p53-MDM2结合抑制剂的设计、合成及生物学活性评价
|
摘要
肿瘤被认为是多基因疾病,一旦控制细胞分化的基因有缺陷从而导致生长调控的失序,研究发现,p53基因是与人类肿瘤相关性最高的肿瘤抑制基因,具有维持基因组稳定、抑制或阻止细胞转化的功能；mdm2是1987年发现的癌基因,其表达产物MDM2蛋白可与p53蛋白结合,并抑制p53的正常生物学功能,从而可导致肿瘤的发生和发展。理论上,阻断MDM2对p53的作用可恢复p53正常功能,因此,抑制MDM2蛋白和p53相互作用被认为是抗肿瘤药物研究中的重要靶点之
本论文在文献调研和文献工作总结的基础上,建立了基于p53-MDM2结合抑制剂小分子的药效团模型,并利用药效团模型,结合分子骨架迁越、电子等排、分子宏观性质与微观结构的集合等理性药物设计方法,对先导化合物Nutlin-1进行了结构修饰,保留咪唑啉骨架,对2位苯基、1位N上的连接侧链及4,5位芳环上的取代基进行结构改造和优化,共合成25个分子；对所得化合物进行了p53-MDM2结合抑制活性测试,初步构效关系表明,2-苯环及对位氯原子取代的4,5-二苯对保持p53-MDM2结合抑制活性是必须,N-1侧链取代基的不同以及侧链连接方式的改变对活性有较大影响。在此基础上,进行了第二轮的结构修饰,以改变侧链的结构为主要手段,分别在N-1位引入各种烷基酯、氨基酸作为连接链,连接链末端为各种杂环及含氮片断,考察N-1侧链对活性的影响,共合成化合物26个,蛋白荧光偏振测试及抗肿瘤活性测试均显示出该轮设计合成的化合物活性较阳性对照有较大提高。为了进一步深入了解该类化合物的结合模式,本文构建了3D-QSAR模型,该模型具有较好的预测和评价能力。
在上述研究的基础上,论文在寻找全新母核结构的p53-MDM2结合抑制剂方面亦进行了一些新的探索。a.鉴于咪唑啉母核易被氧化成咪唑,因而设计、合成了15个2,4,5-三芳基咪唑衍生物,其p53-MDM2结合抑制活性及肿瘤细胞增殖抑制活性筛选结果表明,该类化合物具有中等强度的p53-MDM2结合抑制活性(～20μM)及中等到较强的肿瘤细胞增殖抑制活性。b.根据骨架跃迁、电子等排等经典设计思想,用3-氨基吡唑、3-甲酰吡唑等母核结构代替咪唑,合成了一系列取代芳基杂环类化合物共38个,p53-MDM2结合抑制活性及肿瘤细胞增殖抑制活性筛选结果表明,3-氨基吡唑类化合物的肿瘤细胞增殖抑制活性并未不理想,但p53-MDM2结合抑制活性较咪唑类化合物有所提高(～10μM)；3-甲酰吡唑类化合物的p53-MDM2结合抑制活性较弱。c.以目前体外活性最高的螺环-吲哚林-2-酮类化合物为先导,设计、合成了一系列螺环-吲哚林-2-酮类化合物共26个,其p53-MDM2结合抑制及肿瘤细胞增殖抑制活性结果显示,该类化合物对p53野生型细胞株活性较弱,但对p53突变型细胞株(SW620)表现出中等到较强的抑制活性,推测该类化合物具有不同的作用模式,对治疗p53突变型肿瘤具有进一步深入研究的价值。
同时,为测定目标分子p53-MDM2(?)了结合抑制活性,研究过程中成功表达、纯MDM2蛋白,并建立了基于荧光偏振的活性测试方法,为全文活性测试提供了实验基础。
The p53tumor suppressor is controlled by MDM2, which binds p53and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2to impair p53function. Therefore, restoration of p53activity by inhibiting the p53-MDM2binding represents an attractive novel approach to cancer therapy. Recently developed potent and selective small-molecule antagonists of the p53-MDM2interaction have been used to demonstrate the proof-of-concept for this approach.
According to previous research and literature summary, a pharmacophore model was set up based on the information of p53-MDM2binding structure and structures of known p53-MDM2binding inhibitors. The pharmacophore model revealed that three hydrophobic groups on the core structure were necessary for a good p53-MDM2binding inhibitor, and the introduction of hydrogen acceptor groups might also improve the inhibitory activities. In our first-round design, three new series of imidazoline derivatives were designed and synthesized using Nultins as lead compounds. The imidazoline scaffold of Nutlins was retained as the core structure with a focus on modifying the phenyl groups on the imidazoline ring and the N-1side chain of Nutlins. Based on the obtained data, a preliminary SAR was disclosed that the2-phenyl group and4,5-di(4-cholo)phenyls were essential for the potency, and the N-1substituents displayed a very important role in remaining the potencies as well. Then a series of novel Nutlin analogues, utilizing carbamates, amino acids, amino-acid esters or amino-acid amides as the N-1substituents were designed and synthesized to discover new p53-MDM2binding inhibitors with enhanced p53-MDM2binding inhibitory activities and anti-proliferative potencies. Then CoMFA study which was carried out based on the obtained data helped in understanding the interaction between the ligand and the receptor.
Then, some preliminary work was carried out in order to discover novel scaffold p53-MDM2binding inhibitors:a. a series of152,4,5-triphenyl imidazole derivatives was designed due to the imidazoline could get oxidized into imidazole, and their p53-MDM2binding inhibitory activities were tested as well as their anti-proliferative activities. The result exhibited that some derivatives performed medium inhibitory activities (-20μM), however, most of them showed medium to high anti-proliferative activities, which lead to a new thought in discovering novel p53-MDM2binding inhibitors. Thus, by utilizing classic drug design principle, such as bioisosteric replacement and scaffold hopping, a new series of3-amino pyrazole and3-carboxyl pyrazole was designed, synthesized and evaluated their p53-MDM2binding inhibitory activities and anti-proliferative activities. The result for38obtained compounds was concluded that3-amino pyrazole compounds had improved p53-MDM2binding inhibitory activities (～10μM) though they did not show promising anti-proliferative activities, and3-carboxyl pyrazole compounds was not good for their p53-MDM2binding inhibitory activities. As for the structural diversities, we employed spiro-indolinone compounds, which was reported the most potent compounds so far in vitro, as lead compounds, designed and synthesized a series of new spiro-indolinone derivatives, however, this series showed weak activities against cell lines expressing wtp53, but to cell lines have p53mutated (SW620), some compounds exhibited very promising activities, as a matter of concern, this series of derivatives may take part in other mechanism of p53pathway, and may be valuable for treating p53mutated cancer.
Meanwhile, for the purpose of testing p53-MDM2binding inhibitory activities of obtained molecules, MDM2protein was expressed and purified, and a FP-based testing assay was set up for the first time at home.
本论文在文献调研和文献工作总结的基础上,建立了基于p53-MDM2结合抑制剂小分子的药效团模型,并利用药效团模型,结合分子骨架迁越、电子等排、分子宏观性质与微观结构的集合等理性药物设计方法,对先导化合物Nutlin-1进行了结构修饰,保留咪唑啉骨架,对2位苯基、1位N上的连接侧链及4,5位芳环上的取代基进行结构改造和优化,共合成25个分子；对所得化合物进行了p53-MDM2结合抑制活性测试,初步构效关系表明,2-苯环及对位氯原子取代的4,5-二苯对保持p53-MDM2结合抑制活性是必须,N-1侧链取代基的不同以及侧链连接方式的改变对活性有较大影响。在此基础上,进行了第二轮的结构修饰,以改变侧链的结构为主要手段,分别在N-1位引入各种烷基酯、氨基酸作为连接链,连接链末端为各种杂环及含氮片断,考察N-1侧链对活性的影响,共合成化合物26个,蛋白荧光偏振测试及抗肿瘤活性测试均显示出该轮设计合成的化合物活性较阳性对照有较大提高。为了进一步深入了解该类化合物的结合模式,本文构建了3D-QSAR模型,该模型具有较好的预测和评价能力。
在上述研究的基础上,论文在寻找全新母核结构的p53-MDM2结合抑制剂方面亦进行了一些新的探索。a.鉴于咪唑啉母核易被氧化成咪唑,因而设计、合成了15个2,4,5-三芳基咪唑衍生物,其p53-MDM2结合抑制活性及肿瘤细胞增殖抑制活性筛选结果表明,该类化合物具有中等强度的p53-MDM2结合抑制活性(～20μM)及中等到较强的肿瘤细胞增殖抑制活性。b.根据骨架跃迁、电子等排等经典设计思想,用3-氨基吡唑、3-甲酰吡唑等母核结构代替咪唑,合成了一系列取代芳基杂环类化合物共38个,p53-MDM2结合抑制活性及肿瘤细胞增殖抑制活性筛选结果表明,3-氨基吡唑类化合物的肿瘤细胞增殖抑制活性并未不理想,但p53-MDM2结合抑制活性较咪唑类化合物有所提高(～10μM)；3-甲酰吡唑类化合物的p53-MDM2结合抑制活性较弱。c.以目前体外活性最高的螺环-吲哚林-2-酮类化合物为先导,设计、合成了一系列螺环-吲哚林-2-酮类化合物共26个,其p53-MDM2结合抑制及肿瘤细胞增殖抑制活性结果显示,该类化合物对p53野生型细胞株活性较弱,但对p53突变型细胞株(SW620)表现出中等到较强的抑制活性,推测该类化合物具有不同的作用模式,对治疗p53突变型肿瘤具有进一步深入研究的价值。
同时,为测定目标分子p53-MDM2(?)了结合抑制活性,研究过程中成功表达、纯MDM2蛋白,并建立了基于荧光偏振的活性测试方法,为全文活性测试提供了实验基础。
The p53tumor suppressor is controlled by MDM2, which binds p53and negatively regulates its transcriptional activity and stability. Many tumors overproduce MDM2to impair p53function. Therefore, restoration of p53activity by inhibiting the p53-MDM2binding represents an attractive novel approach to cancer therapy. Recently developed potent and selective small-molecule antagonists of the p53-MDM2interaction have been used to demonstrate the proof-of-concept for this approach.
