine D, (S)-cochlearin G, and (S,S)-alexidine, thereby underscoring the potential of asymmetric electrosynthesis to achieve complex molecular architectures sustainably.

Influence of chain length of amido betaines and amine degree of diamines on the binary supramolecular assembly and viscosity dynamics of amido betaine/diamine coacervates

Recently, there has been growing interest in the hierarchical assemblies of zwitterionic betaine amphiphiles across various fields due to their utility as stimuli-responsive materials. Herein, we systematically investigate the binary supramolecular assembly of zwitterionic amido betaines and diamines to determine how alkyl chain length of amido betaines (CnDAB) and amine degree of diamines influence their relaxation dynamics of the resultant coacervates. To this end, we synthesized five CnDAB molecules with systematically varying carbon chain lengths (n = 12, 14, 16, 18, and 20) and conjugated them with three different diamines (ethylenediamine, EDA; n,n'-dimethylethylenediamine, DMEDA; and n,n,n',n'-tetramethylethylenediamine,TMEDA). We employed rheology to compare the bulk properties and relaxation dynamics of these assemblies as well as to gain insight into their responsiveness to pH stimulus. All betaine/diamine co-assemblies for all pH values showed shear-thinning behavior while the onset of shear thinning behavior showed some variation for the shear rate inducing such an onset. By changing molecular architecture of co-assembling pairs, zero-shear viscosity values varied from ∼10−1 Pa s to ∼103 Pa s at a concentration of 100 mM CnDAB and 50 mM diamine in water. Four-order-of-magnitude difference in viscosity with small changes in molecular architecture and pH indicates that precise tuning of the rheological properties is possible simply by controlling the self-assembly tendencies and nano-to-micro scale aggregation morphologies through bi-molecular design. Out of 15 different combinations of betaine and diamine pairs studied, the primary amine EDA conjugated with C18DAB resulted in the highest degree of pH-controlled viscosity changes (i.e., highest pH-responsivity). Below 16-carbon alkyl chains on the betaines, pH responsiveness mostly disappeared. Overall, this systematic study brings new insights into the molecular structure-property relationships of amido betaine/diamine systems, which are widely used in diverse sets of applications and fields.

The role of the size of affinity ligands in the detection and characterization of extracellular vesicles

Surface proteins on the membrane of nano-sized extracellular vesicles (EVs) not only play crucial roles in cell-to-cell communication, but also are specific binding targets for EV detection, isolation and tracking. The low abundance of protein biomarkers on EV surface, the formation of clusters and the complex EV surface network impose significant challenges to the study of EVs. Employing bulky sized affinity ligands, such as antibodies, in the detection and characterization of these vesicles often result in reduced sensitivity of detection or poor quantification of proteins on the EV surface. By virtue of their small size and high specificity, Affibody molecules emerge as a potential alternative to their monoclonal antibody counterparts as robust affinity ligands in EV research. In this study, we present a theoretical framework on the superiority of anti-HER2 Affibodies over anti-HER2 antibodies in labeling and detecting HER2-positive EVs, followed by the demonstration of the advantages of HER2 Affibodies in accessing EV surface and the detection of EVs through multiple types of approaches including fluorescence intensity, colorimetry, and fluorescence polarization. HER2 Affibodies outperformed by 10-fold over three HER2 antibody clones in accessing HER2-positive EVs derived from different human cancer cell lines. Furthermore, HRP-Affibody molecules could detect EVs from cancer cells spiked into human serum with at least a 2-fold higher sensitivity compared with that of their antibody counterparts. In addition, in fluorescence polarization assays in which no separation of free from bound ligand is required, FITC-labeled HER2 Affibodies could sensitively detect HER2-positive EVs with a clinically relevant limit of detection, whilst HER2 antibodies failed to detect EVs in the same conditions. With the demonstrated superiority in accessing and detecting surface targets over bulky-sized antibodies in EVs, Affibodies may become the next-generation of affinity ligands in the precise characterization and quantification of molecular architecture on the surface of EVs.

Relaxation Editing in NMR Using a New Two-Dimensional Long-Lived Coherence Method for Mixture Analysis.

