Molecular Analogues Research Articles

Synthetic modeling of the structure and function of the rare-earth dependent methanol dehydrogenase cofactor.

Historically, rare-earth ions have been considered irrelevant to biology. Recently, the active sites of certain methanol dehydrogenase (MDH) enzymes have been shown to contain a redox-inactive, rare-earth (RE) cation coordinated by the redox-active pyrroloquinoline quinone (PQQ) cofactor. Importantly, it was demonstrated that rare earths were essential for the growth of certain methylotrophs that incorporated the XoxF-MDH. In this chapter, we summarize the optimized synthesis of a previously published rare-earth complex that serves as a model of the active site of this RE-containing MDH enzyme. The structure and reactivity of the metalated complex, [La(LQQ)(NO3)3] are also discussed. [La(LQQ)(NO3)3] catalytically oxidizes the test alcohol substrate, p-methylbenzyl alcohol, 4MeBnOH, to p-methylbenzaldehyde, 4MePhCHO, in the presence of a base (2,6-lutidine) and a terminal oxidant (ferrocenium hexafluorophosphate) with ~17 turnovers. By studying this synthetic model, we have developed a body of evidence about both the reactivity and the mechanism of dehydrogenation of alcohols as a molecular analogue to a native, rare-earth dependent enzyme.

Direct observation of defect modes in molecular aggregate analogs

In this work we investigate defect modes localized at the ends and within the bulk of 1D metamaterial analogs of molecular aggregates. The study is undertaken in the microwave regime, where the cm scale of the metamaterial analog provides an opportunity to directly probe the modes deep within their near fields in ways not easily achieved in molecular systems. To demonstrate the power of this approach we compare our observations to predictions from a simple Su, Schrieffer, and Heeger (SSH) model and find good qualitative agreement.

Interfacial Field-Driven Proton-Coupled Electron Transfer at Graphite-Conjugated Organic Acids.

Interfacial proton-coupled electron transfer (PCET) reactions are central to the operation of a wide array of energy conversion technologies, but molecular-level insights into interfacial PCET are limited. At carbon surfaces, designer sites for interfacial PCET can be incorporated by conjugating organic acid functional groups to graphite edges though aromatic phenazine linkages. At these graphite-conjugated catalysts (GCCs) bearing organic acid moieties, PCET is driven by complex interfacial electrostatic and field gradients that are difficult to probe experimentally. Herein, the spatially inhomogeneous interfacial electrostatic potentials and electric fields of GCC organic acids are computed as functions of applied potential. The calculated proton-coupled redox potentials for the PCET reactions at the GCC phenazine bridges and organic acid sites are in agreement with cyclic voltammetry measurements for a series of GCC acids. The trends in these redox potentials are explained in terms of the acidity of the molecular analogues and continuous conjugation between the acid and the graphite surface. The calculations illustrate that this conjugation is interrupted in a GCC acetic acid system, providing an explanation for the absence of a cyclic voltammetry peak corresponding to PCET at this acid site. This combined theoretical and experimental study demonstrates the critical role of continuous conjugation and strong electronic coupling between the GCC acid site and the graphite to enable interfacial field-driven PCET at the acid site. Understanding the connection between the atomic structure of the surface and the interfacial electrostatic potentials and fields that govern PCET thermochemistry may guide heterogeneous catalyst design.

Electro-Oligomerization of Vindoline

In a break from traditional oncolytic agents based on dimeric combinations [1] of catharanthine and vindoline [2] units, higher cytotoxicity of a designed dimeric vindoline is predicted [3] via its interfacial docking between α- and β-tubulins. Electrosynthesis potentially is a route to higher molecular weight analogs of vindoline. Out of the three dimers resulting from electrochemical oxidation of vindoline [4] only one was characterized; chemical formation of trimeric vindoline [5] has been reported.Even though vindoline is commonly referred to as a dihydro-indole alkaloid [6], its electrochemistry [7] is dominantly reflective of structurally related anilines. Like electro-polymerization of anilines, our work based on anodic cyclic voltammetry of vindoline suggests formation of vindoline oligomers that readily pass into solution.