According to previous research and literature summary, a pharmacophore model was set up based on the information of p53-MDM2binding structure and structures of known p53-MDM2binding inhibitors. The pharmacophore model revealed that three hydrophobic groups on the core structure were necessary for a good p53-MDM2binding inhibitor, and the introduction of hydrogen acceptor groups might also improve the inhibitory activities. In our first-round design, three new series of imidazoline derivatives were designed and synthesized using Nultins as lead compounds. The imidazoline scaffold of Nutlins was retained as the core structure with a focus on modifying the phenyl groups on the imidazoline ring and the N-1side chain of Nutlins. Based on the obtained data, a preliminary SAR was disclosed that the2-phenyl group and4,5-di(4-cholo)phenyls were essential for the potency, and the N-1substituents displayed a very important role in remaining the potencies as well. Then a series of novel Nutlin analogues, utilizing carbamates, amino acids, amino-acid esters or amino-acid amides as the N-1substituents were designed and synthesized to discover new p53-MDM2binding inhibitors with enhanced p53-MDM2binding inhibitory activities and anti-proliferative potencies. Then CoMFA study which was carried out based on the obtained data helped in understanding the interaction between the ligand and the receptor.
Then, some preliminary work was carried out in order to discover novel scaffold p53-MDM2binding inhibitors:a. a series of152,4,5-triphenyl imidazole derivatives was designed due to the imidazoline could get oxidized into imidazole, and their p53-MDM2binding inhibitory activities were tested as well as their anti-proliferative activities. The result exhibited that some derivatives performed medium inhibitory activities (-20μM), however, most of them showed medium to high anti-proliferative activities, which lead to a new thought in discovering novel p53-MDM2binding inhibitors. Thus, by utilizing classic drug design principle, such as bioisosteric replacement and scaffold hopping, a new series of3-amino pyrazole and3-carboxyl pyrazole was designed, synthesized and evaluated their p53-MDM2binding inhibitory activities and anti-proliferative activities. The result for38obtained compounds was concluded that3-amino pyrazole compounds had improved p53-MDM2binding inhibitory activities (～10μM) though they did not show promising anti-proliferative activities, and3-carboxyl pyrazole compounds was not good for their p53-MDM2binding inhibitory activities. As for the structural diversities, we employed spiro-indolinone compounds, which was reported the most potent compounds so far in vitro, as lead compounds, designed and synthesized a series of new spiro-indolinone derivatives, however, this series showed weak activities against cell lines expressing wtp53, but to cell lines have p53mutated (SW620), some compounds exhibited very promising activities, as a matter of concern, this series of derivatives may take part in other mechanism of p53pathway, and may be valuable for treating p53mutated cancer.
Meanwhile, for the purpose of testing p53-MDM2binding inhibitory activities of obtained molecules, MDM2protein was expressed and purified, and a FP-based testing assay was set up for the first time at home.
引文
[1]Fakharzadeh SS, Rosenblum-Vos L, Murphy M, Hoffman EK, George DL Structure and organization of amplified DNA on double minutes containing the mdm2 oncogene[J]. Genomics,1993,15(2):283-290.
[2]Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci,1999,55(1):96-107.
[3]Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation[J]. Cell,1992,69(7):1237-1245.
[4]Bond GL, Hu WW, Levine AJ. MDM2 is a central node in the p53 pathway:12 years and counting[J]. Current Cancer Drug Targets,2005,5(1):3-8.
[5]Wade M, Wang YV, Wahl GM. The p53 orchestra:Mdm2 and Mdmx set the tone[J]. Trends in Cell Biology,2010,20(5):299-309.
[6]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway[J]. Nature Reviews Cancer,2009,9(12):862-873.
[7]Vassilev LT. p53 Activation by small molecules:Application in oncology[J]. Journal of Medicinal Chemistry,2005,48(14):4491-4499.
[8]Bottger A, Bottger V, Sparks A, Liu W-L, F S, Howard, Lane DP. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo[J]. Curr Biol,1997,7:860-869.
[9]Blaydes JP, Gire V, Rowson JM, Wynford-Thomasa D. Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2[J]. Oncogene,1997,14(15):1859-1868.
[10]Wasylyk C, Salvi R, Argentini M, Dureuil C, Delumeau I, Abecassis J, Debussche L, Wasylyk B. p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53[J]. Oncogene,1999,18:1921-1934.
[11]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends in Molecular Medicine,2007,13(1):23-31.
[12]Sasaki M, Nie L, Maki CG MDM2 Binding Induces a Conformational Change in p53 That Is Opposed by Heat-shock Protein 90 and Precedes p53 Proteasomal Degradation[J]. J Biol Chem,2007,282(19):14626-14634.
[13]Stoll R, Renner C, Hansen S, Palme S, Klein C, Belling A, Zeslawski W, Kamionka M, Rehm T, Mu'hlhahn P, Schumacher R, Hesse F, Kaluza B, Voelter W, Engh RA, Holak TA. Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53[J]. Biochemistry,2001,(40):336-344.
[14]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. 1,4-Benzodiazepine-2,5-diones as Small Molecule Antagonists of the HDM2-p53 Interaction:Discovery and SAR[J]. Bioorg Med Chem Lett,2005,(15):765-770.
[15]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Maruga'n JJ, Raboisson P, Schubert C, Koblish HK, Zhao S, Franks CF, Lattanze J, Carver TE, Cummings MD, Maguire D, Grasberger BL, Maroney AC, Lu T. Enhanced Pharmacokinetic Properties of 1,4-benzodiazepine-2,5-dione Antagonists of the HDM2-p53 Protein-Protein Interaction through Structure-Based Drug Design[J]. Bioorg Med Chem Lett,2006,16:3310-3314.
[16]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Fotouhi N. In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2[J]. Science,2004,303:844-8848.
[17]Westwell AD. Inhibitors of the Hdm2:p53 Complex as Antitumour Agents[J]. Drug Discovery Today,2006,11(7):371.
[18]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-Molecule MDM2 Antagonists Reveal Aberrant p53 Signaling in Cancer: Implications for Therapy [J]. Proceedings of National Acadamy of Sciences of the United States of America,2006,103(6):1888-1893.
[19]Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J. MDMX Overexpression Prevents p53 Activation by the MDM2 Inhibitor Nutlin[J]. J Biol Chem,2006,281(44): 33030-33035.
[20]LaRusch GA, Jackson MW, Dunbar JD, Warren RS, Donner DB, Mayo LD. Nutlin3 Blocks Vascular Endothelial Growth Factor Induction by Preventing the Interaction between Hypoxia Inducible Factor 1A and Hdm2[J]. Cancer Res,2007, 67(2):450-454.
[21]Hardcastle IR, Ahmed SU, Atkins H, Calvert AH, Curtin NJ, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willemsc HMG, Lunec J. Isoindolinone-Based inhibitors of the MDM2-p53 Protein-Protein Interaction[J]. Bioorg Med Chem Lett,2005,15:1515-1520.
[22]Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HMG, Lunec J. Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction Based on an Isoindolinone Scaffold[J]. J Med Chem,2006,49:6209-6221.
[23]Zhao JH, Liu ZH, Yin DL, Chen J, Luo AP, Wu M. Initial Evaluation of mdm2 Inhibitors Based on MDM2-p53 Complex Structure[J]. Chine J Cancer, 2001,20(4):354-357.
[24]Zhao J, Wang M, Chen J, Luo A, Wang X, Wu M, Yin D, Liu Z. The Initial Evaluation of Non-Peptidic Small-Molecule HDM2 Inhibitors Based on P53-HDM2 Complex Structure[J]. Cancer Lett,2002,183:69-77.
[25]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an inactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[26]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[27]Galatin PS, Abraham DJ. A Nonpeptidic Sulfonamide Inhibits the MDM2-p53 Interaction and Activates p53-Dependent Transcription in mdm2-Overexpressing Cells[J]. J Med Chem,2004,47:4163-4165.
[28]Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, Pramanik A, Selivanova G. Small Molecule RITA Binds to p53, Blocks p53-HDM-2 Interaction and Activates p53 Function in Tumors[J]. Nat Med,2004,10(12): 1321-1328.
[29]Lu Y, Nikolovska-Coleska Z, Fang X, Gao W, Shangary S, Qiu S, Qin D, Wang S. Discovery of a Nanomolar Inhibitor of the Human Murine Double Minute 2 (MDM2)-p53 Interaction through an Integrated, Virtual Database Screening Strategy [J]. J Med Chem,2006,49:3759-3762.
[30]Zhuang C, Miao Z, Zhu L, Zhang Y, Guo Z, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Zhang W. Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the MDM2-p53 protein-protein interaction[J]. Eur J Med Chem,2011,46(11):5654-5661.
[31]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science,2004,303(5659): 844-848.
[32]Proskurnina MV, Lozinskaya NA, Tkachenko SE, Zefirov NS. Reaction of aromatic aldehydes with ammonium acetate[J]. Russian Journal of Organic Chemistry, 2002,38(8):1149-1153.
[1]Claiborne CF, Liverton NJ, Nguyen KT. An efficient synthesis of tetrasubstituted imidazoles from N-(2-oxo)-amides[J]. Tetrahedron Letters,1998,39(49): 8939-8942.
[2]Fazeny-Dorner B, Veitl M, Wenzel C, Piribauer M, Rossler K, Dieckmann K, Ungersbock K, Marosi C. Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme[J]. Anti-Cancer Drugs,2003,14(6):437-442.
[3]Haluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agentsfJ]. European Journal of Cancer,2002,38(13):1685-1700.
[4]Kotteas E, Alamara C, Kiagia M, Pantazopoulos K, Boufas A, Provata A, Charpidou A, Syrigos KN. Safety and efficacy of zoledronic acid rapid infusion in lung cancer patients with bone metastases:A single institution experience[J]. Anticancer Research,2008,28(1B):529-533.
[5]Perez-Ruixo JJ, Piotrovskij V, Zhang S, Hayes S, De Porre P, Zannikos P. Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer atients[J]. British Journal of Clinical Pharmacology,2006,62(1):81-96.
[6]Krezel I. New derivatives of imidazole as potential anticancer agents[J]. Farmaco,1998,53(5):342-345.
[7]Sarshar S, Zhang CZ, Moran EJ, Krane S, Rodarte JC, Benbatoul KD, Dixon R, Mjalli AMM.2,4,5-trisubstituted imidazoles:Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 1[J]. Bioorganic & Medicinal Chemistry Letters,2000,10(23):2599-2601.
