Biorelevant Molecules Research Articles

Recent Advances in Bipolar Electrochemiluminescence for Analytical Application

Background: Bipolar electrode (BPE), as an immersed electrical conductor in the electrolyte, can be polarized into cathodic and anodic poles under a sufficient electric field without direct contact, which affords a unique way to promote asymmetrical reactions at two poles. Up to date, bipolar electrochemistry has been widely used in the preparation of Janus materials, the fabrication of sensing/screening platform, target focusing and microswimmers. However, the wireless feature of BPE makes monitoring the Faradaic current difficult. Electrochemiluminescence (ECL), the light emission via an electrochemical reaction, matches the feature of bipolar electrochemistry well and is widely adopted to achieve the record of the Faradaic current flowing through the BPE. The objective of the present review aims to demonstrate the most recent advances in analytical applications (2016-2020) in combination with the high sensitive ECL as the output. Methods: Due to the difficulty of the recording of the Faradaic current flowing the BPE, the ECL, as a simple, sensitive and detectable signal-out, has become a popular method for analytical application based on the BPE. This review mainly summarizes the recent research of BPE/ECL according to the configuration and sensing principle of BPE designed in the ECL analysis. Results: Various sensors based on the BPE/ECL have been proposed for the electroactive targets and the bio-relevant molecules without the electroactivity by different ingenious designs. Besides, the microelectrode array and ultra-microelectrode (UME) array have also been applied in the BPE/ECL field to achieve the high temporal-spatial resolution imaging of the sample molecules based on the BPE microelectrode array. Conclusion: The combination of BPE and ECL provides a simple, portable and versatile sensor strategy for various targets due to the unique advantages of BPE and ECL, and can be applied for the fast, accurate and point-of-care diagnostics of numerous diseases. Though the BPE/ECL analysis has many merits such as high-throughput, excellent sensitivity, and high spatial-temporal resolution, the sensitive and commercial ECL analysis based on the BPE is still difficult to realize and the analysis research of BPE/ECL is still in the early stage.

Solvent assisted excited-state deactivation pathways in isolated 2,7-diazaindole-S1-3 (S = Water and Ammonia) complexes

The role of solvent molecules in the deactivation of photo-excited 2,7-diazaindole (DAI) – (H2O)1-3 and DAI – (NH3)1-3 complexes were computationally investigated. An excited-state proton transfer (ESPT) path from the solvent to the DAI molecule was followed using the TD-DFT-D4 (B3LYP) level of theory. The computed potential energy profile of ESPT process has shown intersection between ππ* and nπ* states facilitated via relative stabilization of the nπ* state with decreasing N(7)-Hb bond length. The ESPT process, starting from the DAI-Sn (ππ*) state, crosses through a barrier ranging from 27 to 36 kJmol−1 for water complexes and 26–30 kJmol−1 for ammonia complexes. The energy of the excited state was rapidly decreased with a shorter N(7)-Hb bond length. Subsequently, a significant trend of finding a second intersection between the ground and the excited state was observed for all the complexes. The results firmly suggested a significant deactivation channel of excited azaindole derivatives. In the present system, two competing channels, ESPT and ESHT, were found to be energetically accessible. The energy barriers associated with the ESPT barriers for DAI-(H2O)1-3 complexes are similar to the ESHT barrier, depicting equal dominance of both processes. The increased basicity of the N(7) atom in the excited state resulted a facile ESPT process from the water to N(7) of the DAI molecule. However, DAI-(NH3)1-3 complexes show clear preference for ESHT over ESPT process owing to its higher gas-phase pKa value making it a poor proton donor. The above systems can be used as a model to computationally and experimentally investigate the competing radiative and deactivation pathways of photo-excited solvated complexes of N-H-bearing bio-relevant molecules via proton and hydrogen transfer reactions.

Photodeprotection Reaction Mechanisms of Caged Species Utilizing a Photochromism Function.

Acetoxy-1,2,2-tri(aryl)ethanone (1) is a novel and visual release-and-report system that contains the photochromic diarylethylene function attached to the photocage dimethoxybenzoin platform. However, the mechanism of 1 cyclization and a subsequent deprotection remains unclear. Here, we use femtosecond and nanosecond transient absorption spectroscopies in combination with density functional theory computations to study the detailed reaction mechanism. The photodeprotection proceeds with competition between pathways initiated by two different configurations of the singlet excited state of 1 (labeled as 11LE and 11CT); the stepwise elimination after cyclization of 11LE constitutes the predominant pathway, whereas the concerted removal of acetic acid after cyclization of 11CT is the minor pathway. These results contribute to a detailed photodeprotection mechanism of 1 and provide new insights into the effect of geometric configurations of intermediates on the photodeprotection pathways. This new information can help in the further development of this type of the photolabile protecting group (PPG) for the protection of biorelevant molecules and in the design of an improved and versatile release-and-report PPG.

NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes and the ligand effects on regioselectivity

Alkene hydrocarbonation reactions have been developed to supplement traditional electrophile-nucleophile cross-coupling reactions. The branch-selective hydroalkylation method applied to a broad range of unactivated alkenes remains challenging. Herein, we report a NiH-catalysed proximal-selective hydroalkylation of unactivated alkenes to access β- or γ-branched alkyl carboxylic acids and β-, γ- or δ-branched alkyl amines. A broad range of alkyl iodides and bromides with different functional groups can be installed with excellent regiocontrol and availability for site-selective late-stage functionalization of biorelevant molecules. Under modified reaction conditions with NiCl2(PPh3)2 as the catalyst, migratory hydroalkylation takes place to provide β- (rather than γ-) branched products. The keys to success are the use of aminoquinoline and picolinamide as suitable directing groups and combined experimental and computational studies of ligand effects on the regioselectivity and detailed reaction mechanisms.

An Eco-Friendly Synthetic Approach through C(sp3)-H Functionalization of the Viral Fusion “Spike Protein” Inhibitors

The use of organic chemistry to synthesize bio-relevant molecules has been a prime interest of the drug discovery sentients. Recently, our group found 2-styryl substituted quinoline as an anticancer and viral fusion inhibitor through the binding of the gp-41 spike protein. So, we through to synthesize various molecules with an eco-friendly approach. However, various approaches have been reported with the metal, additive, base, and acids to synthesize highly important 2-styrylquinoline from the 2-alkyl quinoline. Still, none of the approaches was reported with the restricted 4-hydroxyquinoline substrate because of their dual nucleophilic nature. The selectivity raises an important issue in this concern substrate. The present protocol overcomes the dual nucleophilic character of the hydroxyl-linked substrate through an optimized eco-friendly sp3 C-H activation approach. The designed protocol for synthesizing gp-41 inhibitors as viral entry inhibitors claimed as metal, acid, and base along with the solvent-free protocol.

Silver(I)-Catalyzed Reductive Cross-Coupling of Aldehydes to Structurally Diverse Cyclic and Acyclic Ethers.

A range of medium-sized cyclic ethers (5 to 11 membered) have been effectively synthesized through intramolecular reductive coupling of dialdehydes initiated by 50 ppm to 0.5% of AgNTf2 with hydrosilane at 25 °C. The catalytic system is also suitable for the coupling of two different monoaldehydes to provide unsymmetrical ethers. This protocol features broad functional group compatibility, high product diversity, high efficiency, and utility in the late-stage modification of complex biorelevant molecules.

Diversity-Oriented Synthesis of Fluoromethylated Arenes via Palladium-Catalyzed C-H Fluoromethylation of Aryl Iodides.

Herein we report the first versatile and expeditious method for the site-selective C-H fluoromethylation of aryl iodides via Pd/norbornene cooperative catalysis, which could work as a robust toolbox for the diversity-oriented synthesis (DOS) of fluoromethylated arenes. This methodology features the use of the low-cost industrial raw material CH2IF as the fluoromethyl source, an excellent functional group tolerance, and a broad ipso termination scope and can be expanded to the late-stage modification of biorelevant molecules.

Applications of triarylborane materials in cell imaging and sensing of bio-relevant molecules such as DNA, RNA, and proteins.

Triarylboranes have been known for more than 100 years and have found potential applications in various fields such as anion sensors and optoelectronics, for example in organic light emitting diodes (OLEDs), field effect transistors (OFETs), and organic photovoltaic devices. However, biological applications, such as bioimaging agents and biomolecule sensors have evolved much more recently. This review summarises progress in this relatively young field and highlights the potential of triarylboranes in biological applications.

Electrochemical Trifluoromethoxylation of (Hetero)aromatics with a Trifluoromethyl Source and Oxygen.

