以NF-κB为靶点的氮杂环化合物的三维定量构效分析
|
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q~2分别为0.823和0.795;非交叉验证相关系数R~2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R_3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R_5、R_6位应引入负电性基团、避免引入疏水性基团;而R_6位引入氢键给体基团对化合物活性有利;(3)取代基R_7位引入小体积基团有利于化合物活性的提高;(4)R_4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IC_(50)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IC_(50)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。
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 q~2 of 0.823 and 0.795,respectively,and the conventional correlation coefficient R~2 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_(pred)~2 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 R_3 part;(2) It can improve the compound activity to introduce the group considering higher electronegativity,less hydrophobic,hydrogen-bond donor properties in substituent R_6 part;and to introduce the group considering higher electronegativity,less hydrophobic properties in substituent R_5 part;(3) It can improve the compound activity to introduce the group considering small volume property in substituent R_7 part;(4) The steric and electrostatic effect in the substituent R_4 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 IC_(50) 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 IC_(50) 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.
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 q~2 of 0.823 and 0.795,respectively,and the conventional correlation coefficient R~2 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_(pred)~2 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 R_3 part;(2) It can improve the compound activity to introduce the group considering higher electronegativity,less hydrophobic,hydrogen-bond donor properties in substituent R_6 part;and to introduce the group considering higher electronegativity,less hydrophobic properties in substituent R_5 part;(3) It can improve the compound activity to introduce the group considering small volume property in substituent R_7 part;(4) The steric and electrostatic effect in the substituent R_4 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 IC_(50) 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 IC_(50) 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.
引文
1.Sen R,Baltimore D.Inducibility of kappa immunoglobulin enhancer-binding protein Nf-kappa B by a posttranslational mechanism.Cell.1986 Dec 26;47(6):921-8.
2.Karin M,Yamamoto Y,Wang QM.The IKK NF-kappa B system:a treasure trove for drug development.Nat Rev Drug Discov.2004 Jan;3(1):17-26.
3.Baeuerle PA,Baltimore D.NF-kappa B:ten years after.Cell.1996 Oct 4;87(1):13-20.
4.Beg AA,Baltimore D.An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.Science.1996 Nov 1;274(5288):782-4.
5.Verma IM,Stevenson JK,Schwarz EM,Van Antwerp D,Miyamoto S.Rel/NF-kappa B/I kappa B family:intimate tales of association and dissociation.Genes Dev.1995 Nov 15;9(22):2723-35.
6.Frelin C,Imbert V,Bottero V,Gonthier N,Samraj AK,Schulze-Osthoff K,et al.Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO.Cell Death Differ.2008 Jan;15(1):152-60.
7.RothwarfDM,Zandi E,Natoli G,Karin M.IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.Nature.1998 Sep 17;395(6699):297-300.
8.Senftleben U,Cao Y,Xiao G,Greten FR,Krahn G,Bonizzi G,et al.Activation by IKKalpha of a second,evolutionary conserved,NF-kappa B signaling pathway.Science.2001 Aug 24;293(5534):1495-9.
9.Krappmann D,Emmerich F,Kordes U,Scharschmidt E,Dorken B,Scheidereit C.Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells.Oncogene.1999 Jan 28;18(4):943-53.
10.Nakshatri H,Bhat-Nakshatri P,Martin DA,Goulet RJ,Jr.,Sledge GW,Jr.Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth.Mol Cell Biol.1997 Jul;17(7):3629-39.
11.Shackelford RE,Kaufmann WK,Paules RS.Cell cycle control,checkpoint mechanisms,and genotoxic stress.Environ Health Perspect.1999 Feb;107 Suppl 1:5-24.
12.Hinz M,Krappmann D,Eichten A,Heder A,Scheidereit C,Strauss M.NF-kappaB function in growth control:regulation of cyclin D1 expression and G0/G1-to-S-phase transition.Mol Cell Biol.1999 Apr;19(4):2690-8.
13.Chen F,Castranova V,Shi X.New insights into the role of nuclear factor-kappaB in cell growth regulation.Am J Pathol.2001 Aug;159(2):387-97.
14.Chen F,Lu Y,Zhang Z,Vallyathan V,Ding M,Castranova V,et al.Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45induction by arsenite.J Biol Chem.2001 Apr 6;276(14):11414-9.