The exploration of metabolomics and targeted segments of proteins stands as a pivotal facet of Nuclear Magnetic Resonance (NMR) analysis, furnishing valuable insights into molecular architectures and potential therapeutic applications. The issue of spectral congestion frequently presents challenges in ascribing distinct peaks within the confines of both one-dimensional (1D) and two-dimensional (2D) NMR spectra. Numerous strategies have been proposed to resolve specific resonances in NMR spectra differentially. Among these approaches, relaxation editing emerges as a viable solution. In the realm of relaxation phenomena within NMR, Long-Lived States (LLS) and Long-Lived Coherences (LLC) manifest as promising phenomena, offering enhanced relaxation lifetimes in comparison to the traditional longitudinal (T1) and transverse (T2) relaxation times for coupled nuclear spins. Notably, LLC presents a pathway to attenuate uncoupled high-intensity peaks, effectively diminishing their impact. The foundation of this technique rests upon the premise that the relaxation lifetime in the rotating frame (T1ρ) remains smaller than TLLC. In pursuit of refining spectral assignments within complex mixtures, we introduce a new pulse sequence tailored for LLC Total Correlation Spectroscopy (LLC-TOCSY). This demonstrates efficacy in extracting LLC signals within configurations involving multiple coupled spins, thereby decluttering the spectrum and enhancing the accuracy of peak assignments. To validate the effectiveness of this method, a collection of samples was subjected to scrutiny, yielding compelling results.

Spatial mapping of hepatic ER and mitochondria architecture reveals zonated remodeling in fasting and obesity

The hepatocytes within the liver present an immense capacity to adapt to changes in nutrient availability. Here, by using high resolution volume electron microscopy, we map how hepatic subcellular spatial organization is regulated during nutritional fluctuations and as a function of liver zonation. We identify that fasting leads to remodeling of endoplasmic reticulum (ER) architecture in hepatocytes, characterized by the induction of single rough ER sheet around the mitochondria, which becomes larger and flatter. These alterations are enriched in periportal and mid-lobular hepatocytes but not in pericentral hepatocytes. Gain- and loss-of-function in vivo models demonstrate that the Ribosome receptor binding protein1 (RRBP1) is required to enable fasting-induced ER sheet-mitochondria interactions and to regulate hepatic fatty acid oxidation. Endogenous RRBP1 is enriched around periportal and mid-lobular regions of the liver. In obesity, ER-mitochondria interactions are distinct and fasting fails to induce rough ER sheet-mitochondrion interactions. These findings illustrate the importance of a regulated molecular architecture for hepatocyte metabolic flexibility.

Full‐Color Electrochromics with Donor‐Gradient Architectures for Chameleon‐Like Adaptive Camouflage

AbstractMulticolor electrochromics have emerged as a promising solution for achieving active color modulation akin to chameleon‐like adaptive camouflage. However, the development of electrochromics with full‐color tunability still remains challenging, given the weak molecular polarity of inherent active materials and the difficulty in forming polarizer orbitals under varying applied voltages. Employing molecular polarity adjustments, a novel electrochromic polymer is successfully developed with a donor‐gradient design of molecular architecture, enabling comprehensive full‐color tunability. The polymer demonstrates outstanding overall electrochromic performance, including fast switching (around 1.4 s), high coloration efficiency (395.1 cm2 C−1@550 nm) and excellent reversibility (over 92% retention after 5000 cycles). Leveraging the full‐color tunability and rapid response, the electrochromic polymer is further integrated with sensing and control modules to create an environmental adaptive camouflage prototype system capable of seamlessly blending colors with dynamic background environments. This work is expected to provide a straightforward approach for developing full‐color electrochromics for electrochromic camouflage applications.

Dual Photoredox and Nickel Catalysis in Regioselective Diacylation: Exploring the Versatility of Nickel Oxidation States in Allene Activation.

We present a nickel-catalyzed regioselective radical diacylation of allenes with ketoacids to produce 1,4-dione products by dual photoredox and nickel catalysis. This integrated approach merges redox-active oxidative addition and reductive elimination steps with migratory insertion. The acyl radical generated in the photoredox cycle sequentially adds to Ni(I) and Ni(II) intermediates following a Ni(I)-Ni(II)-Ni(II)-Ni(III)-Ni(I) catalytic cycle. This methodology, supported by DFT calculations, demonstrates the potential of nickel catalysis in the creation of complex molecular architectures.

