کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1394453 1501158 2012 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Design, synthesis and biological evaluation of 5-hydroxy, 5-substituted-pyrimidine-2,4,6-triones as potent inhibitors of gelatinases MMP-2 and MMP-9
موضوعات مرتبط
مهندسی و علوم پایه شیمی شیمی آلی
پیش نمایش صفحه اول مقاله
Design, synthesis and biological evaluation of 5-hydroxy, 5-substituted-pyrimidine-2,4,6-triones as potent inhibitors of gelatinases MMP-2 and MMP-9
چکیده انگلیسی

Matrix metalloproteinases (MMPs) are attractive biological targets that play a key role in many physiopathological processes such as degradation of extracellular matrix proteins, release and cleavage of cell-surface receptors, tumour progression, homeostatic regulation and innate immunity. A series of 5-hydroxy, 5-substituted pyrimidine-2,4,6-triones were rationally designed, prepared and tested as inhibitors of gelatinases MMP-2 and MMP-9 and collagenase MMP-8. On one side, the presence of the 5-hydroxyl group, that represents an typical feature of this class of compounds, ensured an attractive pharmacokinetic profile while on the other suitably substituted biaryl molecular fragments, attached to position 5 through a ketomethylene linker, guaranteed favourable interaction in the deep region of the S1′ enzymatic subsite. This rational design led to the discovery of highly potent MMP inhibitors. In particular, biphenyl derivatives bearing at the para position COCH3 and OCF3 substituents permitted to inhibit gelatinases MMP-2 and MMP-9, with IC50 values as low as 30 nM and 21 nM, respectively, whereas the introduction at the same position of the bulkier SO2CH3 group afforded a potent collagenase MMP-8 inhibitor with an IC50 value equal to 66 nM. Molecular docking simulations allowed us to elucidate key interactions driving the binding of the top active compounds towards their preferred MMP target.

Figure optionsDownload as PowerPoint slideHighlights
► MMPs represent appealing biological targets for many physiopathological processes.
► 5-Hydroxy, 5-substituted pyrimidine-2,4,6-triones are valid ZBGs.
► The exclusive presence of the 5-hydroxyl group was promising for ADME.
► IC50 values as good as 30 nM and 21 nM were obtained towards MMP-2 and MMP-9.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: European Journal of Medicinal Chemistry - Volume 58, December 2012, Pages 368–376
نویسندگان
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