15.Beg AA,Sha WC,Bronson RT,Ghosh S,Baltimore D.Embryonic lethality and liver degeneration in mice lacking the Re1A component of NF-kappa B.Nature.1995Jul 13;376(6536):167-70.
16.Doi TS,Marino MW,Takahashi T,Yoshida T,Sakakura T,Old LJ,et al.Absence of tumor necrosis factor rescues Re1A-deficient mice from embryonic lethality.Proc Natl Acad Sci U S A.1999 Mar 16;96(6):2994-9.
17.Kucharczak J,Simmons MJ,Fan Y,Gelinas C.To be,or not to be:NF-kappaB is the answer—role of Rel/NF-kappaB in the regulation of apoptosis.Oncogene.2003Dec 8;22(56):8961-82.
18.Bian X,McAllister-Lucas LM,Shao F,Schumacher KR,Feng Z,Porter AG,et al.NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells.J Biol Chem.2001 Dec 28;276(52):48921-9.
19.Campbell KJ,Rocha S,Perkins ND.Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B.Mol Cell.2004 Mar 26;13(6):853-65.
20.杨光华,文继舫,王美清等.病理学(第五版).北京:人民卫生出版社;2000.
21.Dustin ML,Springer TA.Lymphocyte function-associated antigen-1(LFA-1)interaction with intercellular adhesion molecule-1(ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells.J Cell Biol.1988Jul;107(1):321-31.
22.Huang S,Pettaway CA,Uehara H,Bucana CD,Fidler IJ.Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis,invasion,and metastasis.Oncogene.2001 Jul 12;20(31):4188-97.
23.Karashima T,Sweeney P,Kamat A,Huang S,Kim SJ,Bar-Eli M,et al.Nuclear factor-kappaB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8.Clin Cancer Res.2003 Jul;9(7):2786-97.
24.张斌,卫僧,王杨.Nf-κb,Mmp-7在胃癌中的表达及意义.河南肿瘤学杂志.2004(01).
25.Shibata A,Nagaya T,Imai T,Funahashi H,Nakao A,Seo H.Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells.Breast Cancer Res Treat.2002 Jun;73(3):237-43.
26.Blackwell TS,Christman JW.The role of nuclear factor-kappa B in cytokine gene regulation.Am J Respir Cell Mol Biol.1997 Jul;17(1):3-9.
27.Paillard F.Induction of apoptosis with I-kappaB,the inhibitor of NF-kappaB.Hum Gene Ther.1999 Jan 1;10(1):1-3.
28.Ghorab MM,Abdel-Gawad SM,El-Gaby MS.Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents.Farmaco.2000Apr;55(4):249-55.
29.Johan C.Kapteyn JBP,Maarten A.De Waard,.Biochemical Mechanisms Involved in Selective Fungitoxicity of Two Sterol 14alpha-Demethylation Inhibitors,Prochloraz and Quinconazole:Accumulation and Metabolism Studies.Pesticide Science.1992;36(2):85-93.
30.黄润秋,李慧英,马军安,邱德文.4-肟醚基喹唑啉类化合物的合成及其抗植物病毒tmv活性.高等学校化学学报.1996(04).
31.刘昕,黄李杨.O-(4-喹唑啉)羟肟酸硫代酯(酰胺)类化合物的合成及生物活性.应用化学.1999(02).
32.Gineinah MM,El-Sherbeny MA,Nasr MN,Maarouf AR.Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives.Arch Pharm(Weinheim).2002;335(11-12):556-62.
33.Mishani E,Abourbeh G,Rozen Y,Jacobson O,Laky D,Ben David I,et al.Novel carbon-11 abeled 4-imethylamino but 2-enoic acid[4-(phenylamino)-quinazoline -6-yl]-amides:potential PET bioprobes for molecular imaging of EGFR-positive rumors.Nucl Med Biol.2004 May;31(4):469-76.
34.刘云海 秦丁吴.板蓝根化学成分的研究(Ⅲ).中草药.2002(02).
35.Lee JY,Lee YS,inventors;4-(Phenylamino)-[1,4]dioxano-2.3-glquinazoline derivatives and process for preparing the same[P].2003.
36.Keledjian K,Borkowski A,Kim G,Isaacs JT,Jacobs SC,Kyprianou N.Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin.Prostate.2001 Jul 1;48(2):71-8.
