Dipartimento Farmaco-Chimico, Università degli Studi Aldo Moro, Via Orabona 4, 70126 Bari, Italy.
ChemMedChem. 2011 Jul 4;6(7):1258-68. doi: 10.1002/cmdc.201000540. Epub 2011 Mar 15.
A number of matrix metalloproteinases (MMPs), proteins important in the balance of bone remodeling, play a critical role both in cancer metastasis and in bone matrix turnover associated with the presence of cancer cells in bone. Here, we report the synthesis and biological evaluation of a new class of MMP inhibitors characterized by a bisphosphonate function as the zinc binding group. Since the bisphosphonate group is also implicated in osteoclast inhibition and provides a preferential affinity to biological apatite, the new molecules can be regarded as bone-seeking medicinal agents. Docking experiments were performed to clarify the mode of binding of bisphosphonate inhibitors in the active site of MMP-2. The most promising of the studied bisphosphonates showed nanomolar inhibition against MMP-2 and resulted in potent inhibition of osteoclastic bone resorption in vitro.
许多基质金属蛋白酶（MMPs）在骨重塑的平衡中起着重要作用，它们在癌症转移和与癌细胞存在于骨骼相关的骨基质周转中都起着关键作用。在这里，我们报告了一类新的 MMP 抑制剂的合成和生物学评价，其特点是双膦酸盐作为锌结合基团。由于双膦酸盐基团也与破骨细胞抑制有关，并为生物磷灰石提供了优先亲和力，因此新分子可以被视为寻骨药物。进行了对接实验以阐明双膦酸盐抑制剂在 MMP-2 活性位点中的结合模式。在所研究的双膦酸盐中最有前途的一种对 MMP-2 具有纳摩尔抑制作用，并导致体外破骨细胞骨吸收的有效抑制。
