The Dawn of a New Era: Targeting the "Undruggables" with Antibody-Based Therapeutics.

The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more "undruggable" targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

Diastereo- and enantioselective synthesis of biaryl aldehydes bearing both axial and central chirality.

We describe herein an intriguing method for the synthesis of biaryl aldehydes bearing both axial and central chirality through a desymmetric [3 + 2] cycloaddition reaction of activated isocyanides with prochiral biaryl dialdehydes under silver catalysis. This protocol features excellent enantioselectivity, 100% atom economy, good functional group compatibility, and operational simplicity.

pH-triggered cancer-targeting polymers: From extracellular accumulation to intracellular release.

Stimuli-responsive polymers are promising to achieve targeted delivery, improved stability during circulation, and controlled release of therapeutic and diagnostic agents. Among them, pH-responsive polymeric nanocarriers have attracted significant attention as pH varies in different body fluids (e.g., stomach, intestine, and colon) and intracellular organelles (e.g., endosome, lysosome, and mitochondria) to maintain homeostasis, while distinctive pH changes are also found in certain pathological states. For example, the extracellular environment of the tumor is acidic, which can be employed to drive selective delivery. During the internalization process, since most nanocarriers enter cells upon endocytosis where a drop of pH from 6.5 to 5.0 can occur from endosome to lysosome, pH-sensitive groups have been developed for enhanced cargo release. In this review, both non-covalent and covalent interactions responsive to pH changes are introduced, with a focus on the structure-property relationship and their applications in cancer targeting and endosomal escape.

Sensitive Imaging of Cellular RNA via Cascaded Proximity-Induced Fluorogenic Reactions.

Owing to its important biological functions, RNA has become a promising molecular biomarker of various diseases. With a dynamic change in its expression level and a relatively low amount within the complicated biological matrix, signal amplification detection based on DNA probes has been put forward, which is helpful for early diagnosis and prognostic prediction. However, conventional methods are confined to cell lysates or dead cells and are not only time-consuming in sample preparation but also inaccessible to the spatial-temporal information of target RNAs. To achieve live-cell imaging of specific RNAs, both the detection sensitivity and intracellular delivery issues should be addressed. Herein, a new cascaded fluorogenic system based on the combination of hybridization chain reactions (HCRs) and proximity-induced bioorthogonal chemistry is developed, in which a bioorthogonal reaction pair (a tetrazine-quenched dye and its complementary dienophile) is brought into spatial proximity upon target RNA triggering the HCR to turn on and amplify the fluorescence in one step, sensitively indicating the cellular distribution of RNA with minimal false positive results caused by unspecific degradation. Facilitated by a biodegradable carrier based on black phosphorus with high loading capacity and excellent biocompatibility, the resulting imaging platform allows wash-free tracking of target RNAs inside living cells.

Torsional Strain-Independent Catalytic Enantioselective Synthesis of Biaryl Atropisomers.

Catalytic asymmetric dynamic kinetic resolution of configurationally labile bridged biaryls is emerging as a powerful strategy for atropisomer synthesis. However, the reported examples suffer from an inherent challenge as the reactivity is highly dependent on the torsional strain of the biaryl substrates, which significantly narrows down the scope and hampers the application. Herein, we report our discovery and development of a torsional strain-independent reaction between biaryl thionolactones and activated isocyanides. By employing auto-tandem silver catalysis, a universal synthesis of both tri- and tetra-ortho-substituted thiazole-containing biaryls was realized in high yields with high enantioselectivities. In addition, these products could be facilely converted to a novel type of bridged biaryls bearing an eight-membered lactone. Mechanistic studies were carried out to elucidate the cause of this unusual torsional strain-independent reactivity.

Simultaneous Construction of C-N Axial and Central Chirality via Silver-Catalyzed Desymmetrizative [3 + 2] Cycloaddition of Prochiral N-Aryl Maleimides with Activated Isocyanides.

Herein, we report an unprecedented strategy for the simultaneous construction of a remote C-N stereogenic axis and three contiguous stereogenic carbon centers via silver-catalyzed desymmetrizative [3 + 2] cycloaddition of prochiral N-aryl maleimides with activated isocyanides. This method features operational simplicity, wide substrate scope, high efficiency, and good to excellent stereoselectivity. Notably, it represents the first example of catalytic enantioselective synthesis of C-N atropisomers with the use of activated isocyanides.

Cooperative catalysis-enabled C-N bond cleavage of biaryl lactams with activated isocyanides.

The catalytic reaction of biaryl lactams with activated isocyanides is reported for the first time. By employing a cooperative catalytic system, oxazole-containing axially chiral biaryl anilines were obtained in high yields with excellent enantioselectivities. The key to the success lies in the atroposelective amide C-N bond cleavage with activated isocyanides.

