Sulfonyl phosphonic 1,4-dithia-7-azaspiro[4,4]nonane derivatives as matrix metalloproteinase inhibitors: Synthesis, a docking study, and biological evaluation.

A series of novel sulfonyl phosphonic 1,4-dithia-7-azaspiro[4,4]nonane derivatives were designed, synthesized, and assayed for their activity against matrix metalloproteinase-2 (MMP-2). Results indicated that all of the compounds exhibited moderate inhibitory activity against MMP-2 compared to LY52 (the control) (IC50 = 0.95 ± 0.09 µM). Several selected compounds were also examined for their antiproliferative activity against SKOV3, HL60, and A549 cells. Notably, all of the tested compounds had slightly lower antiproliferative activity against SKOV3 cells than that of LY52. Compound 6d displayed the greatest inhibitory activity in an enzymatic assay and a cell-based assay, which means that this compound is a good candidate for further development of phosphonate-based MMP inhibitors.