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New Type of Metalloproteinase Inhibitor: Design and Synthesis of New Phosphonamide-Based Hydroxamic Acids

2002; American Chemical Society; Volume: 45; Issue: 4 Linguagem: Inglês

10.1021/jm0103211

1520-4804

Masaaki Sawa, Takao Kiyoi, Kiriko Kurokawa, Hiroshi Kumihara, Minoru Yamamoto, Tomohiro Miyasaka, Yasuko Ito, Ryoichi Hirayama, Tomomi Inoue, Yasuyuki Kirii, Eiji Nishiwaki, Hiroshi Ohmoto, Yu Maeda, Etsuko Ishibushi, Yoshimasa Inoue, Kiyoshi Yoshino, Hirosato Kondo,

Carbohydrate Chemistry and Synthesis

A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar K(i) values against MMP-1, -3, -9, and TACE and also showed nanomolar IC(50) values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.