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Design, Synthesis and Biological Evaluation of Novel Curcumin Analogues as Inhibitors of Matrix Metalloproteinases and Pro-inflammatory Cytokines.

机译：新型姜黄素类似物作为基质金属蛋白酶和促炎细胞因子抑制剂的设计，合成和生物学评估。

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摘要

There are two principal reasons why we age: 1) the toxicity of oxygen species; 2) the continuous degradation of collagen by groups of enzymes such as the matrix metalloproteinases (MMPs). The MMPs are a group of more than 25 structurally zinc-containing enzymes that are involved in the degradation of numerous extracellular, pericellular and non-matrix proteins. In many disease conditions their levels and proteinase activity rise, producing pathological and serious structural damage. Tetracyclines (TCs) are known inhibitors of mammalian-derived MMPs, and non-antibiotic formulations of doxycycline are FDA-approved to treat periodontitis and the chronic inflammatory skin disease, rosacea. However, a significant limitation is that the FDA only permits the use of subantimicrobial doses of these antibiotics for these diseases to prevent antibiotic side-effects. Therefore a series of chemically-modified TCs (CMTs), which are no longer anti-bacterial at any dose, were developed, but a significant side-effect was increased photosensitivity. Accordingly, in order to avoid these limitations, a series of chemically-modified curcumins (CMCs) were prepared and evaluated as new MMP inhibitors because they have the same zinc-binding site as the TCs, namely a polyenolic assembly. The current lead compound, CMC2.24 [a bis-(demethoxy) phenylaminocarbonyl derivative of curcumin], exhibits inhibitory IC50 values in vitro, ranging from 2-8 micromolar against two collagenases (MMP-8 and MMP-13), two gelatinases (MMP-2 and MMP-9), MMP-3, MMP-7 and MMP-12. The zinc-binding as well as the acidity constants of these CMCs were evaluated and correlated to their potency as MMP-inhibitors in vitro. An in vitro lipophilicity study and in vivo pharmacokinetics were also carried out for curcumin and CMC2.24. The results show that CMC2.24 is more bioavailable in rat serum, and is retained in organ tissues such as the liver, heart, spleen, lung, kidney and brain in comparison with curcumin, which showed much lower levels of retention in these tissues. It was also found that the production of the pro-inflammatory cytokines and the chemokines including TNF-alpha, IL-1beta; and MCP-1 was significantly reduced by CMC2.24 and a related trione (CMC2.5) in cell culture. Collateral studies with CMC2.24 involving its effects on various disease models are discussed.
机译：我们老化的主要原因有两个：1）氧气的毒性； 2）通过诸如基质金属蛋白酶（MMP）之类的酶不断降解胶原蛋白。 MMP是一组超过25种结构上含锌的酶，它们参与许多细胞外，周细胞和非基质蛋白的降解。在许多疾病条件下，它们的水平和蛋白酶活性都会升高，从而导致病理性和严重的结构损伤。四环素（TCs）是哺乳动物来源的MMP的已知抑制剂，而强力霉素的非抗生素制剂经FDA批准可治疗牙周炎和慢性炎症性皮肤病，酒渣鼻。但是，一个明显的限制是，FDA仅允许将亚抗生素剂量的这些抗生素用于这些疾病，以预防抗生素的副作用。因此，开发了一系列化学修饰的TC（CMT），它们在任何剂量下都不再具有抗菌性，但是显着的副作用是增加了光敏性。因此，为了避免这些限制，制备了一系列化学修饰的姜黄素（CMC）并作为新的MMP抑制剂进行了评估，因为它们具有与TC相同的锌结合位点，即多烯类化合物。当前的先导化合物CMC2.24 [姜黄素的双-（去甲氧基）苯基氨基羰基衍生物）在体外表现出抑制IC50值，对2种胶原酶（MMP-8和MMP-13），2种明胶酶（ MMP-2和MMP-9），MMP-3，MMP-7和MMP-12。对这些CMC的锌结合以及酸度常数进行了评估，并将其与体外MMP抑制剂的功效相关联。还对姜黄素和CMC2.24进行了体外亲脂性研究和体内药代动力学。结果表明，与姜黄素相比，CMC2.24在大鼠血清中的生物利用度更高，并且保留在器官组织（例如肝脏，心脏，脾脏，肺，肾和脑）中，而姜黄素在这些组织中的保留水平要低得多。还发现促炎性细胞因子和趋化因子包括TNF-α，IL-1β的产生。细胞培养中的CMC2.24和相关三酮（CMC2.5）显着降低了MCP-1。讨论了涉及CMC2.24对各种疾病模型影响的附带研究。

著录项

  • 作者

    Zhang, Yu.;

  • 作者单位

    State University of New York at Stony Brook.;

  • 授予单位 State University of New York at Stony Brook.;
  • 学科 Chemistry Biochemistry.;Chemistry Inorganic.;Chemistry Organic.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 298 p.
  • 总页数 298
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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