Prebiotically-relevant low polyion multivalency can improve functionality of membraneless compartments

Multivalent polyions can undergo complex coacervation, producing membraneless compartments that accumulate ribozymes and enhance catalysis, and offering a mechanism for functional prebiotic compartmentalization in the origins of life. Here, we evaluate the impact of lower, more prebiotically-relevant, polyion multivalency on the functional performance of coacervates as compartments. Positively and negatively charged homopeptides with 1–100 residues and adenosine mono-, di-, and triphosphate nucleotides are used as model polyions. Polycation/polyanion pairs are tested for coacervation, and resulting membraneless compartments are analyzed for salt resistance, ability to provide a distinct internal microenvironment (apparent local pH, RNA partitioning), and effect on RNA structure formation. We find that coacervates formed by phase separation of the shorter polyions more effectively generated distinct pH microenvironments, accumulated RNA, and preserved duplexes than those formed by longer polyions. Hence, coacervates formed by reduced multivalency polyions are not only viable as functional compartments for prebiotic chemistries, they can outperform higher molecular weight analogues.

Molecular Prussian Blue Analogues: From Bulk to Molecules and Low-dimensional Aggregates

Cyanide-bridged mixed-valence Co-Fe multi-nuclear complexes, 0D molecular Prussian blue analogues (PBAs), have variable molecular structures and flexible electronic states. In this highlight review...

From Molecules to Porous Materials: Integrating Discrete Electrocatalytic Active Sites into Extended Frameworks.

Metal–organic and covalent–organic frameworks can serve as a bridge between the realms of homo- and heterogeneous catalytic systems. While there are numerous molecular complexes developed for electrocatalysis, homogeneous catalysts are hindered by slow catalyst diffusion, catalyst deactivation, and poor product yield. Heterogeneous catalysts can compensate for these shortcomings, yet they lack the synthetic and chemical tunability to promote rational design. To narrow this knowledge gap, there is a burgeoning field of framework-related research that incorporates molecular catalysts within porous architectures, resulting in an exceptional catalytic performance as compared to their molecular analogues. Framework materials provide structural stability to these catalysts, alter their electronic environments, and are easily tunable for increased catalytic activity. This Outlook compares molecular catalysts and corresponding framework materials to evaluate the effects of such integration on electrocatalytic performance. We describe several different classes of molecular motifs that have been included in framework materials and explore how framework design strategies improve on the catalytic behavior of their homogeneous counterparts. Finally, we will provide an outlook on new directions to drive fundamental research at the intersection of reticular-and electrochemistry.

Low-bandgap push–pull molecules in polymer matrices for use in thin-film organic photovoltaic devices

Conjugated polymers are widely used in thin-film organic photovoltaic devices to absorb light and serve as electron donors or acceptors. Small molecular analogues are attractive substitutes because they have fully defined structures, can be purified rigorously, and are typically more soluble and volatile. However, producing active films composed primarily of small molecules remains challenging. We have devised bulk heterojunction solar cells in which poly(3-hexylthiophene-2,5-diyl) and poly[[9-(1-octylnonyl)-9H-carbazole-2,7-diyl]-2,5-thiophenediyl-2,1,3-benzothiadiazole-4,7-diyl-2,5-thiophenediyl] are used as matrices to prepare films containing low-bandgap push–pull molecules as electron donors and (6,6)-phenyl-C61-butyric acid methyl ester or (6,6)-phenyl-C71-butyric acid methyl ester as electron acceptors. Compared with reference devices devoid of push–pull molecular additives, increases in power conversion efficiencies up to 30.4% were measured.

Low molecular weight heparan sulfate containing facial skin care for reducing inflammation and restoring aged-skin homeostasis.

Chronic exposure of the skin to environmental factors, including solar radiation and air pollution, promotes skin aging by inducing inflammation which damages the skin. Heparan sulfate (HS) is one of the glycosaminoglycans, which has a central role in modulating skin repair. In its appearance in the skin, HS is large and highly polar and therefore unable to penetrate the skin. As a component in a topical formulation, the modified to a low molecular weight heparan sulfate analog (LMW-HS) showed biological modulation activity. This review discusses the potential role of topical formulations containing LMW-HS in restoring aged-skin homeostasis and skin health. An expert panel of dermatologists who regularly treat clinical signs of facial photoaging explored the role of LMW-HS containing formulations for reducing inflammation and facial-aging signs. For this purpose, evidence from the conducted literature searches was used together with expert opinion and experience of the panel. Extrinsic factors contribute to skin aging through oxidative stress, stimulating inflammation involved in extracellular matrix degradation. Evidence showed that chemokines require heparan sulfate for their full range of functional activities during innate immunity. Studies showed the LMW-HS containing topical formulation to penetrate the skin within 48hours of once-daily application. LMW-HS used in the periorbital area improved discoloration and wrinkles at Week 2 with continuous improvement up to Week 12. The LMW-HS containing formulation showed improvements in skin condition when applied on photo-damaged skin, indicating its therapeutic potential.

