摘要
在非甾体类抗炎药(NSAIDs)中,COX-2抑制剂或“昔布类药物”能选择性抑制诱导型环氧合酶。此外,有证据表明磺胺型昔布类药物还能对人碳酸酐酶的多种亚型(CA, EC 4.2.1.1)有抑制作用,但甲基砜类不能。在这点上,塞来昔布和伐地考昔结构中具有磺酰胺基,能与酶活性位点上的锌离子结合,它们是与肿瘤相关的人碳酸酐酶IX型(hCA IX)的一类纳摩级抑制剂。另外,如美洛昔康和氯诺昔康这种昔康类非甾体类抗炎药,具有一个环状的磺酰叔胺结构,它们是这一亚型的微摩尔级抑制剂。磺胺抗炎药的多重药效可以归结于对碳酸酐酶(CA)和环氧酶(COX)的双重抑制作用,可以证明炎症和缺氧的信号通路均与肿瘤的发生发展有关,也表明基于这些化合物防治肿瘤可能的多重药理作用,应该进一步深入探讨它们的抗肿瘤活性。
关键词: 肿瘤,碳酸酐酶抑制剂,昔布,COX-2抑制剂,昔康
Current Medicinal Chemistry
Title:Dual Cyclooxygenase and Carbonic Anhydrase Inhibition by Nonsteroidal Anti-Inflammatory Drugs for the Treatment of Cancer
Volume: 22 Issue: 24
Author(s): Celeste De Monte, Simone Carradori, Andrea Gentili, Adriano Mollica, Daniela Trisciuoglio and Claudiu T. Supuran
Affiliation:
关键词: 肿瘤,碳酸酐酶抑制剂,昔布,COX-2抑制剂,昔康
摘要: Among the class of nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors or “coxibs” selectively inhibit the activity of the inducible isoform of cyclooxygenase. Moreover, there is emerging evidence that the sulfonamide-type coxibs, but not the methylsulfones, display an inhibitory activity also against several isoforms of human carbonic anhydrase (CA, EC 4.2.1.1). In this regard, celecoxib and valdecoxib, possessing a primary sulfonamide that binds to the zinc ion at the active site of the enzyme, are nanomolar inhibitors of the cancer-related hCA IX isoform. Also meloxicam and lornoxicam, NSAIDs belonging to the class of “oxicams”, that contain a cyclic tertiary sulfonamide moiety, inhibit this isoform at low micromolar concentrations. The multiple pharmacological effects of the sulfonamide anti-inflammatory agents could be ascribed to the dual inhibition of CA and COX enzymes, supporting the evidence that inflammation and hypoxia pathways are involved in cancer onset and progression and suggesting that the antitumoral activity of these compounds should be further explored for their possible use in the polypharmacology of cancer prevention and therapy.
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Celeste De Monte, Simone Carradori, Andrea Gentili, Adriano Mollica, Daniela Trisciuoglio and Claudiu T. Supuran , Dual Cyclooxygenase and Carbonic Anhydrase Inhibition by Nonsteroidal Anti-Inflammatory Drugs for the Treatment of Cancer, Current Medicinal Chemistry 2015; 22 (24) . https://dx.doi.org/10.2174/0929867322666150716113501
DOI https://dx.doi.org/10.2174/0929867322666150716113501 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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