[8]Zhang CZ, Sarshar S, Moran EJ, Krane S, Rodarte JC, Benbatoul KD, Dixon R, Mjalli AMM.2,4,5-trisubstituted imidazoles:Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2[J]. Bioorganic & Medicinal Chemistry Letters,2000,10(23):2603-2605.
[9]Lopez-Rodriguez ML, Murcia M, Benhamu B, Viso A, Campillo M, Pardo L. 3-D-QSAR/CoMFA and recognition models of benzimidazole derivatives at the 5-HT4 receptor[J]. Bioorganic & Medicinal Chemistry Letters,2001,11(21):2807-2811.
[10]Gust R, Wiglenda T. Structure-activity relationship study to understand the estrogen receptor-dependent gene activation of aryl-and alkyl-substituted 1H-imidazoles[J]. Journal of Medicinal Chemistry,2007,50(7):1475-1484.
[11]Naimi-Jamal MR, Mokhtari J, Dekamin MG, Kaupp G. Sodium Tetraalkoxyborates:Intermediates for the Quantitative Reduction of Aldehydes and Ketones to Alcohols through Ball Milling with NaBH(4)[J]. European Journal of Organic Chemistry,2009,(21):3567-3572.
[12]Murphy JA, Cutulic SPY, Findlay NJ, Zhou SZ, Chrystal EJT. Metal-Free Reductive Cleavage of C-O sigma-bonds in Acyloin Derivatives by an Organic Neutral Super-Electron-Donor[J]. Journal of Organic Chemistry,2009,74(22):8713-8718.
[13]Hicks LD, Hyatt JL, Moak T, Edwards CC, Tsurkan L, Wierdl M, Ferreira AM, Wadkins RM, Potter PM. Analysis of the inhibition of mammalian carboxylesterases by novel fluorobenzoins and fluorobenzils[J]. Bioorganic & Medicinal Chemistry,2007,15(11):3801-3817.
[14]Okimoto M, Takahashi Y, Nagata Y, Sasaki G, Numata K. Electrochemical oxidation of benzoins to benzils in the presence of a catalytic amount of KI in basic media[J]. Synthesis-Stuttgart,2005,(5):705-707.
[15]Paul M, Pal N, Rana BS, Sinha AK, Bhaumik A. New mesoporous titanium-phosphorus mixed oxides having bifunctional catalytic activity[J]. Catalysis Communications,2009,10(15):2041-2045.
[16]Boettcher A, Buschmann N, Furet P, Groell J-M, Kallen J, Hergovich Lisztwan J, Masuya K, Mayr L, Vaupel A.3-Imidazolylindoles for treatment of proliferative diseases and their preparation.,WO2008119741 [P].
[17]Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery [J]. Cell Cycle, 2010,9(6):1104-1111.
[18]Romeiro GA, Pereira LOR, de Souza M, Ferreira VF, Cunha AC. A new and efficient procedure for preparing 1,2,3-triazoles[J]. Tetrahedron Letters, 1997,38(29):5103-5106.
[19]Nishiguchi GA, Rodriguez AL, Katzenellenbogen JA. Diaryl-dialkyl-substituted pyrazoles:regioselective synthesis and binding affinity for the estrogen receptor[J]. Bioorganic & Medicinal Chemistry Letters,2002,12(6): 947-950.
[20]Ramajayam R, Giridhar R, Yadav MR, Balaraman R, Djaballah H, Shum D, Radu C. Synthesis, antileukemic and antiplatelet activities of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines[J]. Eur J Med Chem,2008,43(9):2004-2010.
[21]Neckers DC, Hauck G. Reactions of diphenylcyclopropenone and tetracyclones with potassium superoxide[J]. J Org Chem,1983,48(24):4691-4695.
[22]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an mactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[23]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[24]Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science,1996,274(5289):948-953.
[25]Garcia-Echeverria C, Chene P, Blommers MJJ, Furet P. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53[J]. Journal of Medicinal Chemistry,2000,43(17):3205-3208.
[26]Sakurai K, Schubert C, Kahne D. Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2[J]. Journal of the American Chemical Society,2006,128(34):11000-11001.
[27]Vassilev LT. Small-molecule antagonists of MDM2-p53 binding Research tools and potential therapeutics [J]. Cell Cycle,2004,3(4):419-421.
[28]Ding K, Lu YP, Nikolovska-Coleska Z, Wang GP, Qiu S, Shangary S, Gao W, Qin DG, Stuckey J, Krajewski K, Roller PP, Wang SM. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction[J]. Journal of Medicinal Chemistry,2006,49(12):3432-3435.
[29]Vine KL, Locke JM, Ranson M, Pyne SG, Bremner JB. An investigation into the cytotoxicity and mode of action of some novel N-alkyl-substituted isatins[J]. J Med Chem,2007,50(21):5109-5117.
[30]Hirai T, Togo H. Preparation and synthetic use of polymer-supported acetoacetate reagent[J]. Synthesis,2005,(16):2664-2668.
[31]Ghandi M, Taheri A, Abbasi A. A facile synthesis of chromeno[3,4-c]spiropyrrolidine-oxindoles via 1,3-dipolar cycloadditions[J]. Tetrahedron,2010,66(34):6744-6748.
[1]Vogelstein B, Lane D, Levine AJ. Surfing the p53 network[J]. Nature, 2000,408(6810):307-310.
[2]Levine AJ. p53, the cellular gatekeeper for growth and division[J]. Cell, 1997,88(3):323-331.
[3]Harris SL, Levine AJ. The p53 pathway:positive and negative feedback loops[J]. Oncogene,2005,24(17):2899-2908.
[4]Michael D, Oren M. The MDM2-p53 module and the ubiquitin system [J]. Seminars in Cancer Biology,2003,13(1):49-58.
[5]Eldeiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. Wafl, a Potential Mediator of P53 Tumor Suppression[J]. Cell,1993,75(4):817-825.
[6]Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The P21 Cdk-Interacting Protein Cipl Is a Potent Inhibitor of G1 Cyclin-Dependent Kinases[J]. Cell,1993,75(4):805-816.
[7]Bunz F, Hwang PM, Torrance C, Waldman T, Zhang YG, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B. Disruption of p53 in human cancer cells alters the responses to therapeutic agents[J]. Journal of Clinical Investigation, 1999,104(3):263-269.
[8]Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. P21 Is a Universal Inhibitor of Cyclin Kinases[J]. Nature,1993,366(6456):701-704.
[9]Poyurovsky MV, Prives C. Unleashing the power of p53:lessons from mice and men[J]. Genes & Development,2006,20(2):125-131.
[10]Oren M. Decision making by p53:life, death and cancer[J]. Cell Death and Differentiation,2003,10(4):431-442.
[11]Vousden KH, Lu X. Live or let die:the cell's response to p53[J]. Nat Rev Cancer,2002,2(8):594-604.
[12]Hainaut P, Hollstein M. p53 and human cancer:the first ten thousand mutations[J]. Adv Cancer Res,2000,77:81-137.
[13]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels:drugging the p53 pathway[J]. Nat Rev Cancer,2009,9(12):862-873.
[14]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends Mol Med, 2007,13(1):23-31.
[15]Fakharzadeh SS, Rosenblum-Vos L, Murphy M, Hoffman EK, George DL. Structure and organization of amplified DNA on double minutes containing the mdm2 oncogene[J]. Genomics,1993,15(2):283-290.
[16]Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci,1999,55(1):96-107.
[17]Bond GL, Hu WW, Levine AJ. MDM2 is a central node in the p53 pathway:12 years and counting[J]. Current Cancer Drug Targets,2005,5(1):3-8.
[18]Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53[J]. Nature,1997,387(6630):296-299.
[19]Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53[J]. Febs Letters,1997,420(1):25-27.
[20]Kubbutat MHG, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2[J]. Nature,1997,387(6630):299-303.
[21]Leng RP, Lin YP, Ma WL, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation[J]. Cell,2003,112(6):779-791.
[22]Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM. The ubiquitin ligase COP1 is a critical negative regulator of p53[J]. Nature,2004,429(6987):86-92.
[23]Chen DL, Kon N, Li MY, Zhang WZ, Qin J, Gu W. ARF-BP1/mule is a critical mediator of the ARF tumor suppressor[J]. Cell,2005,121(7):1071-1083.
[24]Toledo F, Wahl GM. Regulating the p53 pathway:in vitro hypotheses, in vivo veritas[J]. Nature Reviews Cancer,2006,6(12):909-923.
[25]Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The Mdm-2 Oncogene Product Forms a Complex with the P53 Protein and Inhibits P53-Mediated Transactivation[J]. Cell,1992,69(7):1237-1245.
[26]Wade M, Wang YV, Wahl GM. The p53 orchestra:Mdm2 and Mdmx set the tone[J]. Trends in Cell Biology,2010,20(5):299-309.
[27]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels:drugging the p53 pathway[J]. Nature Reviews Cancer,2009,9(12):862-873.
[28]Vassilev LT. p53 Activation by small molecules:Application in oncology[J]. Journal of Medicinal Chemistry,2005,48(14):4491-4499.
[29]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends in Molecular Medicine,2007,13(1):23-31.
[30]Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science,1996,274(5289):948-953.
[31]Stoll R, Renner C, Hansen S, Palme S, Klein C, Belling A, Zeslawski W, Kamionka M, Rehm T, Mu'hlhahn P, Schumacher R, Hesse F, Kaluza B, Voelter W, Engh RA, Holak TA. Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53[J]. Biochemistry,2001,(40):336-344.
[32]Khan S, R. US200400043114. Bornic.acid aryl analogs[P].
[33]Adams J, Behnke M, Chen SW, Cruickshank AA, Dick LR, Grenier L, Klunder JM, Ma YT, Plamondon L, Stein RL. Potent and selective inhibitors of the proteasome:Dipeptidyl boronic acids[J]. Bioorganic & Medicinal Chemistry Letters, 1998,8(4):333-338.
[34]Luke RWA, Hudson K, Hayward DF, Fielding C, Cotton R, Best R, Giles MB, Veldman MH, Griffiths LA, Jewsbury PJ, Breeze AL, Embrey KJ. Design and Synthesis of Small Molecule Inhibitors of the MDM2-p53 Interaction as Potential Anti-tumor Agents[J]. Proc Am Assoc Cancer Res,1999,40:4099.