Four-Component Statistical Copolymers by RAFT Polymerization.

This manuscript serves as the starting point for in-depth research of multicomponent, statistical, methacrylate-based copolymers that potentially mimic the behavior of proteins in aqueous solutions. These synthetic macromolecules are composed of specially chosen comonomers: methacrylic acid (MAA), oligoethylene glycol methyl ether methacrylate (OEGMA475), 2-(dimethylamino)ethyl methacrylate (DMAEMA) and benzyl methacrylate (BzMA). Monomer choice was based on factors such as the chemical nature of pendant functional groups, the polyelectrolyte/polyampholyte and amphiphilic character and the overall hydrophobic-hydrophilic balance (HLB) of the obtained quaterpolymers. Their synthesis was achieved via a one-pot reversible addition fragmentation chain transfer (RAFT) polymerization in two distinct compositions and molecular architectures, linear and hyperbranched, respectively, in order to explore the effects of macromolecular topology. The resulting statistical quaterpolymers were characterized via 1H-NMR and ATR-FTIR spectroscopies. Their behavior in aqueous solutions was studied by dynamic (DLS) and electrophoretic light scattering (ELS) and fluorescence spectroscopy (FS), producing vital information concerning their self-assembly and the structure of the formed aggregates. The physicochemical studies were extended by tuning parameters such as the solution pH and ionic strength. Finally, the quaterpolymer behavior in FBS/PBS solutions was investigated to test their colloid stability and biocompatibility in an in vivo-mimicking, biological fluid environment.

Fluorinated Organic Polymers for Cancer Drug Delivery.

In the realm of cancer therapy, the spotlight is on nanoscale pharmaceutical delivery systems, especially polymer-based nanoparticles, for their enhanced drug dissolution, extended presence in the bloodstream, and precision targeting achieved via surface engineering. Leveraging the amplified permeation and retention phenomenon, these systems concentrate therapeutic agents within tumor tissues. Nonetheless, the hurdles of systemic toxicity, biological barriers, and compatibility with living systems persist. Fluorinated polymers, distinguished by their chemical idiosyncrasies, are poised for extensive biomedical applications, notably in stabilizing drug metabolism, augmenting lipophilicity, and optimizing bioavailability. Material science heralds the advent of fluorinated polymers that, by integrating fluorine atoms, unveil a suite of drug delivery merits: the hydrophobic traits of fluorinated alkyl chains ward off lipid or protein disruption, the carbon-fluorine bond's stability extends the drug's lifecycle in the system, and a lower alkalinity coupled with a diminished ionic charge bolsters the drug's ability to traverse cellular membranes. This comprehensive review delves into the utilization of fluorinated polymers for oncological pharmacotherapy, elucidating their molecular architecture, synthetic pathways, and functional attributes, alongside an exploration of their empirical strengths and the quandaries they encounter in both experimental and clinical settings.

GraphEGFR: Multi-task and transfer learning based on molecular graph attention mechanism and fingerprints improving inhibitor bioactivity prediction for EGFR family proteins on data scarcity.

The proteins within the human epidermal growth factor receptor (EGFR) family, members of the tyrosine kinase receptor family, play a pivotal role in the molecular mechanisms driving the development of various tumors. Tyrosine kinase inhibitors, key compounds in targeted therapy, encounter challenges in cancer treatment due to emerging drug resistance mutations. Consequently, machine learning has undergone significant evolution to address the challenges of cancer drug discovery related to EGFR family proteins. However, the application of deep learning in this area is hindered by inherent difficulties associated with small-scale data, particularly the risk of overfitting. Moreover, the design of a model architecture that facilitates learning through multi-task and transfer learning, coupled with appropriate molecular representation, poses substantial challenges. In this study, we introduce GraphEGFR, a deep learning regression model designed to enhance molecular representation and model architecture for predicting the bioactivity of inhibitors against both wild-type and mutant EGFR family proteins. GraphEGFR integrates a graph attention mechanism for molecular graphs with deep and convolutional neural networks for molecular fingerprints. We observed that GraphEGFR models employing multi-task and transfer learning strategies generally achieve predictive performance comparable to existing competitive methods. The integration of molecular graphs and fingerprints adeptly captures relationships between atoms and enables both global and local pattern recognition. We further validated potential multi-targeted inhibitors for wild-type and mutant HER1 kinases, exploring key amino acid residues through molecular dynamics simulations to understand molecular interactions. This predictive model offers a robust strategy that could significantly contribute to overcoming the challenges of developing deep learning models for drug discovery with limited data and exploring new frontiers in multi-targeted kinase drug discovery for EGFR family proteins.