Trifluoromethoxylated aromatics (ArOCF3 ) are valuable structural motifs in the area of drug discovery due to the enhancement of their desired physicochemical properties upon the introduction of the trifluoromethoxy group (CF3 O). Although significant progress has been made recently in the introduction of CF3 O group into aromatics, current methods either require the use of expensive trifluoromethoxylation reagents or require harsh reaction conditions. We present a conceptually new and operationally simple protocol for the direct C-H trifluoromethoxylation of (hetero)aromatics by the combination of the readily available trifluoromethylating reagent and oxygen under electrochemical reaction conditions. This reaction proceeds through the initial generation of CF3 radical followed by conversion to CF3 O radical, addition to (hetero)aromatics and rearomatization. The utility of this electrochemical trifluoromethoxylation is illustrated by the direct incorporation of CF3 O group into a variety of (hetero)aromatics as well as bio-relevant molecules.

Thermodynamic framework for the predicting the properties of amino-benzoic acids

Extensive experimental and theoretical thermochemical studies of 2-, 3-, and 4-amino-benzoic acids have been carried out, including combustion calorimetry, vapor pressure measurements, and high-level quantum-chemical calculations. We have collected available primary experimental results on vapour pressures, phase transitions (solid–solid, solid–liquid, crystal-gas, and liquid–gas), and enthalpies of formation. These data were evaluated using empirical, semi-empirical and quantum chemical methods. The consistent sets of evaluated thermodynamic data were used to develop the “centerpiece” based group-additivity method for predicting enthalpies of formation and enthalpies of vaporization of di- and tri-substituted benzenes. It was found that the agglomeration of three substituents on the benzene ring has no consequences for the energetics of the molecule in terms of additional group-additivity parameters This observation is important to reliably assess the energetics of the bio-relevant molecules.

Recent Advances in the Nitration of Olefins.

Nitroolefins are important synthetic intermediates in the field of organic synthesis as well as in medicinal chemistry. The high reactivity of nitroalkenes due to the polarized double bond which enables them to act as Michael acceptor in conjugate addition reactions, or as a dienophile in cycloaddition makes it an essential synthetic handle for accessing complex molecules. The classical method to prepare nitroolefins is indeed the Henry nitroaldol reaction, where a carbonyl compound and nitroalkane are condensed in presence of base. Direct nitration of olefin, on the other hand, serves as a useful alternative as olefins are abundant, have broad commercial availability and easy to manipulate. In this context, numerous methods have been developed over the last few decades, focusing on direct nitration of styrene and aliphatic olefins. Furthermore, thorough literature search revealed that implementation of this class of reactions are gaining momentum as a preferred pathway to access nitroolefins, despite the presence of a powerful technique such as Henry reaction. In this review, we aim to cover recent advances in direct olefin nitration and their importance in accessing biorelevant molecules, total synthesis targets and future outlook in this specific research area.

Remote C–H Functionalizations by Ruthenium Catalysis

AbstractSynthetic transformations of otherwise inert C–H bonds have emerged as a powerful tool for molecular modifications during the last decades, with broad applications towards pharmaceuticals, material sciences, and crop protection. Consistently, a key challenge in C–H activation chemistry is the full control of site-selectivity. In addition to substrate control through steric hindrance or kinetic acidity of C–H bonds, one important approach for the site-selective C–H transformation of arenes is the use of chelation-assistance through directing groups, therefore leading to proximity-induced ortho-C–H metalation. In contrast, more challenging remote C–H activations at the meta- or para-positions continue to be scarce. Within this review, we demonstrate the distinct character of ruthenium catalysis for remote C–H activations until March 2021, highlighting among others late-stage modifications of bio-relevant molecules. Moreover, we discuss important mechanistic insights by experiments and computation, illustrating the key importance of carboxylate-assisted C–H activation with ruthenium(II) complexes.1 Introduction2 Stoichiometric Remote C–H Functionalizations3 meta-C–H Functionalizations4 para-C–H Functionalizations5 meta-/ortho-C–H Difunctionalizations6 Conclusions

Acridinium Salts and Cyanoarenes as Powerful Photocatalysts: Opportunities in Organic Synthesis

AbstractThe use of organic photocatalysts has revolutionized the field of photoredox catalysis, as it allows access to reactivities that were traditionally restricted to transition‐metal photocatalysts. This Minireview reports recent developments in the use of acridinium ions and cyanoarene derivatives in organic synthesis. The activation of inert chemical bonds as well as the late‐stage functionalization of biorelevant molecules are discussed, with a special focus on their mechanistic aspects.

Acridinium Salts and Cyanoarenes as Powerful Photocatalysts: Opportunities in Organic Synthesis.

