Search

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 vivoefficacy. 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 vivoactivity, 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 BF3-promoted reaction with aryl aldehydes.