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基质金属蛋白酶(MMPs)是高度保守的依赖于锌离子的内切蛋白水解酶家族,对细胞外基质(ECM)的降解、组织重建以及细胞内多种可溶性因子的调控起重要作用。MMPs已被证明在肿瘤生长、侵袭、转移和癌组织的血管生长中发挥着关键作用,与浸润性肿瘤的恶性表型及癌症病人的不良预后密切相关,如果抑制该酶活性,就能有效地控制肿瘤的发生、发展和转移。因此,MMPs已成为肿瘤药物研究和开发中极其重要的靶点。其中,尤以明胶酶(MMP-2,9)与恶性肿瘤最为相关。针对这些靶点设计并合成MMPs抑制剂类抗肿瘤药物,是当前抗肿瘤药物研究中很有发展前景的一类。本文利用基于结构(Structure-Based)和基于机制(Mechanism-Based)的药物设计思想,以甘氨酸为先导化合物,并在分子中引入能与靶酶的疏水性口袋相互作用且具有抗癌活性的1,3,4-噻二唑和苯乙酸骨架,对目标化合物中引入体积不等的取代基,考察不同立体效应对靶酶的作用。本着结构多样性的原则,合成了5个结构确定的目标化合物。对所合成的化合物,通过红外光谱、核磁共振氢谱、核磁共振碳谱等方法进行结构确证。
Matrix metalloproteinases (MMPs) are highly conserved family of zinc-dependent endoproteolytic enzymes that play an important role in the degradation of extracellular matrix (ECM), tissue remodeling and the regulation of various soluble factors in cells. MMPs have been shown to play a key role in tumor growth, invasion, metastasis and angiogenic growth in cancerous tissues and are closely related to the malignant phenotype of infiltrating tumors and poor prognosis in cancer patients. Inhibition of this enzyme can effectively Control of tumor development, development and metastasis. Therefore, MMPs have become extremely important targets in the research and development of oncology drugs. Among them, especially gelatinase (MMP-2, 9) and malignant tumors are the most relevant. Design and synthesis of anti-tumor drugs of MMPs inhibitors targeting these targets is a promising category in the current research of anti-tumor drugs. Based on the structure-based and mechanism-based drug design ideas, glycine as the lead compound and the introduction of 1 in the molecule that can interact with the hydrophobic pocket of the target enzyme and have anticancer activity , 3,4-thiadiazole and phenylacetic acid skeleton, the introduction of the target compounds of varying volume of the substituent, to investigate different three-dimensional effect on the target enzyme. Based on the principle of structural diversity, five target compounds have been synthesized. The synthesized compounds were confirmed by IR, 1HNMR and 1H-NMR spectra.