摘要
恶性肿瘤细胞区别于正常细胞的关键是细胞膜N-糖链的改变,而N-糖链的改变又以岩藻糖的增多最为明显和最具有特异性,但利用肿瘤细胞膜糖链特异性变化或岩藻糖含量增加作为靶点的抗肿瘤药物的研究却相对薄弱。近几年有机硼酸化合物与cis-1, 2-和cis-1, 3-二醇反应生成五元或六元环酯的性质,被广泛应用于分子水平上对不同单糖化合物的识别和检测以及细胞水平上与肿瘤细胞表面过量表达糖链的特异性结合。光动力治疗正在成为治疗肿瘤的新式武器,已被广泛应用于临床,但精确定位较难,肿瘤杀伤深度较浅等不足限制了其在深度肿瘤上的应用,而双光子吸收由于具有长波激发、穿透能力强、高度的空间选择性等特点,使其在光动力学治疗方面展现出了诱人的应用前景。
因此,本论文基于恶性肿瘤产生、转移机制的研究成果,以肿瘤细胞表面糖链末端过量表达的岩藻糖为靶点,利用有机硼酸化合物能够在分子和细胞水平上识别和结合糖分子的性质,结合已有的研究基础设计、合成了新型的有机硼酸双光子吸收剂。这些化合物以识别肿瘤细胞表面过量表达的糖分子的有机硼酸为导航装置,将同时具有肿瘤细胞抑制活性和双光子吸收特性的某些药物或基团传送到表面出现了特异糖链结构的病变组织,以期起到直接杀伤肿瘤细胞和双光子光动力治疗的双重作用。
另外,本论文第三章在综述近年来硼酸肽类蛋白酶体抑制剂的研究进展和合成方法的基础上,运用计算机辅助药物设计,参考相关文献报道,研究总结了硼酸肽类蛋白酶体抑制剂的构效关系,并以此为依据设计并合成了两个系列的硼酸肽类蛋白酶体抑制剂,以期发现高效专一的蛋白酶体抑制剂,进而对了解和推测蛋白酶体相应生物靶点的结构和功能,发现潜在的新型预防和治疗药物有所帮助。
本论文的具体内容包括:
1.以肿瘤细胞表面糖链末端高表达的岩藻糖为靶点,利用有机硼酸化合物特异性识别和结合糖分子的性质,结合已知的具有抗肿瘤活性和双光子吸收性能的D-Π-A-Π-D结构类型的化合物设计、合成了一类有机硼酸双光子吸收剂,共34个新化合物,均经1H NMR,13C NMR以及HRMS验证。
2.用质谱方法(ESI-MS)对化合物与糖在分子水平的结合活性进行了验证,检测了它们与D-葡萄糖、D-半乳糖、L-岩藻糖、D-果糖及D-木糖反应后分子量的变化,结果发现在相同实验条件下它们对除葡萄糖以外的其它糖均有很好的结合。将目标硼酸化合物及其无硼酸结构的对照化合物与斑马鱼胚胎细胞相结合,结果发现目标硼酸化合物在细胞表面形成规则的荧光圈,而无硼酸结构的化合物未出现此种现象,初步判断此类化合物能够结合细胞表面高表达糖链,为进一步深入研究其结合方式奠定了实验基础。
3.为进一步探讨化合物的双光子光动力治疗效应和作用机制等问题,对目标化合物的光学活性进行了深入细致的研究,考察了结构、溶剂等对化合物线性吸收光谱、单光子荧光光谱及双光子荧光光谱的影响,测定了化合物的摩尔吸光系数,荧光量子产率及双光子吸收截面,结果发现:化合物的线性吸收峰、单光子荧光峰及双光子荧光峰均随着电子给体推电子能力的增强和溶剂极性的增大发生红移;由于再吸收效应的影响,化合物的双光子荧光峰相对单光子荧光峰,普遍红移15nm左右;由于各个样品在不同溶剂中的最佳单光子激发波长的差异及荧光淬灭等导致了其单光子荧光强度的可比性变差,从而使荧光量子产率随化合物结构和溶剂极性发生变化但无明显规律;化合物的双光子吸收截面随着电子给体推电子能力的增强而增大。
4.为研究硼酸肽类蛋白酶体抑制剂的构效关系,选择文献报道的同一批91个硼酸肽类蛋白酶体抑制剂为研究对象,用Cerius2 4.11建立了MFA模型,其统计学参数为:交叉验证系数q2 = 0.714,标准偏差Press = 47.167,相关系数r2 = 0.754,表明建立的MFA模型具有较好的预测能力。再结合蛋白酶体与Bortezomib复合物晶体结构得出了此类抑制剂具备的特点为:硼酸部分是维持此类抑制剂活性的关键,由于硼原子有一个空的p轨道,蛋白酶体活性部位Thr1羟基氧原子的一对电子对其进行亲核进攻,并与之共价结合;而硼原子上的两个羟基可与蛋白酶体的氨基酸残基上的N原子形成氢键,稳定与蛋白酶体的结合。P2位点对抑制剂与酶的结合影响较小,但可能引入大的疏水基团能够起到有益的药效作用。P1和P3位点的改变会对抑制剂与蛋白酶体的结合强弱及选择性产生较大的影响。
5.在构效关系研究的基础上,以Bortezomib为先导化合物,结合文献报道的化合物的结构特征,设计了化合物库,用建立的MFA模型对化合物进行了活性预测和柔性叠合打分,并选取了20个目标化合物进行了合成,共合成包括中间体在内的新化合物51个,均经1H NMR,13C NMR及MS验证,测试了13个目标化合物对人乳腺癌细胞MDA-MB-231的初步抗肿瘤细胞抑制活性,未发现明显结果,对蛋白酶体靶点的抑制活性测试正在进行中。
It is known that cell-surface carbohydrates have been associated with the development and progression of many types of cancers. One most specific example associated with the development and progression of human carcinomas is their ability to express fucosylated carbohydrates, which are important components of ligands involved in selectin-mediated cell adhesion and inflammatory responses. Recently, there has been a great deal of interest in using boronic acid compounds for the development of fluorescent sensors targeting monosaccharides and cell surface fucosylated carbohydrate structures. Photodynamic therapy (PDT) is a local light-activate treatment to destroy tumor tissues, particularly skin, esophageal, and lung cancers. The disadvantage of currently available PDT is the low penetration depth of the visible light because of the absorption and the scattering of biological tissues, meaning that this method cannot be applied to the treatment of deep cancers. Due to its merits of highly localized nonlinear excitation, intrinsic three-dimensional resolution and the possibility of an increased penetration depth in tissue, the use of two-photon absorption (2PA) in PDT becomes attractive.
