Luisi Grazia, Angelini Guido, Gasbarri Carla, Laghezza Antonio, Agamennone Mariangela, Loiodice Fulvio, Supuran Claudiu T, Campestre Cristina, Tortorella Paolo
a Department of Pharmacy , "G. d'Annunzio" University of Chieti-Pescara , Chieti , Italy.
b Department of Pharmacy and Pharmaceutical Sciences , "A. Moro" University of Bari , Bari , Italy.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):1260-1264. doi: 10.1080/14756366.2017.1378192.
A series of nanomolar phosphonate matrix metalloproteinase (MPP) inhibitors was tested for inhibitory activity against a panel of selected human carbonic anhydrase (CA, EC 4.2.1.1) isozymes, covering the cancer-associated CA IX and XII. None of the reported sulfonyl and sulfonylamino-derivatives sensitively affected the catalytic activity of the cytosolic isoforms CA I and II, which are considered off-target isoforms in view of their physiological role. The most active inhibitors were in the series of chiral N-(sulfonyl)phosphovaline derivatives, which showed good to excellent inhibitory activity over target CAs, with compound 15 presenting the best isoform-selectivity toward CA IX. We suggest here that the phosphonates have the potential as dual inhibitors of MMPs and CAs, both involved in tumor formation, invasion and metastasis.
测试了一系列纳摩尔浓度的膦酸酯基质金属蛋白酶（MPP）抑制剂对一组选定的人类碳酸酐酶（CA，EC 4.2.1.1）同工酶的抑制活性，这些同工酶涵盖了与癌症相关的CA IX和CA XII。所报道的磺酰基和磺酰氨基衍生物均未对胞质同工酶CA I和CA II的催化活性产生敏感影响，鉴于它们的生理作用，这两种同工酶被认为是脱靶同工酶。活性最高的抑制剂是手性N-（磺酰基）膦酰缬氨酸衍生物系列，该系列对靶标CA表现出良好至优异的抑制活性，化合物15对CA IX表现出最佳的同工酶选择性。我们在此表明，膦酸酯有潜力作为MMP和CA的双重抑制剂，这两种酶都参与肿瘤的形成、侵袭和转移。