37.Jiang S,Zeng Q,Gettayacamin M,Tungtaeng A,Wannaying S,Lim A,et al.Antimalarial activities and therapeutic properties of febrifugine analogs.Antimicrob Agents Chemother.2005 Mar;49(3):1169-76.
38.刘进前,徐小岗,陈秀华,余爱珍,戴祖瑞,张秀平.2,4-二氨基-5-氯-6-取代苄氨基喹唑啉类化合物的合成及其抗疟、抗肿瘤和抗菌活性.药学学报.1991(11).
39.Palanki MSS,Erdman PE,Ren M,Suto M,Bennett BL,Manning A,et al.The design and synthesis of novel orally active inhibitors of AP-1 and NF-[kappa]B mediated transcriptional activation.SAR of In vitro and In vivo studies.Bioorganic &Medicinal Chemistry Letters.2003;13(22):4077-80.
40.赵翠花.喹喔啉、喹唑啉类化合物的设计合成与生物活性研究.上海:中国科学院上海药物研究所;2004.
41.Rewcastle GW,Denny WA,Bridges AJ,Zhou H,Cody DR,McMichael A,et al.Tyrosine kinase inhibitors.5.Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]-and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor.J Med Chem.1995 Sep 1;38(18):3482-7.
42.Bridges AJ,Zhou H,Cody DR,Rewcastle GW,McMichael A,Showalter HD,et al.Tyrosine kinase inhibitors.8.An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline(PD 153035),a potent inhibitor of the epidermal growth factor receptor.J Med Chem.1996 Jan 5;39(1):267-76.
43.Smaill JB,Rewcastle GW,Lop JA,Greis KD,Chan OH,Reyner EL,et al.Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido.J Med Chem.2000 Aug 10;43(16):3199.
44.Rewcastle GW,Palmer BD,Bridges AJ,Showalter HD,Sun L,Nelson J,et al.Tyrosine kinase inhibitors.9.Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.J Med Chem.1996 Feb 16;39(4):918-28.
45.Smaill JB,Showalter HD,Zhou H,Bridges AJ,McNamara DJ,Fry DW,et al.Tyrosine kinase inhibitors.18.6-Substituted 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as soluble,irreversible inhibitors of the epidermal growth factor receptor.J Med Chem.2001 Feb 1;44(3):429-40.
46.吴文娟.喹唑啉类化合物的量子化学与定量构效关系研究.广东:中山大学; 2004.
47.Khanna S,Sobhia ME,Bharatam PV.Additivity of molecular fields:CoMFA study on dual activators of PPARalpha and PPARgamma.J Med Chem.2005 Apr 21;48(8):3015-25.
48.Kovatcheva A,Golbraikh A,Oloff S,Xiao YD,Zheng W,Wolschann P,et al.Combinatorial QSAR of ambergris fragrance compounds.J Chem Inf Comput Sci.2004 Mar-Apr;44(2):582-95.
49.任天瑞,沈裴,汪向.家蝇与大鼠gaba受体抑制剂的药效团模型及其3d-Qsar 研究.高等学校化学学报.2005(03).
50.Yoshii F,Hirono S.Construction of a quantitative three-dimensional model for odor quality using comparative molecular field analysis(CoMFA).Chem Senses.1996 Apr;21(2):201-10.
51.Kappel JC,Yokum TS,Barany G.Parallel solid-phase syntheses of 1,3,4-thiadiazolium-2-aminides.J Comb Chem.2004 Sep-Oct;6(5):746-52.
52.韩晓峰 刘高来.非肽类凝血酶抑制剂的比较分子力场分析.化学学报.2003(07).
53.Klebe G,Abraham U,Mietzner T.Molecular similarity indices in a comparative analysis(CoMSIA) of drug molecules to correlate and predict their biological activity.J Med Chem.1994 Nov 25;37(24):4130-46.
54.Klebe G,Abraham U.Comparative molecular similarity index analysis(CoMSIA)to study hydrogen-bonding properties and to score combinatorial libraries.J Comput Aided Mol Des.1999 Jan;13(1):1-10.
55.陈凯先,蒋华良,嵇汝运.计算机辅助药物设计.原理、方法及应用:上海科学技术出版社.
56.[德]加斯泰格尔,恩格尔著,梁逸曾,徐峻,姚建华译。.化学信息学教程.北京:化学工业出版社;2005.
57.Wold SE,L.,et al.PLS-regression:A Basic Tool of Chemometrics.ChemomIntellLabSyst.2001;58:109-30.