Consequently, in this thesis, the design and synthesis of a novel kind of boronic acid-based two-photon absorption photosensitizers targeting cell surface fucosylated carbohydrate has been described.
Besides, Computer-aided drug design (CADD) has been employed to study the structure-activity relationship (SAR) of peptide boronates proteasome inhibitors. Based on the research result, two series of peptide boronates proteasome inhibitors have been designed and synthesized and in vitro antitumor tests against the tumor cells of MDA-MB-231 of the compounds have been evaluated in chapter 3. The details of this paper are as follows:
1. 34 new boronic acid-based two-photon absorption compouds targeting cell surface fucosylated carbohydrate has been designed, synthesized and characterized by NMR and MS spectrum.
2. The binding affinities with D-glucose, D-galactose, L-fucose, D-frucose, D-xylose, has been examined; Also examined is the recognition of cell surface fucosylated carbohydrate.
3. Single- and two-photon properties of compounds have been systematically investigated, the effect of molecular structure and solvent has also been discussed. With the strengthen of the donor, the single-photon absorption peaks, the single -photon fluorescence peaks and the two-photon fluorescence peaks all have redshifts, and the two-photon absorption cross-sections become bigger.
4. Molecular field analysis (MFA) method was employed to construct peptide boronates proteasome inhibitors’s 3D-QSAR model. The model was proved to be high-predictive by statistical data (q2 = 0.714) and accurate prediction of the compounds. Base on carefully analysis of protein-inhibitor interactions, also the results of references, we identified the character of peptide boronates proteasome inhibitors: the boronic acid was the key pharmacophore, good result may be obtained by the introduction of large hydrophobic moieties at the P2 site, alterations of the P1 and P3 sites may significantly change the binding properties of the inhibitor to the respective proteolytically active sites.
5. Based on the character of peptide boronates proteasome inhibitors, two series of peptide boronates proteasome inhibitors have been designed, synthesized and characterized by NMR and MS spectrum. In vitro tests show that compounds exhibit no cytotoxicity against the tumor cells of MDA-MB-231. Work is in progress to evaluate the inhibitory effects of compounds 1-20 for proteasome.
引文
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