Santamaria Salvatore, Nuti Elisa, Cercignani Giovanni, La Regina Giuseppe, Silvestri Romano, Supuran Claudiu T, Rossello Armando
a Dipartimento di Farmacia , Università di Pisa , Pisa , Italy .
b Dipartimento di Biologia, Unità di Biochimica , Università di Pisa , Pisa , Italy .
J Enzyme Inhib Med Chem. 2015 Dec;30(6):947-54. doi: 10.3109/14756366.2014.1000889. Epub 2015 Feb 19.
We describe the characterisation of a series of 4,4'-biphenylsulfonamides as selective inhibitors of matrix metalloproteases MMP-2 and -13, two enzymes involved in cell invasion and angiogenesis. Double-inhibitor studies in the presence of acetohydroxamic acid show that these molecules do not bind the catalytic zinc. Moreover, two of the characterised inhibitors (11 and 19) act as non-competitive inhibitors, whereas the para-methyl ester derivative 13 behaves as a competitive inhibitor. This finding suggests that this class of molecules binds to a catalytic subsite, possibly the S1'-pocket. Moreover, since these compounds also act as inhibitors of carbonic anhydrases (CAs), another family of enzymes involved in cell invasion, they could be potentially useful as CA/MMP dual target inhibitors with increased efficacy as anticancer agents.
我们描述了一系列4,4'-联苯磺酰胺作为基质金属蛋白酶MMP-2和-13的选择性抑制剂的特性，这两种酶参与细胞侵袭和血管生成。在乙酰氧肟酸存在下的双抑制剂研究表明，这些分子不与催化锌结合。此外，所表征的两种抑制剂（11和19）表现为非竞争性抑制剂，而对甲基酯衍生物13表现为竞争性抑制剂。这一发现表明这类分子与一个催化亚位点结合，可能是S1'-口袋。此外，由于这些化合物还可作为碳酸酐酶（CAs）的抑制剂，碳酸酐酶是另一类参与细胞侵袭的酶，它们有可能作为CA/MMP双靶点抑制剂，作为抗癌剂具有更高的疗效。