[35]Luke R, Jewsbury P, Cotton R. Preparation of amino acid and peptidyl piperazine-4-phenyl derivatives as inhibitors of the interaction between MDM2 and p53.,WO2000015657[P].
[36]Bottger V, Bottger A, Howard SF, Picksley SM, Chene P, GarciaEcheverria C, Hochkeppel HK, Lane DP. Identification of novel mdm2 binding peptides by phage display[J]. Oncogene,1996,13(10):2141-2147.
[37]Duncan SJ, Gruschow S, Williams DH, McNicholas C, Purewal R, Hajek M, Gerlitz M, Martin S, Wrigley SK, Moore M. Isolation and structure elucidation of Chlorofusin, a novel MDM2-p53 antagonist from a Fusarium sp[J]. J Am Chem Soc, 2001,123(4):554-560.
[38]Lee SY, Clark RC, Boger DL. Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusin [J]. Journal of the American Chemical Society,2007,129(32):9860-9861.
[39]Clark RC, Lee SY, Searcey M, Boger DL. The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the MDM2-p53 protein-protein interaction [J]. Natural Product Reports,2009,26(4):465-477.
[40]Kim K, Liu E, Mischke S. Preparation of cis-3,4-dihydroxy-4-phenylpiperidine diethersas anticancer agents.,US2004180929[P].
[41]Ma Y, Lahue B, Shipps G, Wang Y, Bogen S, Voss M, Nair L, Tian Y, Doll (?), Guo Z. Preparation of substituted piperidines that increase p53 activity and the uses thereof.,US2008004287[P].
[42]Galatin PS, Abraham DJ. QSAR:Hydropathic analysis of inhibitors of the MDM2-p53 interaction [J]. Proteins-Structure Function and Genetics,2001,45(3): 169-175.
[43]Galatin PS, Abraham DJ. A nonpeptidic sulfonamide inhibits the MDM2-p53 interaction and activates p53-dependent transcription in mdm2-overexpressing cells[J]. Journal of Medicinal Chemistry,2004,47(17): 4163-4165.
[44]Zheleva DI, McInnes C, Baxter C, Gibson D, Maccallum D, Powers H, Duncan K, Bailey K, Cummings L, Thomas M, Wang S, Turner N, Uhrinova S, Uhrinova S, Barlow P, Taylor P, Walkinshaw M, Lane D, Fischer P. Bisarylsulfonamides-Novel Small Molecule Inhibitors of MDM2-p53 Interaction [J]. American Association for Cancer Research,2004,11:1281-1282.
[45]Shudong W, Gibson D, Duncan K, Bailey K, Thomas M, Maccallum D, Zheleva DI, Turner N, John, Fischer P, Martin. Bisarylsulfonamide Compounds and Their Use in Cancer Therapy[J].2003.
[46]Fry DC, Emerson SD, Palme S, Vu BT, Liu CM, Podlaski F. NMR structure of a complex between MDM2 and a small molecule inhibitor[J]. Journal of Biomolecular Nmr,2004,30(2):163-173.
[47]Vassilev LT. Small-molecule antagonists of MDM2-p53 binding-Research tools and potential therapeutics[J]. Cell Cycle,2004,3(4):419-421.
[48]Fry DC, Graves B, Vassilev LT. Development of E3-substrate (MDM2-p53)-binding inhibitors:Structural aspects[J]. Ubiquitin and Protein Degradation, Pt B,2005,399:622-633.
[49]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao XL, Vu BT, Qing WG, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy[J]. Proceedings of the National Academy of Sciences of the United States of America,2006,103(6):1888-1893.
[50]Ljungman M. Dial 9-1-1 for p53:Mechanisms of p53 activation by cellular stress[J]. Neoplasia,2000,2(3):208-225.
[51]Thompson T, Tovar C, Yang H, Carvajal D, Vu BT, Xu QL, Wahl GM, Heimbrook DC, Vassilev LT. Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis[J]. Journal of Biological Chemistry, 2004,279(51):53015-53022.
[52]Marine JC, Jochemsen AG. Mdmx as an essential regulator of p53 activity[J]. Biochemical and Biophysical Research Communications,2005,331(3): 750-760.
[53]Marine JC, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check:essential and synergistic functions of Mdm2 and Mdm4[J]. Cell Death and Differentiation,2006,13(6):927-934.
[54]Xia MX, Knezevic D, Tovar C, Huang BY, Heimbrook DC, Vassilev LT. Elevated MDM2 boosts the apoptotic activity of MDM2-p53 binding inhibitors by facilitating MDMX degradation[J]. Cell Cycle,2008,7(11):1604-1612.
[55]Abbas T, Dutta A. p21 in cancer:intricate networks and multiple activities[J]. Nature Reviews Cancer,2009,9(6):400-414.
[56]Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis[J]. Molecular Cancer Therapeutics,2002,1(8):639-649.
[57]Janicke RU, Sohn D, Essmann F, Schulze-Osthoff K. The multiple battles fought by anti-apoptotic p21[J]. Cell Cycle,2007,6(4):407-413.
[58]Xia M, Knezevic D, Vassilev LT. p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation[J]. Oncogene,2011,30(3):346-355.
[59]Yin H, Lee GI, Park HS, Payne GA, Rodriguez JM, Sebti SM, Hamilton AD. Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction[J]. Angewandte Chemie-International Edition,2005,44(18):2704-2707.
[60]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. l,4-Benzodiazepine-2,5-diones as Small Molecule Antagonists of the HDM2-p53 Interaction:Discovery and SAR[J]. Bioorg Med Chem Lett,2005,(15):765-770.
[61]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Maruga'n JJ, Raboisson P, Schubert C, Koblish HK, Zhao S, Franks CF, Lattanze J, Carver TE, Cummings MD, Maguire D, Grasberger BL, Maroney AC, Lu T. Enhanced Pharmacokinetic Properties of 1,4-benzodiazepine-2,5-dione Antagonists of the DM2-p53 Protein-Protein Interaction through Structure-Based Drug Design[J]. Bioorg Med Chem Lett,2006,16:3310-3314.
[62]Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E, Carver T, Asel E, Springer BA, Lane P, Salemme FR. High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery [J]. J Biomol Screen, 2001,6:429-440.
[63]Grasberger BL, Lu TB, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR, Maguire D, Lattanze J, Franks CF, Zhao SY, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone RF. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells[J]. Journal of Medicinal Chemistry,2005,48(4):909-912.
[64]Agrafiotis DK. Stochastic algorithms for maximizing molecular diversity[J]. Journal of Chemical Information and Computer Sciences,1997,37(5): 841-851.
[65]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu TB.1,4-benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction:discovery and SAR[J]. Bioorganic & Medicinal Chemistry Letters, 2005,15(3):765-770.
[66]Leonard K, Marugan JJ, Raboisson P, Calvo R, Gushue JM, Koblish HK, Lattanze J, Zhao SY, Cummings MD, Player MR, Maroney AC, Lu TB. Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity[J]. Bioorganic & Medicinal Chemistry Letters,2006,16(13):3463-3468.
[67]Koblish HK, Zhao SY, Franks CF, Donatelli RR, Tominovich RM, LaFrance LV, Leonard KA, Gushue JM, Parks DJ, Calvo RR, Milkiewicz KL, Marugan JJ, Raboisson P, Cummings MD, Grasberger BL, Johnson DL, Lu TB, Molloy CJ, Maroney AC. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo[J]. Molecular Cancer Therapeutics,2006,5(1):160-169.
[68]Zhuang C, Miao Z, Zhu L, Zhang Y, Guo Z, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Zhang W. Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the MDM2-p53 protein-protein interaction[J]. Eur J Med Chem,2011,46(11):5654-5661.
[69]Hardcastle IR, Ahmed SU, Atkins H, Calvert AH, Curtin NJ, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Ka'llblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willemsc HMG, Lunec J. Isoindolinone-Based inhibitors of the MDM2-p53 Protein-Protein Interaction [J]. Bioorg Med Chem Lett,2005,15:1515-1520.
[70]Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HMG, Lunec J. Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction Based on an Isoindolinone Scaffold[J]. J Med Chem,2006,49:6209-6221.
[71]Riedinger C, Endicott JA, Kemp SJ, Smyth LA, Watson A, Valeur E, Golding BT, Griffin RJ, Hardcastle IR, Noble ME, McDonnell JM. Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction[J]. Journal of the American Chemical Society,2008,130(47): 16038-16044.
[72]Riedinger C, Noble ME, Wright DJ, Mulks F, Hardcastle IR, Endicott JA, McDonnell JM. Understanding Small-Molecule Binding to MDM2:Insights into Structural Effects of Isoindolinone Inhibitors from NMR Spectroscopy[J]. Chemical Biology & Drug Design,2011,77(5):301-308.
[73]Hardcastle IR, Liu JF, Valeur E, Watson A, Ahmed SU, Blackburn TJ, Bennaceur K, Clegg W, Drummond C, Endicott JA, Golding BT, Griffin RJ, Gruber J, Haggerty K, Harrington RW, Hutton C, Kemp S, Lu XC, McDonnell JM, Newell DR, Noble MEM, Payne SL, Revill CH, Riedinger C, Xu Q, Lunec J. Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency [J]. Journal of Medicinal Chemistry,2011,54(5):1233-1243.
[74]Kawato H, Miyazaki M, Sugimoto Y, Naito H, Okayama T, Soga T, Uoto K. Preparation of imidazothiazole derivatives as antitumor agents.,WO2008072655[P].
[75]Chamoin S, Roth H-J, Zimmermann J, Zoller T. PCT Int Appl WO2008065068,WO2008065068[P].
[76]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an inactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[77]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[78]Garcia-Echeverria C, Chene P, Blommers MJJ, Furet P. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53 [J]. Journal of Medicinal Chemistry,2000,43(17):3205-3208.
[79]Sakurai K, Schubert C, Kahne D. Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2[J]. Journal of the American Chemical Society,2006,128(34):11000-11001.
[80]Ding K, Lu YP, Nikolovska-Coleska Z, Wang GP, Qiu S, Shangary S, Gao W, Qin DG, Stuckey J, Krajewski K, Roller PP, Wang SM. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction[J]. Journal of Medicinal Chemistry,2006,49(12):3432-3435.
[81]Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery[J]. Cell Cycle, 2010,9(6):1104-1111.