Diastereo- and Enantioselective Silver-Catalyzed [3+3] Cycloaddition and Kinetic Resolution of Azomethine Imines with Activated Isocyanides.

In contrast to the well-established [3+2] cycloaddition reactions, the catalytic enantioselective [3+n] (n≥3) cycloaddition reaction of activated isocyanides for the preparation of six-membered or larger ring systems has remained underdeveloped. Herein, we report the first example of highly diastereo- and enantioselective [3+3] cycloaddition of activated isocyanides with azomethine imines. By employing silver catalysis, a wide range of biologically important bicyclic 1,2,4-triazines were obtained in high yields (up to 99 %) with good to excellent stereoselectivities (up to >20 : 1 dr, 99 % ee). In addition, the same catalytic system could be applied to both the late-stage functionalization of complex bioactive molecules and the kinetic resolution of racemic azomethine imines, further highlighting its versatility and synthetic utility.

Prediction of Maximum Absorption Wavelength Using Deep Neural Networks.

Fluorescent molecules are important tools in biological detection, and numerous efforts have been made to develop compounds to meet the desired photophysical properties. For example, tuning the wavelength allows an appropriate penetration depth with minimal interference from the autofluorescence/scattering for a better signal-to-noise contrast. However, there are limited guidelines to rationally design or computationally predict the optical properties from first principles, and factors like the solvent effects will make it more complicated. Herein, we established a database (SMFluo1) of 1181 solvated small-molecule fluorophores covering the ultraviolet-visible-near-infrared absorption window and developed new machine learning models based on deep neural networks for accurately predicting photophysical parameters. The optimal system was applied to 120 out-of-sample compounds, and it exhibited remarkable accuracy with a mean relative error of 1.52%. In this new paradigm, a deep learning algorithm is promising to complement conventional theoretical and experimental studies of fluorophores and to greatly accelerate the discovery of new dyes. Due to its simplicity and efficiency, data from newly developed fluorophores can be easily supplemented to this system to further improve the accuracy across various dye families.

In vivo targeted delivery of antibodies into cancer cells with pH-responsive cell-penetrating poly(disulfide)s.

Cell-penetrating poly(disulfide)s (CPDs) are promising vehicles for cytosolic delivery of proteins. However, currently available arginine-rich CPD has rarely been reported for systemic delivery due to its "always" positive charge. Herein, we developed pH-responsive CPDIMD that executes tumor targeting delivery via protonation of imidazole groups within the acidic tumor microenvironment.

Catalytic Atroposelective Dynamic Kinetic Resolution of Biaryl Lactones with Activated Isocyanides.

We report herein an unprecedented atroposelective dynamic kinetic resolution of Bringmann's lactones with C-nucleophiles. By the use of activated isocyanides as the reagent, a wide range of novel axially chiral oxazole-substituted biaryl phenols were accessed in high yields with high enantioselectivities. Key to the success of this process lies in the tandem atroposelective addition of isocyanides to the lactone substrate followed by a rapid cyclization, overcoming the challenge of stereochemical leakage induced by lactol formation.

Isocyanides: Promising Functionalities in Bioorthogonal Labeling of Biomolecules.

Isocyanides have drawn increasing attention in biological applications due to their attractive properties and unique reactivities, which can undergo various reactions, such as multicomponent reactions, α-addition reactions, [4 + 1] cycloaddition reactions, and the reaction scope keeps expanding. In addition to acting as reactants for the preparation of structurally interesting and diverse N-heterocycles or peptidomimetics, this type of functionality may be a good choice in the labeling and modulation of biomolecules due to the high biocompatibility and small size to minimize modifications on the parent molecule. It has been demonstrated that isocyanides can participate in biomolecule labeling through three strategies, including the two-component bioorthogonal reaction, multicomponent reaction, and metal chelation. Among them, the isocyanide-tetrazine reaction has been better studied recently, augmenting the potency of isocyanide as a bioorthogonal handle. This review will focus on the recent progress in isocyanide chemistry for labeling of biomolecules. Meanwhile, methods to introduce isocyano groups into biomacromolecules are also described to facilitate wider applications of this unique functionality.

An in vitro Förster resonance energy transfer-based high-throughput screening assay identifies inhibitors of SUMOylation E2 Ubc9.

