Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors

Novel molecular imaging ligands targeting matrix metalloproteinases 2 and 9 for imaging of unstable atherosclerotic plaques

“…The MMP inhibitor we have developed in this study displays highly potent inhibitory capacity in the range of 0.87 to 1.95 nM at MMP2/9. Although other existing MMP inhibitors display an even higher inhibitory potency [ 4 , 14 ], these inhibitors did not show the high selectivity we have observed. Since MMP2/9 are typically expressed in areas under stress, such as atherosclerotic plaque lesions, the high selectivity for MMP2/9 will allow preferential targeting of atherosclerotic lesions.…”

“…The arylsulfonyl chlorides 7a-d were prepared from the commercially available compounds 5a-d , introduction of the sulphonic acid moiety was achieved with chlorosulphonic acid leading to 6a-d which were treated without intermediate purification with thionyl chloride to yield 7a-d ( S1 Fig ). Subsequent synthesis of 9a-d in a heterogeneous THF/H 2 O system (Schotten-Baumann conditions) as described previously [ 14 ] was unsuccessful. Alternatively, reaction of di- tert -butyl protected iminodiacetic acid with 7a-d in the presence of triethylamine, followed by deprotection with formic acid yielded 9a-d .…”

“…Nonetheless, as our compound 10a is comparable to compound B3 of Santos et al we can speculate that it has similar inhibitory potencies for the other MMP subtypes. Santos et al demonstrated that this compound shows highest inhibitory potency towards MMP2, MMP13 and MMP9 [ 14 ]. We are limited by a lack of metabolite assessment.…”

“…Hydroxamate based MMP inhibitors are the strongest class of MMP inhibitors as they achieve bidentate binding to the Zinc ion region of MMPs, resulting in a distorted geometry. In a key publication of Santos et al [ 14 ], novel non-peptidic hydroxamate-based MMP inhibitors capable of targeting the deep S1’ pocket of MMPs were introduced. We have thereby synthesized a series of halogenated sulfonamide based compounds based on the lead inhibitor presented by Santos et al [ 14 ] as well as traditional sulfonamide based MMP inhibitors.…”

Profiling of alterations in platelet proteins during storage of platelet concentrates

“…It is likely, however, that metalloproteinases play an important role in protein degradation in PLTs 28 during activation, potentially also degrading septins. The DIGE technology would be a tool allowing to assess the impact of specific matrix metalloproteinase inhibitors 29,30 or apoptosis inhibitors on PLT proteome integrity to differentiate whether the changes in the PLT proteome we have seen are apoptosis or activation related.…”