[82]Shangary S, Qin DG, McEachern D, Liu ML, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang GP, Chen JY, Bernard D, Zhang J, Lu YP, Gu QY, Shah RB, Pienta KJ, Ling XL, Kang SM, Guo M, Sun Y, Yang DJ, Wang SM. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition[J]. Proceedings of the National Academy of Sciences of the United States of America,2008,105(10):3933-3938.
[83]Luk K-C, So S-S, Zhang J, Zhang Z. Preparation of oxindoles as inhibitors of MDM2-p53 interaction for the treatment of cancer.,WO2006136606[P].
[84]Vu BT, Vassilev L. Small-Molecule Inhibitors of the MDM2-p53 Interaction[J]. Small-Molecule Inhibitors of Protein-Protein Interactions,2011,348: 151-172.
[85]Ding Q, Liu J-J, Zhang Z. Preparation of spiroindolinone derivatives as antitumor agents, WO2007104714[P].
[86]Chen L, Ding Q, Liu J-J, Yang S, Zhang Z. Preparation of spiroindolinone derivatives as antiproliferative and anticancer agents.,US20080009486[P].
[87]Ding Q, Jiang N, Yang S, Zhang J, Zhang Z. Preparation of 2,3-dihydrospiro[indole-3,30-piperidine]-2,60-dione derivatives as anticancer agents.,US20090156610[P].
[88]Boettcher A, Buschmann N, Furet P, Groell J-M, Kallen J, Hergovich Lisztwan J, Masuya K, Mayr L, Vaupel A.3-Imidazolylindoles for treatment of proliferative diseases and their preparation.,WO2008119741 [P].
[89]Domling A. Small molecular weight protein-protein interaction antagonists-an insurmountable challenge?[J]. Current Opinion in Chemical Biology,2008,12(3): 281-291.
[90]Doemling A. Selective and dual-action p53/mdm2/mdm4 antagonists.,WO2008130614[P].
[91]Allen JG, Bourbeau MP, Wohlhieter GE, Bartberger MD, Michelsen K, Hungate R, Gadwood RC, Gaston RD, Evans B, Mann LW, Matison ME, Schneider S, Huang X, Yu DY, Andrews PS, Reichelt A, Long AM, Yakowec P, Yang EY, Lee TA, Oliner JD. Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2-Tumor Protein 53 Protein-Protein Interaction[J]. Journal of Medicinal Chemistry,2009,52(22):7044-7053.
[92]Burdack C, Kalinski C, Ross G, Weber L, Khazak V. Pyrrolidin-2-ones as HDM2 ligands and their preparation and use in the treatment of cancer and viral infection.,WO2010028862[P].
[93]Arts J, Blattner C, Kulikov R, Valckx A, Descamps S, Janssen C, Gerardus M, Schoentjes B. Small molecule inhibitors of Hdm2-proteasome binding for use in therapy., WO2008132155[P].
[94]Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, Pramanik A, Selivanova G. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors[J]. Nature Medicine,2004,10(12): 1321-1328.
[95]Nieves-Neira W, Rivera MI, Kohlhagen G, Hursey ML, Pourquier P, Sausville EA, Pommier Y. DNA protein cross-links produced by NSC 652287, a novel thiophene derivative active against human renal cancer cells[J]. Molecular Pharmacology,1999,56(3):478-484.
[96]Rivera MI, Stinson SF, Vistica DT, Jorden JL, Kenney S, Sausville EA. Selective toxicity of the tricyclic thiophene NSC652287 in renal carcinoma cell lines-Differential accumulation and metabolism[J]. Biochemical Pharmacology,1999,57(11): 1283-1295.
[97]Krajewski M, Ozdowy P, D'Silva L, Rothweiler U, Holak TA. NMR indicates that the small molecule RITA does not block MDM2-p53 binding in vitro[J]. Nature Medicine,2005,11(11):1135-1136.
[98]Yang J, Ahmed A, Ashcroft M. Activation of a unique p53-dependent DNA damage response[J]. Cell Cycle,2009,8(10):1630-1632.
[99]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-Molecule MDM2 Antagonists Reveal Aberrant p53 Signaling in Cancer: Implications for Therapy[J]. Proceedings of National Acadamy of Sciences of the United States of America,2006,103(6):1888-1893.
[100]Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database[J]. Nucleic Acids Research,1998,26(15):3453-3459.
[101]Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition [J]. Proc Natl Acad Sci U S A,2008,105(10):3933-3938.
[2]Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci,1999,55(1):96-107.
[3]Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation[J]. Cell,1992,69(7):1237-1245.
[4]Bond GL, Hu WW, Levine AJ. MDM2 is a central node in the p53 pathway:12 years and counting[J]. Current Cancer Drug Targets,2005,5(1):3-8.
[5]Wade M, Wang YV, Wahl GM. The p53 orchestra:Mdm2 and Mdmx set the tone[J]. Trends in Cell Biology,2010,20(5):299-309.
[6]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels: drugging the p53 pathway[J]. Nature Reviews Cancer,2009,9(12):862-873.
[7]Vassilev LT. p53 Activation by small molecules:Application in oncology[J]. Journal of Medicinal Chemistry,2005,48(14):4491-4499.
[8]Bottger A, Bottger V, Sparks A, Liu W-L, F S, Howard, Lane DP. Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo[J]. Curr Biol,1997,7:860-869.
[9]Blaydes JP, Gire V, Rowson JM, Wynford-Thomasa D. Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2[J]. Oncogene,1997,14(15):1859-1868.
[10]Wasylyk C, Salvi R, Argentini M, Dureuil C, Delumeau I, Abecassis J, Debussche L, Wasylyk B. p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53[J]. Oncogene,1999,18:1921-1934.
[11]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends in Molecular Medicine,2007,13(1):23-31.
[12]Sasaki M, Nie L, Maki CG MDM2 Binding Induces a Conformational Change in p53 That Is Opposed by Heat-shock Protein 90 and Precedes p53 Proteasomal Degradation[J]. J Biol Chem,2007,282(19):14626-14634.
[13]Stoll R, Renner C, Hansen S, Palme S, Klein C, Belling A, Zeslawski W, Kamionka M, Rehm T, Mu'hlhahn P, Schumacher R, Hesse F, Kaluza B, Voelter W, Engh RA, Holak TA. Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53[J]. Biochemistry,2001,(40):336-344.
[14]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. 1,4-Benzodiazepine-2,5-diones as Small Molecule Antagonists of the HDM2-p53 Interaction:Discovery and SAR[J]. Bioorg Med Chem Lett,2005,(15):765-770.
[15]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Maruga'n JJ, Raboisson P, Schubert C, Koblish HK, Zhao S, Franks CF, Lattanze J, Carver TE, Cummings MD, Maguire D, Grasberger BL, Maroney AC, Lu T. Enhanced Pharmacokinetic Properties of 1,4-benzodiazepine-2,5-dione Antagonists of the HDM2-p53 Protein-Protein Interaction through Structure-Based Drug Design[J]. Bioorg Med Chem Lett,2006,16:3310-3314.
[16]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Fotouhi N. In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2[J]. Science,2004,303:844-8848.
[17]Westwell AD. Inhibitors of the Hdm2:p53 Complex as Antitumour Agents[J]. Drug Discovery Today,2006,11(7):371.
[18]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-Molecule MDM2 Antagonists Reveal Aberrant p53 Signaling in Cancer: Implications for Therapy [J]. Proceedings of National Acadamy of Sciences of the United States of America,2006,103(6):1888-1893.
[19]Hu B, Gilkes DM, Farooqi B, Sebti SM, Chen J. MDMX Overexpression Prevents p53 Activation by the MDM2 Inhibitor Nutlin[J]. J Biol Chem,2006,281(44): 33030-33035.
[20]LaRusch GA, Jackson MW, Dunbar JD, Warren RS, Donner DB, Mayo LD. Nutlin3 Blocks Vascular Endothelial Growth Factor Induction by Preventing the Interaction between Hypoxia Inducible Factor 1A and Hdm2[J]. Cancer Res,2007, 67(2):450-454.
[21]Hardcastle IR, Ahmed SU, Atkins H, Calvert AH, Curtin NJ, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willemsc HMG, Lunec J. Isoindolinone-Based inhibitors of the MDM2-p53 Protein-Protein Interaction[J]. Bioorg Med Chem Lett,2005,15:1515-1520.
[22]Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HMG, Lunec J. Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction Based on an Isoindolinone Scaffold[J]. J Med Chem,2006,49:6209-6221.
[23]Zhao JH, Liu ZH, Yin DL, Chen J, Luo AP, Wu M. Initial Evaluation of mdm2 Inhibitors Based on MDM2-p53 Complex Structure[J]. Chine J Cancer, 2001,20(4):354-357.
[24]Zhao J, Wang M, Chen J, Luo A, Wang X, Wu M, Yin D, Liu Z. The Initial Evaluation of Non-Peptidic Small-Molecule HDM2 Inhibitors Based on P53-HDM2 Complex Structure[J]. Cancer Lett,2002,183:69-77.
[25]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an inactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[26]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[27]Galatin PS, Abraham DJ. A Nonpeptidic Sulfonamide Inhibits the MDM2-p53 Interaction and Activates p53-Dependent Transcription in mdm2-Overexpressing Cells[J]. J Med Chem,2004,47:4163-4165.
[28]Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, Pramanik A, Selivanova G. Small Molecule RITA Binds to p53, Blocks p53-HDM-2 Interaction and Activates p53 Function in Tumors[J]. Nat Med,2004,10(12): 1321-1328.
[29]Lu Y, Nikolovska-Coleska Z, Fang X, Gao W, Shangary S, Qiu S, Qin D, Wang S. Discovery of a Nanomolar Inhibitor of the Human Murine Double Minute 2 (MDM2)-p53 Interaction through an Integrated, Virtual Database Screening Strategy [J]. J Med Chem,2006,49:3759-3762.
[30]Zhuang C, Miao Z, Zhu L, Zhang Y, Guo Z, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Zhang W. Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the MDM2-p53 protein-protein interaction[J]. Eur J Med Chem,2011,46(11):5654-5661.
[31]Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C, Fotouhi N, Liu EA. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2[J]. Science,2004,303(5659): 844-848.
