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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.

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 BF 3 -promoted reaction with aryl aldehydes.

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.

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.

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.