Bifunctional Metal-Organic Nanoballs Featuring Lewis Acidic and Basic Sites as a New Platform for One-Pot Tandem Catalysis.

The design and synthesis of polyhedra using coordination-driven self-assembly has been an intriguing research area for synthetic chemists. Metal-organic polyhedra are a class of intricate molecular architectures that have garnered significant attention in the literature due to their diverse structures and potential applications. Hereby, we report Cu-MOP, a bifunctional metal-organic cuboctahedra built using 2,6-dimethylpyridine-3,5-dicarboxylic acid and copper acetate at room temperature. The presence of both Lewis basic pyridine groups and Lewis acidic copper sites imparts catalytic activity to Cu-MOP for the tandem one-pot deacetalization-Knoevenagel/Henry reactions. The effect of solvent system and time duration on the yields of the reactions was studied, and the results illustrate the promising potential of these metal-organic cuboctahedra, also known as nanoballs for applications in catalysis.

Naturally Occurring Norsteroids and Their Design and Pharmaceutical Application.

The main focus of this review is to introduce readers to the fascinating class of lipid molecules known as norsteroids, exploring their distribution across various biotopes and their biological activities. The review provides an in-depth analysis of various modified steroids, including A, B, C, and D-norsteroids, each characterized by distinct structural alterations. These modifications, which range from the removal of specific methyl groups to changes in the steroid core, result in unique molecular architectures that significantly impact their biological activity and therapeutic potential. The discussion on A, B, C, and D-norsteroids sheds light on their unique configurations and how these structural modifications influence their pharmacological properties. The review also presents examples from natural sources that produce a diverse array of steroids with distinct structures, including the aforementioned A, B, C, and D-nor variants. These compounds are sourced from marine organisms like sponges, soft corals, and starfish, as well as terrestrial entities such as plants, fungi, and bacteria. The exploration of these steroids encompasses their biosynthesis, ecological significance, and potential medical applications, highlighting a crucial area of interest in pharmacology and natural product chemistry. The review emphasizes the importance of researching these steroids for drug development, particularly in addressing diseases where conventional medications are inadequate or for conditions lacking sufficient therapeutic options. Examples of norsteroid synthesis are provided to illustrate the practical applications of this research.

Synchronous Regulation of Hydrophobic Molecular Architecture and Interface Engineering for Robust WORM‐Type Memristor

AbstractIn the context of human active response to exponentially increasing data volumes, memristors have emerged as a focal point in systematic problem‐solving approaches. Particularly, organic memristors, characterized by excellent scalability, flexibility, and 3D stacking capabilities, have shown its tremendous potential in innovative electronic applications. However, the modulation of molecular assembly and interface interaction at the electrode surface poses a challenging task, despite their crucial role in determining the memristive performance. Herein, a collaborative method involving hydrophobic molecular design and interface engineering is proposed to generate high‐quality nanofilms with optimal photoelectric and electrochemical properties. By subjecting the bottom electrode to O2 plasma treatment and chemical modification using a hydrophobic ionic liquid poly(diallyldimethylammonium) bis(trifluoromethanesulfonyl)imide (PTFSI), the hydrophobic compound DN demonstrates exceptional affinity and stronger intermolecular interactions with the electrode surface. Consequently, the two‐terminal device array comprising Al/DN@PTFSI/ITO exhibits robust non‐volatile write‐once‐read‐many times (WORM) memory behavior, resulting in a tripling production yield from 30% to 92% along with a lower threshold voltage of 1.5 V, higher ON/OFF current ratio of 103 and excellent stability. This study presents a versatile approach to optimize the film assembly and material/electrode interface, thereby accelerating the development of organic memristors toward future applications.