[32]Proskurnina MV, Lozinskaya NA, Tkachenko SE, Zefirov NS. Reaction of aromatic aldehydes with ammonium acetate[J]. Russian Journal of Organic Chemistry, 2002,38(8):1149-1153.
[1]Claiborne CF, Liverton NJ, Nguyen KT. An efficient synthesis of tetrasubstituted imidazoles from N-(2-oxo)-amides[J]. Tetrahedron Letters,1998,39(49): 8939-8942.
[2]Fazeny-Dorner B, Veitl M, Wenzel C, Piribauer M, Rossler K, Dieckmann K, Ungersbock K, Marosi C. Second-line chemotherapy with dacarbazine and fotemustine in nitrosourea-pretreated patients with recurrent glioblastoma multiforme[J]. Anti-Cancer Drugs,2003,14(6):437-442.
[3]Haluska P, Dy GK, Adjei AA. Farnesyl transferase inhibitors as anticancer agentsfJ]. European Journal of Cancer,2002,38(13):1685-1700.
[4]Kotteas E, Alamara C, Kiagia M, Pantazopoulos K, Boufas A, Provata A, Charpidou A, Syrigos KN. Safety and efficacy of zoledronic acid rapid infusion in lung cancer patients with bone metastases:A single institution experience[J]. Anticancer Research,2008,28(1B):529-533.
[5]Perez-Ruixo JJ, Piotrovskij V, Zhang S, Hayes S, De Porre P, Zannikos P. Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer atients[J]. British Journal of Clinical Pharmacology,2006,62(1):81-96.
[6]Krezel I. New derivatives of imidazole as potential anticancer agents[J]. Farmaco,1998,53(5):342-345.
[7]Sarshar S, Zhang CZ, Moran EJ, Krane S, Rodarte JC, Benbatoul KD, Dixon R, Mjalli AMM.2,4,5-trisubstituted imidazoles:Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 1[J]. Bioorganic & Medicinal Chemistry Letters,2000,10(23):2599-2601.
[8]Zhang CZ, Sarshar S, Moran EJ, Krane S, Rodarte JC, Benbatoul KD, Dixon R, Mjalli AMM.2,4,5-trisubstituted imidazoles:Novel nontoxic modulators of P-glycoprotein mediated multidrug resistance. Part 2[J]. Bioorganic & Medicinal Chemistry Letters,2000,10(23):2603-2605.
[9]Lopez-Rodriguez ML, Murcia M, Benhamu B, Viso A, Campillo M, Pardo L. 3-D-QSAR/CoMFA and recognition models of benzimidazole derivatives at the 5-HT4 receptor[J]. Bioorganic & Medicinal Chemistry Letters,2001,11(21):2807-2811.
[10]Gust R, Wiglenda T. Structure-activity relationship study to understand the estrogen receptor-dependent gene activation of aryl-and alkyl-substituted 1H-imidazoles[J]. Journal of Medicinal Chemistry,2007,50(7):1475-1484.
[11]Naimi-Jamal MR, Mokhtari J, Dekamin MG, Kaupp G. Sodium Tetraalkoxyborates:Intermediates for the Quantitative Reduction of Aldehydes and Ketones to Alcohols through Ball Milling with NaBH(4)[J]. European Journal of Organic Chemistry,2009,(21):3567-3572.
[12]Murphy JA, Cutulic SPY, Findlay NJ, Zhou SZ, Chrystal EJT. Metal-Free Reductive Cleavage of C-O sigma-bonds in Acyloin Derivatives by an Organic Neutral Super-Electron-Donor[J]. Journal of Organic Chemistry,2009,74(22):8713-8718.
[13]Hicks LD, Hyatt JL, Moak T, Edwards CC, Tsurkan L, Wierdl M, Ferreira AM, Wadkins RM, Potter PM. Analysis of the inhibition of mammalian carboxylesterases by novel fluorobenzoins and fluorobenzils[J]. Bioorganic & Medicinal Chemistry,2007,15(11):3801-3817.
[14]Okimoto M, Takahashi Y, Nagata Y, Sasaki G, Numata K. Electrochemical oxidation of benzoins to benzils in the presence of a catalytic amount of KI in basic media[J]. Synthesis-Stuttgart,2005,(5):705-707.
[15]Paul M, Pal N, Rana BS, Sinha AK, Bhaumik A. New mesoporous titanium-phosphorus mixed oxides having bifunctional catalytic activity[J]. Catalysis Communications,2009,10(15):2041-2045.
[16]Boettcher A, Buschmann N, Furet P, Groell J-M, Kallen J, Hergovich Lisztwan J, Masuya K, Mayr L, Vaupel A.3-Imidazolylindoles for treatment of proliferative diseases and their preparation.,WO2008119741 [P].
[17]Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery [J]. Cell Cycle, 2010,9(6):1104-1111.
[18]Romeiro GA, Pereira LOR, de Souza M, Ferreira VF, Cunha AC. A new and efficient procedure for preparing 1,2,3-triazoles[J]. Tetrahedron Letters, 1997,38(29):5103-5106.
[19]Nishiguchi GA, Rodriguez AL, Katzenellenbogen JA. Diaryl-dialkyl-substituted pyrazoles:regioselective synthesis and binding affinity for the estrogen receptor[J]. Bioorganic & Medicinal Chemistry Letters,2002,12(6): 947-950.
[20]Ramajayam R, Giridhar R, Yadav MR, Balaraman R, Djaballah H, Shum D, Radu C. Synthesis, antileukemic and antiplatelet activities of 2,3-diaryl-6,7-dihydro-5H-1,4-diazepines[J]. Eur J Med Chem,2008,43(9):2004-2010.
[21]Neckers DC, Hauck G. Reactions of diphenylcyclopropenone and tetracyclones with potassium superoxide[J]. J Org Chem,1983,48(24):4691-4695.
[22]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an mactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[23]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[24]Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science,1996,274(5289):948-953.
[25]Garcia-Echeverria C, Chene P, Blommers MJJ, Furet P. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53[J]. Journal of Medicinal Chemistry,2000,43(17):3205-3208.
[26]Sakurai K, Schubert C, Kahne D. Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2[J]. Journal of the American Chemical Society,2006,128(34):11000-11001.
[27]Vassilev LT. Small-molecule antagonists of MDM2-p53 binding Research tools and potential therapeutics [J]. Cell Cycle,2004,3(4):419-421.
[28]Ding K, Lu YP, Nikolovska-Coleska Z, Wang GP, Qiu S, Shangary S, Gao W, Qin DG, Stuckey J, Krajewski K, Roller PP, Wang SM. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction[J]. Journal of Medicinal Chemistry,2006,49(12):3432-3435.
[29]Vine KL, Locke JM, Ranson M, Pyne SG, Bremner JB. An investigation into the cytotoxicity and mode of action of some novel N-alkyl-substituted isatins[J]. J Med Chem,2007,50(21):5109-5117.
[30]Hirai T, Togo H. Preparation and synthetic use of polymer-supported acetoacetate reagent[J]. Synthesis,2005,(16):2664-2668.
[31]Ghandi M, Taheri A, Abbasi A. A facile synthesis of chromeno[3,4-c]spiropyrrolidine-oxindoles via 1,3-dipolar cycloadditions[J]. Tetrahedron,2010,66(34):6744-6748.
[1]Vogelstein B, Lane D, Levine AJ. Surfing the p53 network[J]. Nature, 2000,408(6810):307-310.
[2]Levine AJ. p53, the cellular gatekeeper for growth and division[J]. Cell, 1997,88(3):323-331.
[3]Harris SL, Levine AJ. The p53 pathway:positive and negative feedback loops[J]. Oncogene,2005,24(17):2899-2908.
[4]Michael D, Oren M. The MDM2-p53 module and the ubiquitin system [J]. Seminars in Cancer Biology,2003,13(1):49-58.
[5]Eldeiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B. Wafl, a Potential Mediator of P53 Tumor Suppression[J]. Cell,1993,75(4):817-825.
[6]Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ. The P21 Cdk-Interacting Protein Cipl Is a Potent Inhibitor of G1 Cyclin-Dependent Kinases[J]. Cell,1993,75(4):805-816.
[7]Bunz F, Hwang PM, Torrance C, Waldman T, Zhang YG, Dillehay L, Williams J, Lengauer C, Kinzler KW, Vogelstein B. Disruption of p53 in human cancer cells alters the responses to therapeutic agents[J]. Journal of Clinical Investigation, 1999,104(3):263-269.
[8]Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D. P21 Is a Universal Inhibitor of Cyclin Kinases[J]. Nature,1993,366(6456):701-704.
[9]Poyurovsky MV, Prives C. Unleashing the power of p53:lessons from mice and men[J]. Genes & Development,2006,20(2):125-131.
[10]Oren M. Decision making by p53:life, death and cancer[J]. Cell Death and Differentiation,2003,10(4):431-442.
[11]Vousden KH, Lu X. Live or let die:the cell's response to p53[J]. Nat Rev Cancer,2002,2(8):594-604.
[12]Hainaut P, Hollstein M. p53 and human cancer:the first ten thousand mutations[J]. Adv Cancer Res,2000,77:81-137.
[13]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels:drugging the p53 pathway[J]. Nat Rev Cancer,2009,9(12):862-873.
[14]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends Mol Med, 2007,13(1):23-31.
[15]Fakharzadeh SS, Rosenblum-Vos L, Murphy M, Hoffman EK, George DL. Structure and organization of amplified DNA on double minutes containing the mdm2 oncogene[J]. Genomics,1993,15(2):283-290.
[16]Freedman DA, Wu L, Levine AJ. Functions of the MDM2 oncoprotein[J]. Cell Mol Life Sci,1999,55(1):96-107.
[17]Bond GL, Hu WW, Levine AJ. MDM2 is a central node in the p53 pathway:12 years and counting[J]. Current Cancer Drug Targets,2005,5(1):3-8.
[18]Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53[J]. Nature,1997,387(6630):296-299.
[19]Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53[J]. Febs Letters,1997,420(1):25-27.
[20]Kubbutat MHG, Jones SN, Vousden KH. Regulation of p53 stability by Mdm2[J]. Nature,1997,387(6630):299-303.
[21]Leng RP, Lin YP, Ma WL, Wu H, Lemmers B, Chung S, Parant JM, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation[J]. Cell,2003,112(6):779-791.
[22]Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, O'Rourke K, Koeppen H, Dixit VM. The ubiquitin ligase COP1 is a critical negative regulator of p53[J]. Nature,2004,429(6987):86-92.