SUMOylation is one of the posttranslational modifications that mediate cellular activities such as transcription, DNA repair, and signal transduction and is involved in the cell cycle. However, only a limited number of small molecule inhibitors have been identified to study its role in cellular processes. Here, we report a Förster resonance energy transfer (FRET) high-throughput screening assay based on the interaction between E2 Ubc9 and E3 PIAS1. Of the 3200 compounds screened, 34 (1.1%) showed higher than 50% inhibition and 4 displayed dose-response inhibitory effects. By combining this method with a label-free surface plasmon resonance (SPR) assay, false positives were excluded leading to discovering WNN0605-F008 and WNN1062-D002 that bound to Ubc9 with KD values of 1.93 ± 0.62 and 5.24 ± 3.73 µM, respectively. We examined the effect of the two compounds on SUMO2-mediated SUMOylation of RanGAP1, only WNN0605-F008 significantly inhibited RanGAP1 SUMOylation, whereas WNN1062-D002 did not show any inhibition. These compounds, with novel chemical scaffolds, may serve as the initial material for developing new SUMOylation inhibitors.

Divergent, Enantioselective Synthesis of Pyrroles, 3H-Pyrroles and Bicyclic Imidazolines by Ag- or P-Catalyzed [3+2] Cycloaddition of Allenoates with Activated Isocyanides.

The divergent, stereoselective formal [3+2] cycloadditions of allenoates with activated isocyanides catalyzed by silver or phosphine-based catalysts were investigated. Silver catalysis is capable of delivering a range of 3H-pyrroles in high stereoselectivities. These enantioenriched heterocycles can either undergo sequential cyclisation with isocyanoacetates to deliver unprecedented bicyclic imidazolines with excellent yields and stereoselectivity or undergo unusual aromatization pathways leading to polysubstituted pyrroles. On the other hand, a simple mix-and-go procedure using an amino acid-derived phosphine as the catalyst produces pyrroles bearing a benzylic stereocenter with good enantioselectivity.

Catalyst-Enabled Scaffold Diversity: Highly Chemo- and Stereoselective Synthesis of Tricyclic Ketals and Triarylmethanes.

The first catalytic cascade reaction of activated isocyanides with para-quinone methide-aryl esters is presented. Catalyst-enabled divergent pathways have also been achieved to deliver skeletally diverse products. While Ag catalysis leads to an unprecedented highly diastereoselective synthesis of tricyclic ketals, a simple procedure employing Cu catalysis produces oxazole-containing triarylmethanes in high efficiency through an unexpected C-C bond cleavage.

Three-component reactions of isocyanoacetates, amines and 3-formylchromones initiated by an unexpected aza-Michael addition.

We present herein a new mode of three-component reactions between isocyanoacetates, amines and 3-formylchromones. Both experimental and DFT studies revealed that this Ag-catalyzed unusual transformation is initiated by a facile aza-Michael addition instead of the conventional imine condensation. This catalytic method enables an efficient synthesis of polysubstituted pyrroles.

A new trend to determine biochemical parameters by quantitative FRET assays.

Förster resonance energy transfer (FRET) has been widely used in biological and biomedical research because it can determine molecule or particle interactions within a range of 1-10 nm. The sensitivity and efficiency of FRET strongly depend on the distance between the FRET donor and acceptor. Historically, FRET assays have been used to quantitatively deduce molecular distances. However, another major potential application of the FRET assay has not been fully exploited, that is, the use of FRET signals to quantitatively describe molecular interactive events. In this review, we discuss the use of quantitative FRET assays for the determination of biochemical parameters, such as the protein interaction dissociation constant (K(d)), enzymatic velocity (k(cat)) and K(m). We also describe fluorescent microscopy-based quantitative FRET assays for protein interaction affinity determination in cells as well as fluorimeter-based quantitative FRET assays for protein interaction and enzymatic parameter determination in solution.

Catalytic divergent synthesis of 3H or 1H pyrroles by [3 + 2] cyclization of allenoates with activated isocyanides.

The cyclization of allenoates with activated isocyanides was reported for the first time. While Ag catalysis led to an unprecedented enantioselective synthesis of 3H pyrroles, a simple procedure using PPh3 produced a wide range of polysubstituted 1H pyrroles with high efficiency.

Azadipyrromethene-based Zn(II) complexes as nonplanar conjugated electron acceptors for organic photovoltaics.

The effectiveness of new a electron acceptor for organic solar cells is demonstrated. The acceptor is a homoleptic zinc(II) complex of 2,6-diphenylethynyl-1,3,7,9-tetraphenylazadipyrromethene. The high power-conversion efficiency obtained is attributed to the acceptor's 3D structure, which prevents crystallization and promotes a favourable nanoscale morphology, its high Voc , and its ability to contribute to light harvesting at 600-800 nm.

Highly diastereo- and enantioselective silver-catalyzed double [3+2] cyclization of α-imino esters with isocyanoacetate.

Presented herein is a new complexity-generating method in which both functionalities of α-imino esters undergo stereoselective cyclization with isocyanoacetates to produce directly linked oxazole-imidazolines, which can be transformed into highly functionalized α,ß-diamino esters and imidazolinium salts in high diastereo- and enantiopurity.