58.Balaban AT,Oniciu DC,Katritzky AR.Aromaticity as a cornerstone of heterocyclic chemistry.Chem Rev.2004 May;104(5):2777-812.
59.Chichibabin AE.Tautomerism of α-aminopyridine.Ⅳ.A method of preparation of pyrimidazole and its homologs.Berichte der Deutschen Chemischen Gesellscaft [Abteilung]B:Abhandlungen.1925;58B:1704-6.
60.Hunt AF,Turner EE.Preparation of tertiary arsines by the Friedel-Crafts reaction.J ChemSocTransactions.1925;127:2667-71.
61.Thomas Meyer UR,Doriano Fabbro,Enrica Alteri,Giorgio Caravatti,Alex Matter,.A derivative of staurosporine(CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.International Journal of Cancer.1989;43(5):851-6.
62.Jaramillo C,de Diego JE,Hamdouchi C,Collins E,Keyser H,S,et al.Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors.Part 1:Design,synthesis,and biological evaluation.Bioorganic &Medicinal Chemistry Letters.2004;14(24):6095-9.
63.Hamdouchi C,Keyser H,Collins E,Jaramillo C,De Diego JE,Spencer CD,et al. The discovery of a new structural class of cyclin-dependent kinase inhibitors,aminoimidazo[1,2-a]pyridines.Mol Cancer Ther.2004 Jan;3(1):1-9.
64.Giatromanolaki A,Sivridis E,Athanassou N,Zois E,Thorpe PE,Brekken RA,et al.The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor"in rheumatoid arthritis and osteoarthritis.J Pathol.2001 May;194(1):101-8.
65.Detmar M.The role of VEGF and thrombospondins in skin angiogenesis.J Dermatol Sci.2000 Dec;24 Suppl 1:S78-84.
66.Carmeliet P,Jain RK.Angiogenesis in cancer and other diseases.Nature.2000Sep 14;407(6801):249-57.
67.Boyer SJ.Small molecule inhibitors of KDR(VEGFR-2) kinase:an overview of structure activity relationships.Curr Top Med Chem.2002 Sep;2(9):973-1000.
68.Hartman GD,Fraley ME,Bilodeau MT.Kinase insert domain-containing receptor kinase inhibitors as anti-angiogenic agents.Expert Opin Investig Drugs.2002Jun;11(6):737-45.
69.Fraley ME,Hoffman WF,Rubino RS,Hungate RW,Tebben AJ,Rutledge RZ,et al.Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines:a new class of KDR kinase inhibitors.Bioorg Med Chem Lett.2002 Oct 7;12(19):2767-70.
70.Fraley ME,Rubino RS,Hoffman WF,Hambaugh SR,Arrington KL,Hungate RW,et al.Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors:improvements in physical properties enhance cellular activity and pharmacokinetics.Bioorg Med Chem Lett.2002 Dec 16;12(24):3537-41.
71.Bilodeau MT,Cunningham AM,Koester TJ,Ciecko PA,Coll KE,Huckle WR,et al.Design and synthesis of 1,5-diarylbenzimidazoles as inhibitors of the VEGF-receptor KDR.Bioorg Med Chem Lett.2003 Aug 4;13(15):2485-8.
72.Wu Z,Fraley ME,Bilodeau MT,Kaufman ML,Tasber ES,Balitza AE,et al.Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR.Bioorg Med Chem Lett.2004 Feb 23;14(4):909-12.
73.Colletti SL,Frie JL,Dixon EC,Singh SB,Choi BK,Scapin G,et al.Hybrid-designed inhibitors of p38 MAP kinase utilizing N-arylpyridazinones.J Med Chem.2003 Jan 30;46(3):349-52.
74.Tobe M,Isobe Y,Tomizawa H,Nagasaki T,Takahashi H,Fukazawa T,et al.Discovery of quinazolines as a novel structural class of potent inhibitors of NF-[kappa]B activation.Bioorganic & Medicinal Chemistry.2003;11(3):383-91.
75.Tobe M,Isobe Y,Tomizawa H,Nagasaki T,Takahashi H,Hayashi H.A novel structural class of potent inhibitors of NF-[kappa]B activation:structure-activity relationships and biological effects of 6-aminoquinazoline derivatives.Bioorganic &Medicinal Chemistry.2003;11(18):3869-78.