[23]Chen DL, Kon N, Li MY, Zhang WZ, Qin J, Gu W. ARF-BP1/mule is a critical mediator of the ARF tumor suppressor[J]. Cell,2005,121(7):1071-1083.
[24]Toledo F, Wahl GM. Regulating the p53 pathway:in vitro hypotheses, in vivo veritas[J]. Nature Reviews Cancer,2006,6(12):909-923.
[25]Momand J, Zambetti GP, Olson DC, George D, Levine AJ. The Mdm-2 Oncogene Product Forms a Complex with the P53 Protein and Inhibits P53-Mediated Transactivation[J]. Cell,1992,69(7):1237-1245.
[26]Wade M, Wang YV, Wahl GM. The p53 orchestra:Mdm2 and Mdmx set the tone[J]. Trends in Cell Biology,2010,20(5):299-309.
[27]Brown CJ, Lain S, Verma CS, Fersht AR, Lane DP. Awakening guardian angels:drugging the p53 pathway[J]. Nature Reviews Cancer,2009,9(12):862-873.
[28]Vassilev LT. p53 Activation by small molecules:Application in oncology[J]. Journal of Medicinal Chemistry,2005,48(14):4491-4499.
[29]Vassilev LT. MDM2 inhibitors for cancer therapy[J]. Trends in Molecular Medicine,2007,13(1):23-31.
[30]Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain[J]. Science,1996,274(5289):948-953.
[31]Stoll R, Renner C, Hansen S, Palme S, Klein C, Belling A, Zeslawski W, Kamionka M, Rehm T, Mu'hlhahn P, Schumacher R, Hesse F, Kaluza B, Voelter W, Engh RA, Holak TA. Chalcone Derivatives Antagonize Interactions between the Human Oncoprotein MDM2 and p53[J]. Biochemistry,2001,(40):336-344.
[32]Khan S, R. US200400043114. Bornic.acid aryl analogs[P].
[33]Adams J, Behnke M, Chen SW, Cruickshank AA, Dick LR, Grenier L, Klunder JM, Ma YT, Plamondon L, Stein RL. Potent and selective inhibitors of the proteasome:Dipeptidyl boronic acids[J]. Bioorganic & Medicinal Chemistry Letters, 1998,8(4):333-338.
[34]Luke RWA, Hudson K, Hayward DF, Fielding C, Cotton R, Best R, Giles MB, Veldman MH, Griffiths LA, Jewsbury PJ, Breeze AL, Embrey KJ. Design and Synthesis of Small Molecule Inhibitors of the MDM2-p53 Interaction as Potential Anti-tumor Agents[J]. Proc Am Assoc Cancer Res,1999,40:4099.
[35]Luke R, Jewsbury P, Cotton R. Preparation of amino acid and peptidyl piperazine-4-phenyl derivatives as inhibitors of the interaction between MDM2 and p53.,WO2000015657[P].
[36]Bottger V, Bottger A, Howard SF, Picksley SM, Chene P, GarciaEcheverria C, Hochkeppel HK, Lane DP. Identification of novel mdm2 binding peptides by phage display[J]. Oncogene,1996,13(10):2141-2147.
[37]Duncan SJ, Gruschow S, Williams DH, McNicholas C, Purewal R, Hajek M, Gerlitz M, Martin S, Wrigley SK, Moore M. Isolation and structure elucidation of Chlorofusin, a novel MDM2-p53 antagonist from a Fusarium sp[J]. J Am Chem Soc, 2001,123(4):554-560.
[38]Lee SY, Clark RC, Boger DL. Total synthesis, stereochemical reassignment, and absolute configuration of chlorofusin [J]. Journal of the American Chemical Society,2007,129(32):9860-9861.
[39]Clark RC, Lee SY, Searcey M, Boger DL. The isolation, total synthesis and structure elucidation of chlorofusin, a natural product inhibitor of the MDM2-p53 protein-protein interaction [J]. Natural Product Reports,2009,26(4):465-477.
[40]Kim K, Liu E, Mischke S. Preparation of cis-3,4-dihydroxy-4-phenylpiperidine diethersas anticancer agents.,US2004180929[P].
[41]Ma Y, Lahue B, Shipps G, Wang Y, Bogen S, Voss M, Nair L, Tian Y, Doll (?), Guo Z. Preparation of substituted piperidines that increase p53 activity and the uses thereof.,US2008004287[P].
[42]Galatin PS, Abraham DJ. QSAR:Hydropathic analysis of inhibitors of the MDM2-p53 interaction [J]. Proteins-Structure Function and Genetics,2001,45(3): 169-175.
[43]Galatin PS, Abraham DJ. A nonpeptidic sulfonamide inhibits the MDM2-p53 interaction and activates p53-dependent transcription in mdm2-overexpressing cells[J]. Journal of Medicinal Chemistry,2004,47(17): 4163-4165.
[44]Zheleva DI, McInnes C, Baxter C, Gibson D, Maccallum D, Powers H, Duncan K, Bailey K, Cummings L, Thomas M, Wang S, Turner N, Uhrinova S, Uhrinova S, Barlow P, Taylor P, Walkinshaw M, Lane D, Fischer P. Bisarylsulfonamides-Novel Small Molecule Inhibitors of MDM2-p53 Interaction [J]. American Association for Cancer Research,2004,11:1281-1282.
[45]Shudong W, Gibson D, Duncan K, Bailey K, Thomas M, Maccallum D, Zheleva DI, Turner N, John, Fischer P, Martin. Bisarylsulfonamide Compounds and Their Use in Cancer Therapy[J].2003.
[46]Fry DC, Emerson SD, Palme S, Vu BT, Liu CM, Podlaski F. NMR structure of a complex between MDM2 and a small molecule inhibitor[J]. Journal of Biomolecular Nmr,2004,30(2):163-173.
[47]Vassilev LT. Small-molecule antagonists of MDM2-p53 binding-Research tools and potential therapeutics[J]. Cell Cycle,2004,3(4):419-421.
[48]Fry DC, Graves B, Vassilev LT. Development of E3-substrate (MDM2-p53)-binding inhibitors:Structural aspects[J]. Ubiquitin and Protein Degradation, Pt B,2005,399:622-633.
[49]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao XL, Vu BT, Qing WG, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: Implications for therapy[J]. Proceedings of the National Academy of Sciences of the United States of America,2006,103(6):1888-1893.
[50]Ljungman M. Dial 9-1-1 for p53:Mechanisms of p53 activation by cellular stress[J]. Neoplasia,2000,2(3):208-225.
[51]Thompson T, Tovar C, Yang H, Carvajal D, Vu BT, Xu QL, Wahl GM, Heimbrook DC, Vassilev LT. Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis[J]. Journal of Biological Chemistry, 2004,279(51):53015-53022.
[52]Marine JC, Jochemsen AG. Mdmx as an essential regulator of p53 activity[J]. Biochemical and Biophysical Research Communications,2005,331(3): 750-760.
[53]Marine JC, Francoz S, Maetens M, Wahl G, Toledo F, Lozano G. Keeping p53 in check:essential and synergistic functions of Mdm2 and Mdm4[J]. Cell Death and Differentiation,2006,13(6):927-934.
[54]Xia MX, Knezevic D, Tovar C, Huang BY, Heimbrook DC, Vassilev LT. Elevated MDM2 boosts the apoptotic activity of MDM2-p53 binding inhibitors by facilitating MDMX degradation[J]. Cell Cycle,2008,7(11):1604-1612.
[55]Abbas T, Dutta A. p21 in cancer:intricate networks and multiple activities[J]. Nature Reviews Cancer,2009,9(6):400-414.
[56]Gartel AL, Tyner AL. The role of the cyclin-dependent kinase inhibitor p21 in apoptosis[J]. Molecular Cancer Therapeutics,2002,1(8):639-649.
[57]Janicke RU, Sohn D, Essmann F, Schulze-Osthoff K. The multiple battles fought by anti-apoptotic p21[J]. Cell Cycle,2007,6(4):407-413.
[58]Xia M, Knezevic D, Vassilev LT. p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation[J]. Oncogene,2011,30(3):346-355.
[59]Yin H, Lee GI, Park HS, Payne GA, Rodriguez JM, Sebti SM, Hamilton AD. Terphenyl-based helical mimetics that disrupt the p53/HDM2 interaction[J]. Angewandte Chemie-International Edition,2005,44(18):2704-2707.
[60]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. l,4-Benzodiazepine-2,5-diones as Small Molecule Antagonists of the HDM2-p53 Interaction:Discovery and SAR[J]. Bioorg Med Chem Lett,2005,(15):765-770.
[61]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Maruga'n JJ, Raboisson P, Schubert C, Koblish HK, Zhao S, Franks CF, Lattanze J, Carver TE, Cummings MD, Maguire D, Grasberger BL, Maroney AC, Lu T. Enhanced Pharmacokinetic Properties of 1,4-benzodiazepine-2,5-dione Antagonists of the DM2-p53 Protein-Protein Interaction through Structure-Based Drug Design[J]. Bioorg Med Chem Lett,2006,16:3310-3314.
[62]Pantoliano MW, Petrella EC, Kwasnoski JD, Lobanov VS, Myslik J, Graf E, Carver T, Asel E, Springer BA, Lane P, Salemme FR. High-Density Miniaturized Thermal Shift Assays as a General Strategy for Drug Discovery [J]. J Biomol Screen, 2001,6:429-440.
[63]Grasberger BL, Lu TB, Schubert C, Parks DJ, Carver TE, Koblish HK, Cummings MD, LaFrance LV, Milkiewicz KL, Calvo RR, Maguire D, Lattanze J, Franks CF, Zhao SY, Ramachandren K, Bylebyl GR, Zhang M, Manthey CL, Petrella EC, Pantoliano MW, Deckman IC, Spurlino JC, Maroney AC, Tomczuk BE, Molloy CJ, Bone RF. Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells[J]. Journal of Medicinal Chemistry,2005,48(4):909-912.
[64]Agrafiotis DK. Stochastic algorithms for maximizing molecular diversity[J]. Journal of Chemical Information and Computer Sciences,1997,37(5): 841-851.
[65]Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Carver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu TB.1,4-benzodiazepine-2,5-diones as small molecule antagonists of the HDM2-p53 interaction:discovery and SAR[J]. Bioorganic & Medicinal Chemistry Letters, 2005,15(3):765-770.