The use of organic photocatalysts has revolutionized the field of photoredox catalysis, as it allows access to reactivities that were traditionally restricted to transition-metal photocatalysts. This Minireview reports recent developments in the use of acridinium ions and cyanoarene derivatives in organic synthesis. The activation of inert chemical bonds as well as the late-stage functionalization of biorelevant molecules are discussed, with a special focus on their mechanistic aspects.

Celebrating Professor Barry M. Trost's 80th Birthday

Celebrating Professor Barry M. Trost's 80^th Birthday

A noninvasive fluorescence imaging-based platform measures 3D anisotropic extracellular diffusion

Diffusion is a major molecular transport mechanism in biological systems. Quantifying direction-dependent (i.e., anisotropic) diffusion is vitally important to depicting how the three-dimensional (3D) tissue structure and composition affect the biochemical environment, and thus define tissue functions. However, a tool for noninvasively measuring the 3D anisotropic extracellular diffusion of biorelevant molecules is not yet available. Here, we present light-sheet imaging-based Fourier transform fluorescence recovery after photobleaching (LiFT-FRAP), which noninvasively determines 3D diffusion tensors of various biomolecules with diffusivities up to 51 µm2 s−1, reaching the physiological diffusivity range in most biological systems. Using cornea as an example, LiFT-FRAP reveals fundamental limitations of current invasive two-dimensional diffusion measurements, which have drawn controversial conclusions on extracellular diffusion in healthy and clinically treated tissues. Moreover, LiFT-FRAP demonstrates that tissue structural or compositional changes caused by diseases or scaffold fabrication yield direction-dependent diffusion changes. These results demonstrate LiFT-FRAP as a powerful platform technology for studying disease mechanisms, advancing clinical outcomes, and improving tissue engineering.

Visible-Light-Induced 1,3-Aminopyridylation of [1.1.1]Propellane with N-Aminopyridinium Salts.

Through the formation of an electron donor-acceptor (EDA) complex, strain-release aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3-aminopyridylated BCPs under mild and metal-free conditions is highlighted by the late-stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P-centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three-component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4-pyridine-functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP-type bioisosteres for applications in drug discovery.

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

AbstractThrough the formation of an electron donor–acceptor (EDA) complex, strain‐release aminopyridylation of [1.1.1]propellane with N‐aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3‐aminopyridylated BCPs under mild and metal‐free conditions is highlighted by the late‐stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P‐centered and CF3 radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three‐component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4‐pyridine‐functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP‐type bioisosteres for applications in drug discovery.

Naturally Inspired Pyrimidines Analogues for Alzheimer's Disease.

Alzheimer’s disease (AD) is a multifarious and developing neurodegenerative disorder. The treatment of AD is still a challenge and availability of drug therapy on the basis of symptoms is not up to the mark. In the context of existence, which is getting worse for the human brain, it is necessary to take care of all critical measures. The disease is caused due to multidirectional pathology of the body, which demands the multi-target-directed ligand (MTDL) approach. This gives hope for new drugs for AD, summarized here in with the pyrimidine based natural product inspired molecule as a lead. The review is sufficient in providing a list of chemical ingredients of the plant to cure AD and screen them against various potential targets of AD. The synthesis of a highly functionalized scaffold in one step in a single pot without isolating the intermediate is a challenging task. In few examples, we have highlighted the importance of this kind of reaction, generally known as multi-component reaction. Multi-component is a widely accepted technique by the drug discovery people due to its high atom economy. It reduces multi-step process to a one-step process, therefore the compounds library can be made in minimum time and cost. This review has highlighted the importance of multicomponent reactions by giving the example of active scaffolds of pyrimidine/fused pyrimidines. This would bring importance to the fast as well as smart synthesis of bio-relevant molecules.

Light-induced primary amines and o-nitrobenzyl alcohols cyclization as a versatile photoclick reaction for modular conjugation

The advent of click chemistry has had a profound impact on many fields and fueled a need for reliable reactions to expand the click chemistry toolkit. However, developing new systems to fulfill the click chemistry criteria remains highly desirable yet challenging. Here, we report the development of light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) as a photoclick reaction via primary amines as direct click handle, to rapid and modular functionalization of diverse small molecules and native biomolecules. With intrinsic advantages of temporal control, good biocompatibility, reliable chemoselectivity, excellent efficiency, readily accessible reactants, operational simplicity and mild conditions, the PANAC photoclick is robust for direct diversification of pharmaceuticals and biorelevant molecules, lysine-specific modifications of unprotected peptides and native proteins in vitro, temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. This strategy provides a versatile platform for organic synthesis, bioconjugation, medicinal chemistry, chemical biology and materials science.