76.章晔,张权,黄煌渊.新型有序纳米介孔生物玻璃材料对体外培养成骨细胞的影响.老年医学与保健.2008(02).
2.Karin M,Yamamoto Y,Wang QM.The IKK NF-kappa B system:a treasure trove for drug development.Nat Rev Drug Discov.2004 Jan;3(1):17-26.
3.Baeuerle PA,Baltimore D.NF-kappa B:ten years after.Cell.1996 Oct 4;87(1):13-20.
4.Beg AA,Baltimore D.An essential role for NF-kappaB in preventing TNF-alpha-induced cell death.Science.1996 Nov 1;274(5288):782-4.
5.Verma IM,Stevenson JK,Schwarz EM,Van Antwerp D,Miyamoto S.Rel/NF-kappa B/I kappa B family:intimate tales of association and dissociation.Genes Dev.1995 Nov 15;9(22):2723-35.
6.Frelin C,Imbert V,Bottero V,Gonthier N,Samraj AK,Schulze-Osthoff K,et al.Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO.Cell Death Differ.2008 Jan;15(1):152-60.
7.RothwarfDM,Zandi E,Natoli G,Karin M.IKK-gamma is an essential regulatory subunit of the IkappaB kinase complex.Nature.1998 Sep 17;395(6699):297-300.
8.Senftleben U,Cao Y,Xiao G,Greten FR,Krahn G,Bonizzi G,et al.Activation by IKKalpha of a second,evolutionary conserved,NF-kappa B signaling pathway.Science.2001 Aug 24;293(5534):1495-9.
9.Krappmann D,Emmerich F,Kordes U,Scharschmidt E,Dorken B,Scheidereit C.Molecular mechanisms of constitutive NF-kappaB/Rel activation in Hodgkin/Reed-Sternberg cells.Oncogene.1999 Jan 28;18(4):943-53.
10.Nakshatri H,Bhat-Nakshatri P,Martin DA,Goulet RJ,Jr.,Sledge GW,Jr.Constitutive activation of NF-kappaB during progression of breast cancer to hormone-independent growth.Mol Cell Biol.1997 Jul;17(7):3629-39.
11.Shackelford RE,Kaufmann WK,Paules RS.Cell cycle control,checkpoint mechanisms,and genotoxic stress.Environ Health Perspect.1999 Feb;107 Suppl 1:5-24.
12.Hinz M,Krappmann D,Eichten A,Heder A,Scheidereit C,Strauss M.NF-kappaB function in growth control:regulation of cyclin D1 expression and G0/G1-to-S-phase transition.Mol Cell Biol.1999 Apr;19(4):2690-8.
13.Chen F,Castranova V,Shi X.New insights into the role of nuclear factor-kappaB in cell growth regulation.Am J Pathol.2001 Aug;159(2):387-97.
14.Chen F,Lu Y,Zhang Z,Vallyathan V,Ding M,Castranova V,et al.Opposite effect of NF-kappa B and c-Jun N-terminal kinase on p53-independent GADD45induction by arsenite.J Biol Chem.2001 Apr 6;276(14):11414-9.
15.Beg AA,Sha WC,Bronson RT,Ghosh S,Baltimore D.Embryonic lethality and liver degeneration in mice lacking the Re1A component of NF-kappa B.Nature.1995Jul 13;376(6536):167-70.
16.Doi TS,Marino MW,Takahashi T,Yoshida T,Sakakura T,Old LJ,et al.Absence of tumor necrosis factor rescues Re1A-deficient mice from embryonic lethality.Proc Natl Acad Sci U S A.1999 Mar 16;96(6):2994-9.
17.Kucharczak J,Simmons MJ,Fan Y,Gelinas C.To be,or not to be:NF-kappaB is the answer—role of Rel/NF-kappaB in the regulation of apoptosis.Oncogene.2003Dec 8;22(56):8961-82.
18.Bian X,McAllister-Lucas LM,Shao F,Schumacher KR,Feng Z,Porter AG,et al.NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells.J Biol Chem.2001 Dec 28;276(52):48921-9.
19.Campbell KJ,Rocha S,Perkins ND.Active repression of antiapoptotic gene expression by RelA(p65) NF-kappa B.Mol Cell.2004 Mar 26;13(6):853-65.
20.杨光华,文继舫,王美清等.病理学(第五版).北京:人民卫生出版社;2000.