[66]Leonard K, Marugan JJ, Raboisson P, Calvo R, Gushue JM, Koblish HK, Lattanze J, Zhao SY, Cummings MD, Player MR, Maroney AC, Lu TB. Novel 1,4-benzodiazepine-2,5-diones as Hdm2 antagonists with improved cellular activity[J]. Bioorganic & Medicinal Chemistry Letters,2006,16(13):3463-3468.
[67]Koblish HK, Zhao SY, Franks CF, Donatelli RR, Tominovich RM, LaFrance LV, Leonard KA, Gushue JM, Parks DJ, Calvo RR, Milkiewicz KL, Marugan JJ, Raboisson P, Cummings MD, Grasberger BL, Johnson DL, Lu TB, Molloy CJ, Maroney AC. Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo[J]. Molecular Cancer Therapeutics,2006,5(1):160-169.
[68]Zhuang C, Miao Z, Zhu L, Zhang Y, Guo Z, Yao J, Dong G, Wang S, Liu Y, Chen H, Sheng C, Zhang W. Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the MDM2-p53 protein-protein interaction[J]. Eur J Med Chem,2011,46(11):5654-5661.
[69]Hardcastle IR, Ahmed SU, Atkins H, Calvert AH, Curtin NJ, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Ka'llblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willemsc HMG, Lunec J. Isoindolinone-Based inhibitors of the MDM2-p53 Protein-Protein Interaction [J]. Bioorg Med Chem Lett,2005,15:1515-1520.
[70]Hardcastle IR, Ahmed SU, Atkins H, Farnie G, Golding BT, Griffin RJ, Guyenne S, Hutton C, Kallblad P, Kemp SJ, Kitching MS, Newell DR, Norbedo S, Northen JS, Reid RJ, Saravanan K, Willems HMG, Lunec J. Small-Molecule Inhibitors of the MDM2-p53 Protein-Protein Interaction Based on an Isoindolinone Scaffold[J]. J Med Chem,2006,49:6209-6221.
[71]Riedinger C, Endicott JA, Kemp SJ, Smyth LA, Watson A, Valeur E, Golding BT, Griffin RJ, Hardcastle IR, Noble ME, McDonnell JM. Analysis of Chemical Shift Changes Reveals the Binding Modes of Isoindolinone Inhibitors of the MDM2-p53 Interaction[J]. Journal of the American Chemical Society,2008,130(47): 16038-16044.
[72]Riedinger C, Noble ME, Wright DJ, Mulks F, Hardcastle IR, Endicott JA, McDonnell JM. Understanding Small-Molecule Binding to MDM2:Insights into Structural Effects of Isoindolinone Inhibitors from NMR Spectroscopy[J]. Chemical Biology & Drug Design,2011,77(5):301-308.
[73]Hardcastle IR, Liu JF, Valeur E, Watson A, Ahmed SU, Blackburn TJ, Bennaceur K, Clegg W, Drummond C, Endicott JA, Golding BT, Griffin RJ, Gruber J, Haggerty K, Harrington RW, Hutton C, Kemp S, Lu XC, McDonnell JM, Newell DR, Noble MEM, Payne SL, Revill CH, Riedinger C, Xu Q, Lunec J. Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency [J]. Journal of Medicinal Chemistry,2011,54(5):1233-1243.
[74]Kawato H, Miyazaki M, Sugimoto Y, Naito H, Okayama T, Soga T, Uoto K. Preparation of imidazothiazole derivatives as antitumor agents.,WO2008072655[P].
[75]Chamoin S, Roth H-J, Zimmermann J, Zoller T. PCT Int Appl WO2008065068,WO2008065068[P].
[76]Wang SM, Ding K, Lu YP, Nikolovska-Coleska Z, Qiu S, Kumar S, Roller PP, Tomita Y, Krajewski K, Deschamps JR. Structure-based design of potent, non-peptide small-molecule inhibitors of the MDM2-p53 interaction starting from an inactive lead[J]. Abstracts of Papers of the American Chemical Society,2005,230: U2700-U2700.
[77]Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding YS, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang SM. Structure-based design of potent non-peptide MDM2 inhibitors[J]. Journal of the American Chemical Society,2005,127(29):10130-10131.
[78]Garcia-Echeverria C, Chene P, Blommers MJJ, Furet P. Discovery of potent antagonists of the interaction between human double minute 2 and tumor suppressor p53 [J]. Journal of Medicinal Chemistry,2000,43(17):3205-3208.
[79]Sakurai K, Schubert C, Kahne D. Crystallographic analysis of an 8-mer p53 peptide analogue complexed with MDM2[J]. Journal of the American Chemical Society,2006,128(34):11000-11001.
[80]Ding K, Lu YP, Nikolovska-Coleska Z, Wang GP, Qiu S, Shangary S, Gao W, Qin DG, Stuckey J, Krajewski K, Roller PP, Wang SM. Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction[J]. Journal of Medicinal Chemistry,2006,49(12):3432-3435.
[81]Popowicz GM, Czarna A, Wolf S, Wang K, Wang W, Domling A, Holak TA. Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery[J]. Cell Cycle, 2010,9(6):1104-1111.
[82]Shangary S, Qin DG, McEachern D, Liu ML, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang GP, Chen JY, Bernard D, Zhang J, Lu YP, Gu QY, Shah RB, Pienta KJ, Ling XL, Kang SM, Guo M, Sun Y, Yang DJ, Wang SM. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition[J]. Proceedings of the National Academy of Sciences of the United States of America,2008,105(10):3933-3938.
[83]Luk K-C, So S-S, Zhang J, Zhang Z. Preparation of oxindoles as inhibitors of MDM2-p53 interaction for the treatment of cancer.,WO2006136606[P].
[84]Vu BT, Vassilev L. Small-Molecule Inhibitors of the MDM2-p53 Interaction[J]. Small-Molecule Inhibitors of Protein-Protein Interactions,2011,348: 151-172.
[85]Ding Q, Liu J-J, Zhang Z. Preparation of spiroindolinone derivatives as antitumor agents, WO2007104714[P].
[86]Chen L, Ding Q, Liu J-J, Yang S, Zhang Z. Preparation of spiroindolinone derivatives as antiproliferative and anticancer agents.,US20080009486[P].
[87]Ding Q, Jiang N, Yang S, Zhang J, Zhang Z. Preparation of 2,3-dihydrospiro[indole-3,30-piperidine]-2,60-dione derivatives as anticancer agents.,US20090156610[P].
[88]Boettcher A, Buschmann N, Furet P, Groell J-M, Kallen J, Hergovich Lisztwan J, Masuya K, Mayr L, Vaupel A.3-Imidazolylindoles for treatment of proliferative diseases and their preparation.,WO2008119741 [P].
[89]Domling A. Small molecular weight protein-protein interaction antagonists-an insurmountable challenge?[J]. Current Opinion in Chemical Biology,2008,12(3): 281-291.
[90]Doemling A. Selective and dual-action p53/mdm2/mdm4 antagonists.,WO2008130614[P].
[91]Allen JG, Bourbeau MP, Wohlhieter GE, Bartberger MD, Michelsen K, Hungate R, Gadwood RC, Gaston RD, Evans B, Mann LW, Matison ME, Schneider S, Huang X, Yu DY, Andrews PS, Reichelt A, Long AM, Yakowec P, Yang EY, Lee TA, Oliner JD. Discovery and Optimization of Chromenotriazolopyrimidines as Potent Inhibitors of the Mouse Double Minute 2-Tumor Protein 53 Protein-Protein Interaction[J]. Journal of Medicinal Chemistry,2009,52(22):7044-7053.
[92]Burdack C, Kalinski C, Ross G, Weber L, Khazak V. Pyrrolidin-2-ones as HDM2 ligands and their preparation and use in the treatment of cancer and viral infection.,WO2010028862[P].
[93]Arts J, Blattner C, Kulikov R, Valckx A, Descamps S, Janssen C, Gerardus M, Schoentjes B. Small molecule inhibitors of Hdm2-proteasome binding for use in therapy., WO2008132155[P].
[94]Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LGGC, Masucci M, Pramanik A, Selivanova G. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors[J]. Nature Medicine,2004,10(12): 1321-1328.
[95]Nieves-Neira W, Rivera MI, Kohlhagen G, Hursey ML, Pourquier P, Sausville EA, Pommier Y. DNA protein cross-links produced by NSC 652287, a novel thiophene derivative active against human renal cancer cells[J]. Molecular Pharmacology,1999,56(3):478-484.
[96]Rivera MI, Stinson SF, Vistica DT, Jorden JL, Kenney S, Sausville EA. Selective toxicity of the tricyclic thiophene NSC652287 in renal carcinoma cell lines-Differential accumulation and metabolism[J]. Biochemical Pharmacology,1999,57(11): 1283-1295.
[97]Krajewski M, Ozdowy P, D'Silva L, Rothweiler U, Holak TA. NMR indicates that the small molecule RITA does not block MDM2-p53 binding in vitro[J]. Nature Medicine,2005,11(11):1135-1136.
[98]Yang J, Ahmed A, Ashcroft M. Activation of a unique p53-dependent DNA damage response[J]. Cell Cycle,2009,8(10):1630-1632.
[99]Tovar C, Rosinski J, Filipovic Z, Higgins B, Kolinsky K, Hilton H, Zhao X, Vu BT, Qing W, Packman K, Myklebost O, Heimbrook DC, Vassilev LT. Small-Molecule MDM2 Antagonists Reveal Aberrant p53 Signaling in Cancer: Implications for Therapy[J]. Proceedings of National Acadamy of Sciences of the United States of America,2006,103(6):1888-1893.
[100]Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database[J]. Nucleic Acids Research,1998,26(15):3453-3459.
[101]Shangary S, Qin D, McEachern D, Liu M, Miller RS, Qiu S, Nikolovska-Coleska Z, Ding K, Wang G, Chen J, Bernard D, Zhang J, Lu Y, Gu Q, Shah RB, Pienta KJ, Ling X, Kang S, Guo M, Sun Y, Yang D, Wang S. Temporal activation of p53 by a specific MDM2 inhibitor is selectively toxic to tumors and leads to complete tumor growth inhibition [J]. Proc Natl Acad Sci U S A,2008,105(10):3933-3938.