Sang Qing-Xiang Amy, Jin Yonghao, Newcomer Robert G, Monroe Sara C, Fang Xuexun, Hurst Douglas R, Lee Seakwoo, Cao Qiang, Schwartz Martin A
Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4390, USA.
Curr Top Med Chem. 2006;6(4):289-316. doi: 10.2174/156802606776287045.
Acting on a broad spectrum of extracellular, intracellular, and membrane-associated substrates, the matrix metalloproteinases (MMPs) are critical to the biological processes of organisms; when aberrantly expressed, many pathological conditions may be born or exacerbated. The prospect of MMP inhibition for therapeutic benefit in cancer, cardiovascular disease, and stroke is reviewed here. MMP inhibitor (MMPI) development constitutes an important branch of research in both academic and industrial settings and advances our knowledge on the structure-function relationship of MMPs. Targeting MMPs in disease treatment is complicated by the fact that MMPs are indispensable for normal development and physiology and by their multi-functionality, possible functional redundancy or contradiction, and context-dependent expression and activity. This complexity was revealed by previous efforts to inhibit MMP activity in the treatment of cancer patients that yielded unsatisfactory results. This review focuses on MMPI development since the late 90s, in terms of natural products and their derivatives, and synthetic compounds of low molecular mass incorporating specific zinc-binding groups (ZBGs). A few polyphenols and flavonoids that exhibit MMPI activities may have chemopreventive and neuro- and cardiovascular-protective effects. A new generation of potent and selective MMPIs with novel ZBGs and inhibition mechanisms have been designed, synthesized, and tested. Although only one collagenase inhibitor (Periostat, doxycycline hyclate) has been approved by the Food and Drug Administration as a drug for the treatment of periodontal disease, new hope is emerging in the form of natural and synthetic MMPIs for the prevention and treatment of stroke, cardiovascular disease, cancer, and other medical conditions.
基质金属蛋白酶（MMPs）作用于广泛的细胞外、细胞内和膜相关底物，对生物体的生物学过程至关重要；当异常表达时，许多病理状况可能会产生或加剧。本文综述了抑制MMPs在癌症、心血管疾病和中风治疗中的潜在益处。MMP抑制剂（MMPI）的开发是学术和工业研究的一个重要分支，它推进了我们对MMPs结构-功能关系的认识。在疾病治疗中靶向MMPs很复杂，因为MMPs对正常发育和生理是不可或缺的，而且它们具有多功能性、可能的功能冗余或矛盾以及依赖于环境的表达和活性。先前在癌症患者治疗中抑制MMP活性的努力产生了不尽人意的结果，这揭示了这种复杂性。本综述聚焦于自90年代末以来MMPI的开发，涉及天然产物及其衍生物，以及含有特定锌结合基团（ZBGs）的低分子量合成化合物。一些具有MMPI活性的多酚和黄酮类化合物可能具有化学预防以及神经和心血管保护作用。已经设计、合成并测试了具有新型ZBGs和抑制机制的新一代强效和选择性MMPIs。尽管只有一种胶原酶抑制剂（Periostat，盐酸多西环素）已被美国食品药品监督管理局批准用于治疗牙周疾病，但天然和合成MMPIs有望用于预防和治疗中风、心血管疾病、癌症及其他病症。