21.Dustin ML,Springer TA.Lymphocyte function-associated antigen-1(LFA-1)interaction with intercellular adhesion molecule-1(ICAM-1) is one of at least three mechanisms for lymphocyte adhesion to cultured endothelial cells.J Cell Biol.1988Jul;107(1):321-31.
22.Huang S,Pettaway CA,Uehara H,Bucana CD,Fidler IJ.Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis,invasion,and metastasis.Oncogene.2001 Jul 12;20(31):4188-97.
23.Karashima T,Sweeney P,Kamat A,Huang S,Kim SJ,Bar-Eli M,et al.Nuclear factor-kappaB mediates angiogenesis and metastasis of human bladder cancer through the regulation of interleukin-8.Clin Cancer Res.2003 Jul;9(7):2786-97.
24.张斌,卫僧,王杨.Nf-κb,Mmp-7在胃癌中的表达及意义.河南肿瘤学杂志.2004(01).
25.Shibata A,Nagaya T,Imai T,Funahashi H,Nakao A,Seo H.Inhibition of NF-kappaB activity decreases the VEGF mRNA expression in MDA-MB-231 breast cancer cells.Breast Cancer Res Treat.2002 Jun;73(3):237-43.
26.Blackwell TS,Christman JW.The role of nuclear factor-kappa B in cytokine gene regulation.Am J Respir Cell Mol Biol.1997 Jul;17(1):3-9.
27.Paillard F.Induction of apoptosis with I-kappaB,the inhibitor of NF-kappaB.Hum Gene Ther.1999 Jan 1;10(1):1-3.
28.Ghorab MM,Abdel-Gawad SM,El-Gaby MS.Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents.Farmaco.2000Apr;55(4):249-55.
29.Johan C.Kapteyn JBP,Maarten A.De Waard,.Biochemical Mechanisms Involved in Selective Fungitoxicity of Two Sterol 14alpha-Demethylation Inhibitors,Prochloraz and Quinconazole:Accumulation and Metabolism Studies.Pesticide Science.1992;36(2):85-93.
30.黄润秋,李慧英,马军安,邱德文.4-肟醚基喹唑啉类化合物的合成及其抗植物病毒tmv活性.高等学校化学学报.1996(04).
31.刘昕,黄李杨.O-(4-喹唑啉)羟肟酸硫代酯(酰胺)类化合物的合成及生物活性.应用化学.1999(02).
32.Gineinah MM,El-Sherbeny MA,Nasr MN,Maarouf AR.Synthesis and antiinflammatory screening of some quinazoline and quinazolyl-4-oxoquinazoline derivatives.Arch Pharm(Weinheim).2002;335(11-12):556-62.
33.Mishani E,Abourbeh G,Rozen Y,Jacobson O,Laky D,Ben David I,et al.Novel carbon-11 abeled 4-imethylamino but 2-enoic acid[4-(phenylamino)-quinazoline -6-yl]-amides:potential PET bioprobes for molecular imaging of EGFR-positive rumors.Nucl Med Biol.2004 May;31(4):469-76.
34.刘云海 秦丁吴.板蓝根化学成分的研究(Ⅲ).中草药.2002(02).
35.Lee JY,Lee YS,inventors;4-(Phenylamino)-[1,4]dioxano-2.3-glquinazoline derivatives and process for preparing the same[P].2003.
36.Keledjian K,Borkowski A,Kim G,Isaacs JT,Jacobs SC,Kyprianou N.Reduction of human prostate tumor vascularity by the alpha1-adrenoceptor antagonist terazosin.Prostate.2001 Jul 1;48(2):71-8.
37.Jiang S,Zeng Q,Gettayacamin M,Tungtaeng A,Wannaying S,Lim A,et al.Antimalarial activities and therapeutic properties of febrifugine analogs.Antimicrob Agents Chemother.2005 Mar;49(3):1169-76.
38.刘进前,徐小岗,陈秀华,余爱珍,戴祖瑞,张秀平.2,4-二氨基-5-氯-6-取代苄氨基喹唑啉类化合物的合成及其抗疟、抗肿瘤和抗菌活性.药学学报.1991(11).
39.Palanki MSS,Erdman PE,Ren M,Suto M,Bennett BL,Manning A,et al.The design and synthesis of novel orally active inhibitors of AP-1 and NF-[kappa]B mediated transcriptional activation.SAR of In vitro and In vivo studies.Bioorganic &Medicinal Chemistry Letters.2003;13(22):4077-80.
