【作者】 王文第；

【导师】 王勤；

【作者基本信息】 兰州大学 ， 生物物理， 2009， 硕士

【摘要】 喹唑啉类化合物是近年来备受研究人员关注的一类杂环化合物,且被发现其对NF-κB信号通路有抑制作用。在第一部分工作中,通过文献调研选取了一系列喹唑啉衍生物,这类化合物已被证明对NF-κB的活化有抑制作用,因此,基于这类化合物是以NF-κB为靶点发挥作用,实验中采用比较分子力场分析法（CoMFA）和比较分子相似性指数分析法（CoMSIA）对该系列化合物进行三维定量构效关系（3D-QSAR）研究,建立了3D-QSAR的CoMFA和CoMSIA模型。计算得到其交叉验证相关系数q²分别为0.823和0.795;非交叉验证相关系数R²分别为0.979和0.980;标准误SEE分别为0.149和0.144,表明该模型合理、可信,并具有良好的预测能力。构效关系分析表明:（1）取代基R₃位（见表2.1,下同）引入大体积、正电性、氢键受体基团对提高化合物活性有利;（2）取代基R₅、R₆位应引入负电性基团、避免引入疏水性基团;而R₆位引入氢键给体基团对化合物活性有利;（3）取代基R₇位引入小体积基团有利于化合物活性的提高;（4）R₄位取代基体积大小、电负性强弱对于化合物活性影响不大;（5）氢键给体基团不会明显降低化合物的生物活性。应用这些规律可指导喹唑啉类NF-κB抑制剂的设计与结构优化,为寻找理想的抗肿瘤化合物提供了重要的依据。咪唑并[1,2-a]吡啶由于其很好的抗癌活性被广泛应用于药物结构中,在第二部分工作中,对功能有机分子化学国家重点实验室合成的一系列新型咪唑并[1,2-a]吡啶衍生物（TIP）进行抗肿瘤活性研究。选取人宫颈癌细胞株HeLa及人急性单核白血病细胞株THP-1为受试细胞株,用不同浓度（0、40、80、160、320、640μM）的TIP类化合物对其进行处理,48 h后,测得细胞增殖活性明显改变,证明这一系列TIP化合物对HeLa及THP-1细胞的增殖有抑制作用,且这种增殖抑制呈浓度依赖关系。对于HeLa细胞株,TIP-06、14号化合物IC₅₀分别达到了54.80及46.96μM,而TIP-08、13不具有明显的细胞毒活性;对于THP-1细胞株,TIP-02、06及08号化合物IC₅₀分别达到了53.01、36.81、27.37μM,化合物TIP-10、14不具有明显的细胞毒活性;说明,HeLa与THP-1细胞株对于这系列TIP化合物的敏感度不同,受试细胞株对于这类化合物具有一定的选择性,而这种抑制选择性与化合物的结构有很大关系,关于这类化合物的构效关系研究会在得到更多的TIP衍生物后进行研究。更多还原

【Abstract】 It is recently proposed that quinazoline derivatives are capable of inhibiting the activation of NF-κB.To obtain some helpful information for designing functional inhibitor based on NF-κB target,3D-Quantitative Structure-Activity Relationship （3D-QSAR） studies such as Comparative Molecular Field Analysis（CoMFA） and Comparative Molecular Similarity Indices Analysis（CoMSIA） on 67 inhibitors, quinazoline derivatives,have been carried out.The CoMFA and CoMSIA models give a cross-validated coefficient q² of 0.823 and 0.795,respectively,and the conventional correlation coefficient R² of 0.979 and 0.980,respectively.The predictive abilities of the two models were further validated by a test set of 12 compounds.The models gave predicted correlation coefficient R2_pred² of 0.950 for CoMFA model and 0.979 for CoMSIA model.Based on the above results,we identified the key structural features that may help to design potent inhibitors with improved activities:（1） It can improve the compound activity to introduce the group considering big volume,lower electronegativity,hydrogen-bond acceptor properties in substituent R₃ part;（2） It can improve the compound activity to introduce the group considering higher electronegativity,less hydrophobic,hydrogen-bond donor properties in substituent R₆ part;and to introduce the group considering higher electronegativity,less hydrophobic properties in substituent R₅ part;（3） It can improve the compound activity to introduce the group considering small volume property in substituent R₇ part;（4） The steric and electrostatic effect in the substituent R₄ is not important to the inhibitory activity;（5） The hydrogen-bond donor effect is not important to the inhibitory activity.The 3D contour maps of CoMFA and CoMSIA provided smooth and interpretable explanation of the structure-activity relation for the compounds,which will guide the design of novel compounds with relatively high inhibitory activity.In the second part of this dissertation,HeLa and THP-1 cells were treated with different concentrations（0,40,80,160,320,640μM） of TIP derivativesfor 48 h,TIP derivatives can inhhibit the proliferation of HeLa and THP-1 cells in a dose-dependent manner in vitro.TIP-06,14 generated the 54.80 and 46.96μM IC₅₀ values in HeLa cells lines,TIP-08 and TIP-13 on HeLa cells did not have a signifigant effects.TIP-02,06 and 08 generated the 53.01,36.81 and 27.37μM IC₅₀ values in THP-1 cells lines,TIP-10 and TIP-14 on THP-1 cells did not have a signifigant effects.The reasults in part two suggest that the sensitivity degree of HeLa andTHP-1 cell line is different with different compounds.更多还原