Multiatom Skeletal Editing to Access SeCN-Containing Bicyclo[1.1.1]pentanes with Antitumor Activity

The development of multiatom skeletal editing strategies that enable the incorporation of multiple pharmacophores into a single molecule is of great significance for both organic synthesis and drug discovery. Herein we combine multiatom skeletal editing with pharmacophore combination to achieve the first synthesis of SeCN-substituted bicyclo[1.1.1]pentanes, along with preliminary antitumor activity evaluation. The method boasts high atom economy and employs only the green solvent 2-methyltetrahydrofuran, requiring no photocatalysts, oxidants, or transition metals. It is highlighted by the successful late-stage modification of amino acids, natural products, and drugs. Notably, phenotypic screening led to the identification of a hit compound (3v) with an unprecedented scaffold, which exhibits superior antitumor activity to that of the positive control drug. This work establishes a research paradigm that delivers new molecular entities for drug discovery via an innovative synthetic platform development.