40.赵翠花.喹喔啉、喹唑啉类化合物的设计合成与生物活性研究.上海:中国科学院上海药物研究所;2004.
41.Rewcastle GW,Denny WA,Bridges AJ,Zhou H,Cody DR,McMichael A,et al.Tyrosine kinase inhibitors.5.Synthesis and structure-activity relationships for 4-[(phenylmethyl)amino]-and 4-(phenylamino)quinazolines as potent adenosine 5'-triphosphate binding site inhibitors of the tyrosine kinase domain of the epidermal growth factor receptor.J Med Chem.1995 Sep 1;38(18):3482-7.
42.Bridges AJ,Zhou H,Cody DR,Rewcastle GW,McMichael A,Showalter HD,et al.Tyrosine kinase inhibitors.8.An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline(PD 153035),a potent inhibitor of the epidermal growth factor receptor.J Med Chem.1996 Jan 5;39(1):267-76.
43.Smaill JB,Rewcastle GW,Lop JA,Greis KD,Chan OH,Reyner EL,et al.Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido.J Med Chem.2000 Aug 10;43(16):3199.
44.Rewcastle GW,Palmer BD,Bridges AJ,Showalter HD,Sun L,Nelson J,et al.Tyrosine kinase inhibitors.9.Synthesis and evaluation of fused tricyclic quinazoline analogues as ATP site inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.J Med Chem.1996 Feb 16;39(4):918-28.
45.Smaill JB,Showalter HD,Zhou H,Bridges AJ,McNamara DJ,Fry DW,et al.Tyrosine kinase inhibitors.18.6-Substituted 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as soluble,irreversible inhibitors of the epidermal growth factor receptor.J Med Chem.2001 Feb 1;44(3):429-40.
46.吴文娟.喹唑啉类化合物的量子化学与定量构效关系研究.广东:中山大学; 2004.
47.Khanna S,Sobhia ME,Bharatam PV.Additivity of molecular fields:CoMFA study on dual activators of PPARalpha and PPARgamma.J Med Chem.2005 Apr 21;48(8):3015-25.
48.Kovatcheva A,Golbraikh A,Oloff S,Xiao YD,Zheng W,Wolschann P,et al.Combinatorial QSAR of ambergris fragrance compounds.J Chem Inf Comput Sci.2004 Mar-Apr;44(2):582-95.
49.任天瑞,沈裴,汪向.家蝇与大鼠gaba受体抑制剂的药效团模型及其3d-Qsar 研究.高等学校化学学报.2005(03).
50.Yoshii F,Hirono S.Construction of a quantitative three-dimensional model for odor quality using comparative molecular field analysis(CoMFA).Chem Senses.1996 Apr;21(2):201-10.
51.Kappel JC,Yokum TS,Barany G.Parallel solid-phase syntheses of 1,3,4-thiadiazolium-2-aminides.J Comb Chem.2004 Sep-Oct;6(5):746-52.
52.韩晓峰 刘高来.非肽类凝血酶抑制剂的比较分子力场分析.化学学报.2003(07).
53.Klebe G,Abraham U,Mietzner T.Molecular similarity indices in a comparative analysis(CoMSIA) of drug molecules to correlate and predict their biological activity.J Med Chem.1994 Nov 25;37(24):4130-46.
54.Klebe G,Abraham U.Comparative molecular similarity index analysis(CoMSIA)to study hydrogen-bonding properties and to score combinatorial libraries.J Comput Aided Mol Des.1999 Jan;13(1):1-10.
55.陈凯先,蒋华良,嵇汝运.计算机辅助药物设计.原理、方法及应用:上海科学技术出版社.
56.[德]加斯泰格尔,恩格尔著,梁逸曾,徐峻,姚建华译。.化学信息学教程.北京:化学工业出版社;2005.
57.Wold SE,L.,et al.PLS-regression:A Basic Tool of Chemometrics.ChemomIntellLabSyst.2001;58:109-30.
58.Balaban AT,Oniciu DC,Katritzky AR.Aromaticity as a cornerstone of heterocyclic chemistry.Chem Rev.2004 May;104(5):2777-812.