Surface-Enhanced Raman Scattering of Phenols and Catechols by a Molecular Analogue of Titanium Dioxide.

Surface-enhanced Raman spectroscopy (SERS) of semiconducting TiO2 was used for studying binding modes and surface reactions of molecules bound at the interface but is generally limited by low signal intensity and lack of authentic structural information. Here, we report a representative titanium-oxide cluster (TOC), i.e., Ti17O24(OiC3H7)20 (Ti17), combines the benefits from both precise structures and intense SERS signals by providing a titania surface. According to the single-crystal X-ray diffraction analysis, phenols and catechols are vertically attached via σ-bonds to the certain sites of Ti17. Ti17 brings about much more intense Raman signals than the reference TiO2 NPs, leading to 10-5-10-6 M analyte detection (enhancement factors are 103-105). The contributions of focusing effect, CHEM effect and resonance mechanism, all of which are found responsible for the higher SERS activity of Ti17 than the reference TiO2 NPs, in the SERS by Ti17 are quantitatively analyzed. This study suggests SERS by TOCs may be promising for detection purposes and structural studies of environmentally and catalytically relevant molecules with fewer assumptions regarding molecular structures or binding mechanisms.

Effects of Selected Resveratrol Analogues on Activation and Polarization of Lipopolysaccharide-Stimulated BV-2 Microglial Cells.

Increasing health-promoting effects of resveratrol and its molecular structural analogues have been discovered, and the acting mechanism has been explored. However, the activity comparison of such compounds in targeting macrophage-related inflammation associated with neurodegenerative diseases remains untouched. In this study, we evaluated the activation and polarization transition of lipopolysaccharide (LPS)-stimulated BV-2 mouse microglial macrophages exposed to resveratrol (RES) and its analogues pterostilbene (PTE), oxyresveratrol (ORES), acetyl-trans-resveratrol (ARES), and trans-2,3,5,4'-tetrahydroxystilbene-2-O-glucopyranoside (TSG). At 10 μM, all of the five stilbene compounds have effectively suppressed the LPS-stimulated BV-2 cell release of proinflammatory mediators such as NO, TNF-α, iNOS, IL-1β, and IL-6. Mechanism study elucidated that they exert anti-inflammatory effects through MAPKs (ERK1/2, JNK, and p38) and NF-κB signaling pathways. Further investigation in treating BV-2 cells with resveratrol and its analogues revealed the reversal of LPS-induced phenotype molecules from M1 (iNOS, IL-1β, IL-6, and CD86) to M2 (Arg1, CD163, and IL-10) subtypes, manifesting that these five stilbenes suppressed inflammation through modulating the polarized phenotypes of BV-2 microglia. Most importantly, PTE demonstrated the most potent inhibitory activity among these five stilbene compounds. Therefore, this study not only highlights microglia-induced inflammatory responses as a potential therapeutic target but also suggests future insights in considering the options of nutraceutical development for resveratrol and its analogues.

Multiplex Stimulated Raman Scattering Imaging Cytometry Reveals Lipid-Rich Protrusions in Cancer Cells under Stress Condition.

SummaryIn situ measurement of cellular metabolites is still a challenge in biology. Conventional methods, such as mass spectrometry or fluorescence microscopy, would either destroy the sample or introduce strong perturbations to target molecules. Here, we present multiplex stimulated Raman scattering (SRS) imaging cytometry as a label-free single-cell analysis platform with chemical specificity and high-throughput capabilities. Using SRS imaging cytometry, we studied the metabolic responses of human pancreatic cancer cells under stress by starvation and chemotherapeutic drug treatments. We unveiled protrusions containing lipid droplets as a metabolic marker for stress-resistant cancer cells. Furthermore, by spectroscopic SRS mapping, we unveiled that triglyceride in lipid droplets are used for local energy production through lipolysis, autophagy, and β-oxidation. Our findings demonstrate the potential of targeting lipid metabolism for selective treatment of stress-resistant cancers. Collectively, these results highlight SRS imaging cytometry as a powerful label-free tool for biological discoveries with a high-throughput, high-content capacity.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

Self-Assembly and Properties of a Discrete Water-Soluble Prussian Blue Analogue FeII/CoIII Cube: Confinement of a Water Molecule in Aqueous Solution.

