Dell'Aica Isabella, Sartor Luigi, Galletti Paola, Giacomini Daria, Quintavalla Arianna, Calabrese Fiorella, Giacometti Cinzia, Brunetta Enrico, Piazza Francesco, Agostini Carlo, Garbisa Spiridione
Department of Experimental Biomedical Sciences, Medical School of Padova, Italy.
J Pharmacol Exp Ther. 2006 Feb;316(2):539-46. doi: 10.1124/jpet.105.096248. Epub 2005 Oct 25.
beta-Lactams, a well known class of antibiotics, have been investigated as inhibitors of the disruptive protease released by inflammatory cells, leukocyte elastase (LE). We have synthesized a new beta-lactam with an N-linked galloyl moiety, the latter identified as strategic in conferring anti-LE properties to some flavonols. This N-galloyl-derivative beta-lactam inhibits the LE activity with a K(i) of 0.7 microM, whereas it exerts weak activity against cathepsin G and protease-3 (IC(50) > 100 microM), and matrix metalloproteinase (MMP)-2 and MMP-9. Without affecting chemotactic response and viability of polymorphonuclear (PMN) leukocytes, the compound efficiently restrains their chemoinvasion (IC(50) of 1-2 microM) blocking the LE-triggered activation of pro-MMP-9, instrumental to extravasation. Daily i.p. injection of compound enhances resolution in a pulmonary inflammation model, significantly reducing consequent fibrosis. These results indicate that the new beta-lactam is a potent anti-inflammatory compound with therapeutic potential.
β-内酰胺是一类著名的抗生素，已被研究作为炎症细胞释放的破坏性蛋白酶——白细胞弹性蛋白酶（LE）的抑制剂。我们合成了一种带有N-连接没食子酰基部分的新型β-内酰胺，后者被认为是赋予某些黄酮醇抗LE特性的关键基团。这种N-没食子酰基衍生物β-内酰胺抑制LE活性的K(i)为0.7微摩尔，而它对组织蛋白酶G和蛋白酶-3（IC(50) > 100微摩尔）以及基质金属蛋白酶（MMP）-2和MMP-9的活性较弱。该化合物在不影响多形核（PMN）白细胞趋化反应和活力的情况下，能有效抑制其化学侵袭（IC(50)为1 - 2微摩尔），阻断LE触发的前MMP-9激活，这对渗出至关重要。每天腹腔注射该化合物可增强肺部炎症模型的炎症消退，显著减少随之而来的纤维化。这些结果表明，这种新型β-内酰胺是一种具有治疗潜力的强效抗炎化合物。
