Enzymatic activation of a matrix metalloproteinase inhibitor

Abstract

Matrix metalloproteinase inhibitors (MMPi) possessing a glucose protecting group on the zinc-binding group (ZBG) show a dramatic increase in inhibitory activity upon cleavage by beta-glucosidase.

Fig. 1

Structures of inhibitors and proinhibitors tested in this study. Compounds include the ZBGs 1-hydroxy-pyridin-2(1H)-one (1), 3-hydroxy-2-methyl-4-pyrone (3) and 3-hydroxy-2-methyl-4-pyrothione (5) as well as the full-length MMPi 1,2-HOPO-2 (7).

Fig. 2

Absorption spectra of the glucose-protected ZBG 2 (0.05 mM, HEPES buffer, pH = 7.5) in the presence of β-glucosidase (16 U) monitored over time. The heavy lines are the initial (dashed) and final (solid) spectra and arrows indicate the change in spectra over time. The spectrum of an authentic sample of ZBG 1 (dotted) is also shown.

Fig. 3

Percent inhibition of MMP-9 with compounds 1–8 tested at 1mMfor 1 and 2, 4mMfor 3 and 4, 125 μM for 5 and 6, and 16 μM for 7 and 8, in the absence (white) and presence (black) of β-glucosidase.

Scheme 1

Synthesis of the glucose-protected MMPi 8.