Decarboxylative stereoretentive C–N coupling by harnessing aminating reagent

In recent decades, strategies involving transition-metal catalyzed carbon-carbon or carbon-heteroatom bond coupling have emerged as potent synthetic tools for constructing intricate molecular architectures. Among these, decarboxylative carbon-nitrogen bond formation using abundant carboxylic acids or their derivatives has garnered notable attention for accessing alkyl- or arylamines, one of key pharmacophores. While several decarboxylative amination methods have been developed, the involvement of a common carboradical intermediate currently poses challenges in achieving stereospecific transformation toward chiral alkylamines. Herein, we present a base-mediated, stereoretentive decarboxylative amidation by harnessing 1,4,2-dioxazol-5-one as a reactive and robust amidating reagent under transition-metal-free ambient conditions, encompassing all types of primary, secondary and tertiary carboxylic acids, thereby providing access to the important pharmacophore, α-chiral amines. This method exhibits high functional group tolerance, convenient scalability, and ease of applicability for 15N-isotope labeling, thus accentuating its synthetic utilities. Experimental and computational mechanistic investigations reveal a sequence of elementary steps: i) nucleophilic addition of carboxylate to dioxazolone, ii) rearrangement to form a dicarbonyl N-hydroxy intermediate, iii) conversion to hydroxamate, followed by a Lossen-type rearrangement, and finally, iv) reaction of the in situ generated isocyanate with carboxylate leading to C–N bond formation in a stereoretentive manner.

2.2]Paracyclophanes: From Selective Functionalization to Optical Properties

AbstractSince their discovery, [2.2]paracyclophane (pCp) and its derivatives have fascinated the scientific community due to their original molecular architecture and unusual electronic behavior. Over the years, significant efforts have been devoted to the development of substituted pCps for a variety of applications in different fields, ranging from organic synthesis and asymmetric catalysis to polymer chemistry and material science. This review describes a series of useful approaches that allow chemists to selectively decorate pCps, control the planar chirality that these molecules can display as soon as they are functionalized, and tune their photophysical behaviors. For each of these aspects of paracyclophane chemistry, selected examples of major advances are presented, and possible directions for future research are outlined. The application of pCp as central core for the development of uncommon 3D luminophores is finally highlighted. Emphasis is placed on the potential use of planar chiral luminescent paracyclophanes as antennas or ligands for the design of multifunctional lanthanide complexes, a quite underdeveloped but highly promising area for future research endeavors.

Block and Statistical Copolymers of Methacrylate Monomers with Dimethylamino and Diisopropylamino Groups on the Side Chains: Synthesis, Chemical Modification and Self-Assembly in Aqueous Media.

The synthesis of amphiphilic diblock and statistical (random) copolymers of poly(dimethylamino ethyl methacrylate) and poly((2-(diisopropylamino) ethyl methacrylate) using the reversible addition-fragmentation chain transfer polymerization technique (RAFT polymerization) is reported. The precursor copolymers were chemically modified to create derivative copolymers of polyelectrolyte and polyampholyte nature with novel solution properties. Moreover, their molecular and physicochemical characteristics, as well as their self-assembly in aqueous media as a function of molecular architecture and composition, are investigated by using size exclusion chromatography, spectroscopic characterization techniques and light scattering techniques. Furthermore, the behavior and properties of the obtained micelles and aggregates were studied, depending on the pH, temperature and ionic strength of the aqueous solutions. The response of the systems to changes in these parameters shows interesting behavior and new properties that are useful for their utilization as nanocarriers of pharmaceutical compounds.

Natural Distribution, Structures, Synthesis, and Bioactivity of Hasubanan Alkaloids.

Hasubanan alkaloids represent a distinct class of alkaloids bearing a structural resemblance to morphine, predominantly found in herbals of the Stephania genus. Their intriguing molecular architecture and potential analgesic properties have captured the interest of medicinal chemists worldwide. This review meticulously examines the natural distribution, structural characteristics, biosynthetic pathways, synthetic methodologies, and biological activities of hasubanans.