Inhibition of Invasion and Capillary-like Tube Formation by Retrohydroxamate-based MMP Inhibitors

Bulletin of the Korean chemical society

Ae-Ri Ji¹  Jung Dae Park¹  Hyun Soo Lee¹  Dong Han Kim¹  Seong Eon Ryu¹  Seung-Woo Yu¹  Bong-Hwan Cho¹  Jae-Hoon Kang¹  Jun Hyoung Park¹  Seung-Su Choi¹  Seung-Taek Lee¹ 

关键词: Inhibitor;    Invasion;    Matrix metalloproteinase (MMP);    N-Formylhydroxylamine;    Retrohydroxamate;   

DOI  :  

学科分类：化学（综合）

来源: Korean Chemical Society

【 摘 要 】

Matrix metalloproteinases (MMPs), a family of zinc-containing endopeptidases, participate in many normal processes such as embryonic development and wound repair, and in many pathological situations such as cancer, atherosclerosis, and arthritis. Peptidomimetic MMP inhibitors were designed and synthesized with Nformylhydroxylamine (retrohydroxamate) as a zinc-binding group and various side chains on the α, P1`, and P2` positions. Using in vitro MMP assays with purified MMPs (MMP-1, MMP-2, MMP-3, MMP-9, and MMP- 14) and fluorogenic peptide substrates, it was found that compounds 2d and 2g selectively inhibit gelatinases (MMP-2 and MMP-9) and interstitial collagenase (MMP-1). They also inhibited the chemo-invasion of fibrosarcoma HT-1080 cells and tube formation of human umbilical vascular endothelial cells in a dosedependent manner. Our results suggest that retrohydroxamate-based MMP inhibitors, especially compounds 2d and 2g, have the potential to be used as therapeutic drugs for cancer and other MMP-related diseases.

【 授权许可】

Unknown