Design and synthesis of novel site-specific antibody-drug conjugates that target TROP2.

The approval of Trodelvy® validates TROP2 as a druggable but challenging target for antibody-drug conjugates (ADCs) to treat metastatic triple-negative breast cancer (mTNBC). Here, based on the TROP2-targeted antibody sacituzumab, we designed and developed several site-specific ADC candidates, which employ MMAE (monomethyl auristatin E) as the toxin, via IgG glycoengineering or affinity-directed traceless conjugation. Systematic evaluation of these site-specific ADCs in homogeneity, hydrophilicity, stability, and antitumor efficiency was conducted. The results indicate that the site-specific ADCs gsADC 3b made from one-step glycoengineering exhibit good aggregation stability and in vivo efficacy, providing a new format of ADCs that target TROP2.

4-Diazoisochroman-3-imines: A Class of Metal Carbene Precursors for the Synthesis of Isochromene Derivatives.

4-Diazoisochroman-3-imines were investigated for their synthetic applications as a new class of metal carbene precursors. Under the catalysis from a Rh(II) complex, this class of α-diazo imidates reacted with alkenes and conjugated dienes through a formal [2 + 1] (i.e., cyclopropanation) or [4 + 3] cycloaddition to furnish spiro[cyclopropane-1,4'-isochroman]-3'-imines and tetrahydroisochromeno[3,4-b] azepines, respectively. When Rh(II)/AgOTf was used as cocatalyst, the formal [3 + 2] cycloaddition of 4-diazoisochroman-3-imines with terminal alkynes took place, leading to the synthesis of 2-aryl-3,5-dihydroisochromeno[3,4-b]pyrroles.

Theoretical study on stability and spectroscopy of C84O2 based on C84(D(2d)).

The relative stabilities of the twenty-three possible isomers for C84O2 based on C84(D(2d)) were studied by using density functional theory (DFT) at B3LYP/6-31G(d) level. The most stable isomer of C84O2 was found to be 1,5,8,9-C84O2 which contains annulene-like structures. In this isomer, two oxygen atoms are added on the same hexagon, which is called a same-ring adduct. The energy gap of C84O2 is narrower than that of C84(D(2d)). The chemical shifts of the bridged carbon atoms in C84O2 are changed upfield compared with those of the same carbon atoms in C84(D(2d)). The same-ring adduct possesses the higher aromaticity than C84(D(2d)). The area within the range of 0.2 nm from the cage center of C84(D(2d)) or C84O2 is the most suitable area for calculating NICS values.

Hiding Payload Inside the IgG Fc Cavity Significantly Enhances the Therapeutic Index of Antibody-Drug Conjugates.

The inadequate understanding of the structure-activity relationship (SAR) of glycosite-specific antibody-drug conjugates (ADCs) hinders its design and development. Herein, we revealed the systemic SAR and structure-toxicity relationship (STR) of gsADCs by constructing 50 gsADC structures bearing three glycan subtypes and diverse linker-drug combinations. According to the results, extra hydrophilic linkers are indispensable for the intact glycan-based gsADCs to achieve better in vivo efficacy. Meanwhile, the gsADCs that conjugate linker-drug complexes onto the terminal sialic acid are more stable and potent than the ones conjugated onto the terminal galactose in vivo. Notably, the LacNAc-based gsADCs, which shortened the spacer and located the linker-drug more inside the immunoglobulin class G (IgG) Fc cavity, showed excellent hydrophilicity, in vivo activity, pharmacokinetics, and safety. Conclusively, we found that hiding the linker-toxin into the Fc cavity can significantly enhance the therapeutic index of LacNAc-based gsADCs, which will benefit the further design of ADCs with optimal druggability.

Multivariate time-series classification with hierarchical variational graph pooling.

In recent years, multivariate time-series classification (MTSC) has attracted considerable attention owing to the advancement of sensing technology. Existing deep-learning-based MTSC techniques, which mostly rely on convolutional or recurrent neural networks, focus primarily on the temporal dependency of a single time series. Based on this, complex pairwise dependencies among multivariate variables can be better described using advanced graph methods, where each variable is regarded as a node in the graph, and their dependencies are regarded as edges. Furthermore, current spatial-temporal modeling (e.g., graph classification) methodologies based on graph neural networks (GNNs) are inherently flat and cannot hierarchically aggregate node information. To address these limitations, we propose a novel graph-pooling-based framework, MTPool, to obtain an expressive global representation of MTS. We first convert MTS slices into graphs using the interactions of variables via a graph structure learning module and obtain the spatial-temporal graph node features via a temporal convolutional module. To obtain global graph-level representation, we design an "encoder-decoder"-based variational graph pooling module to create adaptive centroids for cluster assignments. Then, we combine GNNs and our proposed variational graph pooling layers for joint graph representation learning and graph coarsening, after which the graph is progressively coarsened to one node. Finally, a differentiable classifier uses this coarsened representation to obtain the final predicted class. Experiments on ten benchmark datasets showed that MTPool outperforms state-of-the-art strategies in the MTSC task.

Preparation of 4-Diazoisoquinolin-3-ones via Dimroth Rearrangement and Their Extension to 4-Aryltetrahydroisoquinolin-3-ones.

4-Diazoisoquinolin-3-ones were prepared efficiently via TBAB-promoted rearrangement of 4-diazoisochroman-3-imines under mild reaction conditions. The resulted 4-diazoisoquinolin-3-ones could be conveniently applied for the synthesis of 4-aryltetrahydroisoquinolin-3-ones either by the TfOH-catalyzed reaction with electron-rich arenes or by the BF3-promoted reaction with aryl aldehydes.

Convenient preparation of 4-diazoisochroman-3-imines and 3-subsituted 3,5-dihydroisochromeno[3,4-d][1,2,3]triazoles.

A novel and convenient preparation of 4-diazoisochroman-3-imines through the copper(i)-catalyzed cascade reaction of (2-ethynylphenyl)-methanols with sulfonyl azides is described. The synthesized cyclical α-diazo imidates could readily react with a variety of primary amines to furnish 3-substituted 3,5-dihydroisochromeno[3,4-d][1,2,3]-triazoles under catalyst-free conditions.

Rh-Catalyzed Reactions of 3-Diazoindolin-2-imines: Synthesis of Pyridoindoles and Tetrahydrofuropyrroloindoles.

The rhodium-catalyzed reactions of 3-diazoindolin-2-imines with furans and dihydrofuran furnished 9H-pyrido[2,3-b]indoles and tetrahydrofuro[3',2':4,5]pyrrolo[2,3-b]indoles, respectively. A cascade reaction mechanism involving an α-imino rhodium carbene intermediate is proposed. The starting materials are readily available, and the procedure is facile and efficient.

Cu-catalyzed synthesis of tryptanthrin derivatives from substituted indoles.

A concise method for the preparation of tryptanthrins from indoles via the copper-catalyzed aerobic oxidation is described. The reactions can be carried out under mild reaction conditions with varying functional group tolerance.