Novel types of water-soluble anionic cubic cages, K4[{CoIII(Me3-Tacn)}4{FeII(CN)6}4] and Na4[{CoIII(Me3-Tacn)}4{FeII(CN)6}4] (Me3-Tacn = 1,4,7-trimethyl-1,4,7-triazacyclononane), were prepared by means of a mechanistically designed self-assembly process between [Co(Me3-Tacn)Cl3] and A4[FeII(CN)6] (M = Na or K), consisting of a rate-limiting outer-sphere redox step, followed by a fast substitution/inner-sphere redox reaction sequence. These compounds show remarkable stability in aqueous solution at different pH ranges, displaying neat protonation processes and reversible oxidation with peroxodisulfate to its neutral {FeIII4CoIII4} form. Furthermore, the cages behave as a robust and water-soluble molecular Prussian Blue analogue capable of encapsulating {Na-OH2}+ pairs and K+ cations in aqueous solution, with the cubic structure of the complex being preserved. Substitution of the {Na-OH2}+ pairs by K+ is easily accomplished, and the electrochemical properties of the sodium and potassium salts of the new cages have been found to be dramatically dependent on the encapsulated units.

Preprocessing of Raman Lidar Signal Over a High Altitude Station in India: Practical Considerations

Lidar can provide the range-resolved information about the vertical profiles of optical properties of aerosol content and clouds present in the atmosphere. However, before obtaining the information from received lidar signal we ought to use a few pre-processing techniques such as range-correction, temporal and spatial averaging, dead time correction of the photon counts (PC) signal, correction due to overlap effect, Simulation of molecular Rayleigh signal and gluing analog & PC signals. In this work, we have discussed some of the initial pre-processing techniques ought to be performed before lidar inversion.

The Challenging Detection of Nucleobases from Pre-accretional Astrophysical Ice Analogs

Abstract Amino acids, sugars, and nucleobases are considered as the so-called molecular bricks of life, the major subunits of proteins and genetic materials. All three chemical families have been previously detected in meteorites. In dense molecular cloud ice analogs, the formation of a large set of amino acids and sugars (+derivatives) has been observed. In this contribution, we demonstrate that similar ices (H2O:13CH3OH:NH3 ices, 2:1:1) can also lead to the formation of nucleobases. Using combined UPLC-Orbitrap mass spectrometric and UPLC-SRM-triple quadrupole mass spectrometric analyses, we have unambiguously detected cytosine in these primitive, realistic astrophysical ice analogs. Additionally, a huge variety of nucleobase isomers was observed. These results indicate that all central subunits of biochemical materials may have already been present at early stages of chemical evolution of the protosolar nebula, before accretion toward planetesimals. Consequently, the formation of amino acids, sugars, and nucleobases does not necessarily require secondary alteration processes inside meteoritic parent bodies. They might have been supplied from dense molecular cloud ices toward post-accretional objects, such as nonaqueously modified comets, and subsequently delivered onto the early Earth's surface, potentially triggering the emergence of prebiotic chemistry leading to the first living systems.

Feasibility of ground state spin switching in a molecular analogue of the mixed-metal oxides with the perovskite structure

The carboxylate substitution reaction between the reported all-benzoate complex [Ce3Mn8O8(PhCO2)18(PhCO2H)2] (1) and 2-Cl-benzoic acid has led to isolation of [Ce3Mn8O8(2-Cl-PhCO2)15.3(PhCO2)2.7(H2O)2] (2). The structures of 1 and 2 are very similar, both containing a tetragonally-elongated MnIII8 cuboid with a CeIV at its center and two CeIII attached to opposite faces, but 2 shows extensive disorder in the ligands and the Cl atom positions and occupancies. Variable-temperature (T) solid-state dc and ac magnetic susceptibility data for 2 are significantly different from those for 1 and are assigned as due to small ligand-induced structural perturbation of the core that has brought an A-type antiferromagnetic (AF) excited state much closer to the C-type AF ground state. Fits of the dc χMT vs T data support this interpretation but due to the ligand disorder in 2, a more definitive description of the lowest energy spin states of 2 is not possible. Nevertheless, these results provide important support for the feasibility of ground state spin switching by ligand-induced core perturbation (‘chemical pressure’) in this family, and they encourage further studies.

