[Development of Bioactive Molecules Bearing Hexacoordinated Sulfur Fluoride]

Hexa-coordinated sulfur fluoride compounds have a regular octahedral structure and exhibit distinctive chemical properties. This review describes the application of two hexa-coordinated sulfur fluoride groups as substructures of bioactive compounds. One of them, the pentafluorosulfanyl (SF₅) group, also called a "super-trifluoromethyl group" has attracted considerable attention in recent years because of its strong electron-withdrawing character, high hydrophobicity, and bulky structure. Based on these properties, the SF₅ group has been incorporated in both polar and hydrophobic regions of bioactive compounds, including anti-malarial agents and nuclear receptor ligands. In at least some cases, conversion of conventional functional groups to the SF₅ group has resulted in improved bioactivity and characteristic ligand activity. The second group, the tetrafluorosulfanyl (SF₄) group, is available as a unique linker structure that connects two substructures linearly via a single atom. However, its low chemical stability and the limited scope of current synthetic methods has restricted its utilization. In recent years, research has been directed towards improving its stability and developing new synthetic methods. We designed and synthesized a novel retinoic acid receptor (RAR) ligand containing an SF₄ group as a linker structure and found that it exhibited distinct ligand activity towards RAR. The unique chemical and structural properties of the SF₅ and SF₄ groups are expected to expand the chemical space of bioactive compounds, providing new scope for innovation in medicinal chemistry.