59.Chichibabin AE.Tautomerism of α-aminopyridine.Ⅳ.A method of preparation of pyrimidazole and its homologs.Berichte der Deutschen Chemischen Gesellscaft [Abteilung]B:Abhandlungen.1925;58B:1704-6.
60.Hunt AF,Turner EE.Preparation of tertiary arsines by the Friedel-Crafts reaction.J ChemSocTransactions.1925;127:2667-71.
61.Thomas Meyer UR,Doriano Fabbro,Enrica Alteri,Giorgio Caravatti,Alex Matter,.A derivative of staurosporine(CGP 41 251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.International Journal of Cancer.1989;43(5):851-6.
62.Jaramillo C,de Diego JE,Hamdouchi C,Collins E,Keyser H,S,et al.Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors.Part 1:Design,synthesis,and biological evaluation.Bioorganic &Medicinal Chemistry Letters.2004;14(24):6095-9.
63.Hamdouchi C,Keyser H,Collins E,Jaramillo C,De Diego JE,Spencer CD,et al. The discovery of a new structural class of cyclin-dependent kinase inhibitors,aminoimidazo[1,2-a]pyridines.Mol Cancer Ther.2004 Jan;3(1):1-9.
64.Giatromanolaki A,Sivridis E,Athanassou N,Zois E,Thorpe PE,Brekken RA,et al.The angiogenic pathway "vascular endothelial growth factor/flk-1(KDR)-receptor"in rheumatoid arthritis and osteoarthritis.J Pathol.2001 May;194(1):101-8.
65.Detmar M.The role of VEGF and thrombospondins in skin angiogenesis.J Dermatol Sci.2000 Dec;24 Suppl 1:S78-84.
66.Carmeliet P,Jain RK.Angiogenesis in cancer and other diseases.Nature.2000Sep 14;407(6801):249-57.
67.Boyer SJ.Small molecule inhibitors of KDR(VEGFR-2) kinase:an overview of structure activity relationships.Curr Top Med Chem.2002 Sep;2(9):973-1000.
68.Hartman GD,Fraley ME,Bilodeau MT.Kinase insert domain-containing receptor kinase inhibitors as anti-angiogenic agents.Expert Opin Investig Drugs.2002Jun;11(6):737-45.
69.Fraley ME,Hoffman WF,Rubino RS,Hungate RW,Tebben AJ,Rutledge RZ,et al.Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines:a new class of KDR kinase inhibitors.Bioorg Med Chem Lett.2002 Oct 7;12(19):2767-70.
70.Fraley ME,Rubino RS,Hoffman WF,Hambaugh SR,Arrington KL,Hungate RW,et al.Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors:improvements in physical properties enhance cellular activity and pharmacokinetics.Bioorg Med Chem Lett.2002 Dec 16;12(24):3537-41.
71.Bilodeau MT,Cunningham AM,Koester TJ,Ciecko PA,Coll KE,Huckle WR,et al.Design and synthesis of 1,5-diarylbenzimidazoles as inhibitors of the VEGF-receptor KDR.Bioorg Med Chem Lett.2003 Aug 4;13(15):2485-8.
72.Wu Z,Fraley ME,Bilodeau MT,Kaufman ML,Tasber ES,Balitza AE,et al.Design and synthesis of 3,7-diarylimidazopyridines as inhibitors of the VEGF-receptor KDR.Bioorg Med Chem Lett.2004 Feb 23;14(4):909-12.
73.Colletti SL,Frie JL,Dixon EC,Singh SB,Choi BK,Scapin G,et al.Hybrid-designed inhibitors of p38 MAP kinase utilizing N-arylpyridazinones.J Med Chem.2003 Jan 30;46(3):349-52.
74.Tobe M,Isobe Y,Tomizawa H,Nagasaki T,Takahashi H,Fukazawa T,et al.Discovery of quinazolines as a novel structural class of potent inhibitors of NF-[kappa]B activation.Bioorganic & Medicinal Chemistry.2003;11(3):383-91.
75.Tobe M,Isobe Y,Tomizawa H,Nagasaki T,Takahashi H,Hayashi H.A novel structural class of potent inhibitors of NF-[kappa]B activation:structure-activity relationships and biological effects of 6-aminoquinazoline derivatives.Bioorganic &Medicinal Chemistry.2003;11(18):3869-78.
76.章晔,张权,黄煌渊.新型有序纳米介孔生物玻璃材料对体外培养成骨细胞的影响.老年医学与保健.2008(02).