Separation and determination of alkylamides from prickly ash powder using molecularly imprinting technique

In this work, a molecularly imprinted polymer solid phase extraction method was developed to extract Zanthoxylum alkylamides from prickly ash. Surface molecularly imprinted polymers (SMIP) were prepared using the molecular structural analogs of sanshool as a dummy template molecule and acylated silica as backbone. The structural characteristics of the polymers were determined by Fourier-transform infrared spectroscopy and scanning electron microscopy. Dynamic adsorption and isothermal adsorption were investigated. SMIP was used to prepare a molecularly imprinted solid-phase extraction column (SPEC) for the extraction of Zanthoxylum alkylamides from prickly ash powder, followed by high performance liquid chromatography (HPLC) determination. Through separation by SMIP-SPEC, the purity of alkylamides in prickly ash extracts increased from 27.26%–93.58 %. Good linearity for alkylamides standard solution was obtained in the range of 1.0–800.0 μg/mL, and low detection and quantification limits were 0.044 and 0.147 μg/mL, respectively. The method recoveries at four concentration levels of alkylamides were found within 90.3−97.1 % with relative standard deviations (RSDs) of 2.5%–5.9%. These indicate the good recognition ability and affinity to Zanthoxylum alkylamides of SMIP and the novelty of the method for the extraction of alkylamides. The method described could be used for the enrichment of alkylamides and rapid detection.

The study of the effect of the low molecular analog of neuropeptide Y on behavioral reactions in rats

The study of the effect of the low molecular analog of neuropeptide Y on behavioral reactions in rats

Molecular Control of Heterogeneous Electrocatalysis through Graphite Conjugation.

The efficient interconversion of electrical and chemical energy requires catalysts capable of accelerating multielectron reactions at or near electrified interfaces. These reactions can be performed at metallic surface sites on heterogeneous electrocatalysts or through redox mediation at molecular electrocatalysts. The relative ease of synthesis and characterization for homogeneous catalysts has allowed for molecular-level control over the active site and permitted systematic tuning of activity and selectivity. Similar control is difficult to achieve with heterogeneous electrocatalysts, because they typically exhibit a distribution of active site geometries and local electronic structures, which are challenging to modify with molecular precision. However, metallic heterogeneous electrocatalysts benefit from a continuum of electronic states that distribute the redox burden of multielectron transformations, enabling more efficient catalysis. We envisioned that we could combine the attractive properties of molecular and heterogeneous catalysts by integrating tunable molecular active sites into the delocalized band states of a conductive solid. The Surendranath group has developed a class of electrocatalysts in which molecules are strongly electronically coupled to graphitic electrodes through a conductive, aromatic pyrazine linkage such that they behave like metallic surface active sites. In this Account, we discuss the dual role of these graphite-conjugated catalysts (GCCs) as a platform with which to answer molecular-level questions of metallic active sites and as a tool with which to fundamentally alter the mechanism and enhance the performance of molecular active sites. We begin by describing the electrochemical and spectroscopic studies that demonstrated that GCC sites behave like metallic active sites rather than simply as redox mediators attached to electrode surfaces. We then discuss how electrochemical studies of a series of graphite-conjugated acids enabled the construction of a molecular model for the thermochemistry of proton-coupled electron transfer reactions at GCC sites based on the pKa of the molecular analogue of the conjugated site and the potential of zero free charge of the electrode. In the final section, we discuss the effects of graphite conjugation on the mechanism and rate of oxygen reduction, hydrogen evolution, and carbon dioxide reduction catalysis across four different GCC platforms involving N-heterocycle, organometallic, and metalloporphyrin active sites. We discuss how molecular-level tuning at graphite-conjugated active sites directly correlates to changes in catalytic activity for the oxygen reduction reaction. We demonstrate that graphite-conjugated porphyrins show enhanced catalytic oxygen reduction activity over amide-linked porphyrins. Lastly, we describe how catalysis at graphite-conjugated sites proceeds through mechanisms involving concerted electron transfer and substrate activation, in stark contrast to the mechanisms observed for molecular analogues. Overall, we showcase how GCCs provide a rich platform for controlling heterogeneous catalysis at the molecular level.