1-chlorocarbonyl-2-(9H-fluoren-9-methoxycarbonylamino)-1-methylhydrazine | 250280-35-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 1-chlorocarbonyl-2-(9H-fluoren-9-methoxycarbonylamino)-1-methylhydrazine
• 英文别名: N-chlorocarbonyl-N-methyl-N'-(9-fluorenylmethyloxycarbonyl)hydrazine；2-(chlorocarbonyl)-1-Fmoc-2-methylhydrazine；Fmoc-AzAla-Cl；N'-Fmoc-N-methyl-hydrazinocarbonyl chloride；N'-Fmoc-N-methyl-hydrazincarbonyl chloride；9H-fluoren-9-ylmethyl N-[carbonochloridoyl(methyl)amino]carbamate
• CAS: 250280-35-4
• 化学式: C₁₇H₁₅ClN₂O₃
• 分子量: 330.771
• InChiKey: COFFDUNGRUFUGO-UHFFFAOYSA-N

物化性质

• 熔点：
  62 °C
• 密度：
  1.339±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-chlorocarbonyl-2-(9H-fluoren-9-methoxycarbonylamino)-1-methylhydrazine 在 哌啶 、 N,N-二异丙基乙胺 作用下， 以 DMF (N,N-dimethyl-formamide) 、 二氯甲烷 为溶剂， 反应 4.13h， 生成 [(2R)-2-[[4-[5-[[(1S)-1-(3-chlorophenyl)-2-hydroxyethyl]carbamoyl]-1H-pyrrol-3-yl]-5-methylpyrimidin-2-yl]amino]butyl] 2-methylpropanoate
  参考文献：
  名称：

  [EN] REVERSE-TURN MIMETICS AND METHOD RELATING THERETO
  [FR] MIMETIQUES A ROTATION INVERSE ET PROCEDE ASSOCIE

  摘要：

  公开号：

  WO2005116032A3
• 作为产物：
  描述：

  氯甲酸-9-芴基甲酯 在 二碳酸二叔丁酯 、 碳酸氢钠 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 14.5h， 生成 1-chlorocarbonyl-2-(9H-fluoren-9-methoxycarbonylamino)-1-methylhydrazine
  参考文献：
  名称：

  [EN] MODULATION OF beta-CATENIN/TCF ACTIVATED TRANSCRIPTION
  [FR] MODULATION DE LA TRANSCRIPTION ACTIVEE PAR 20050707WO03031448A1CHOONGWAE PHARMA CORP [KR]20030417WDX1-21,23-32,39-49,54,55Y51-53,55DXYHECHT ANDREAS ET AL: "The p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebrates", EMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL, vol. 19, no. 8, 17 April 2000 (2000-04-17), pages 1839 - 1850, XP001205223, ISSN: 0261-4189HECHT ANDREAS ET ALThe p300/CBP acetyltransferases function as transcriptional coactivators of beta-catenin in vertebratesEMBO (EUROPEAN MOLECULAR BIOLOGY ORGANIZATION) JOURNAL200004171980261-418918391850WX48,50,58-69Y1-33,49,51XYMORIN P J ET AL: "Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE,, US, vol. 275, 21 March 1997 (1997-03-21), pages 1787 - 1790, XP002088507, ISSN: 0036-8075MORIN P J ET ALActivation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APCSCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE,, US199703212750036-807517871790WY1-33YOVING I M ET AL: "Molecular causes of colon cancer", EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, BLACKWELL SCIENTIFIC PUBLICATIONS, XX, vol. 32, no. 6, June 2002 (2002-06-01), pages 448 - 457, XP002265366, ISSN: 0014-2972OVING I M ET ALMolecular causes of colon cancerEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, BLACKWELL SCIENTIFIC PUBLICATIONS, XX2002063260014-2972448457WYD1-33YDTAKEMARU K-I ET AL: "THE TRANSCRIPTIONAL COACTIVATOR CBP INTERACTS WITH BETA-CATENIN TO ACTIVATE GENE EXPRESSION", THE JOURNAL OF CELL BIOLOGY, ROCKEFELLER UNIVERSITY PRESS, US, vol. 149, no. 2, 17 April 2000 (2000-04-17), pages 249 - 254, XP001063381, ISSN: 0021-9525TAKEMARU K-I ET ALTHE TRANSCRIPTIONAL COACTIVATOR CBP INTERACTS WITH BETA-CATENIN TO ACTIVATE GENE EXPRESSIONTHE JOURNAL OF CELL BIOLOGY, ROCKEFELLER UNIVERSITY PRESS, US2000041714920021-9525249254WX48Y1-33,49,51XYMORIN P J: "beta-catenin signaling and cancer", BIOESSAYS, CAMBRIDGE, GB, vol. 21, December 1999 (1999-12-01), pages 1021 - 1030, XP002174509, ISSN: 0265-9247MORIN P Jbeta-catenin signaling and cancerBIOESSAYS, CAMBRIDGE, GB199912210265-924710211030WY1-33,52,53YUS6762185B1KAHN MICHAEL [US], et al20040713WDPX1-33PY38DPXPYUS2004072831A1MOON SUNG HWAN [KR], et al20040415WDPX1-21,23-32PY38DPXPYEMAMI KATAYOON H ET AL: "A small molecule inhibitor of beta-catenin/cyclic AMP response element-binding protein transcription", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 101, no. 34, 24 August 2004 (2004-08-24), pages 12682 - 12687, XP002317529, ISSN: 0027-8424EMAMI KATAYOON H ET ALA small molecule inhibitor of beta-catenin/cyclic AMP response element-binding protein transcriptionPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA20040824101340027-84241268212687WPX1-33PXDANIELS D L ET AL: "beta-catenin: molecular plasticity and drug design", TIBS TRENDS IN BIOCHEMICAL SCIENCES, ELSEVIER PUBLICATION, CAMBRIDGE, EN, vol. 26, no. 11, 1 November 2001 (2001-11-01), pages 672 - 678, XP004326488, ISSN: 0968-0004DANIELS D L ET ALbeta-catenin: molecular plasticity and drug designTIBS TRENDS IN BIOCHEMICAL SCIENCES, ELSEVIER PUBLICATION, CAMBRIDGE, EN2001110126110968-0004672678WA1-33AHEDGEPETH C M ET AL: "Activation of the Wnt signaling pathway: a molecular mechanism for lithium action.", DEVELOPMENTAL BIOLOGY. 1 MAY 1997, vol. 185, no. 1, 1 May 1997 (1997-05-01), pages 82 - 91, XP002326326, ISSN: 0012-1606HEDGEPETH C M ET ALActivation of the Wnt signaling pathway: a molecular mechanism for lithium action.DEVELOPMENTAL BIOLOGY. 1 MAY 19971997050118510012-16068291WX34-37XKLEIN P S ET AL: "A molecular mechanism for the effect of lithium on development.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 6 AUG 1996, vol. 93, no. 16, 6 August 1996 (1996-08-06), pages 8455 - 8459, XP002326327, ISSN: 0027-8424KLEIN P S ET ALA molecular mechanism for the effect of lithium on development.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 6 AUG 19961996080693160027-842484558459AX34,37XSTAAL F J T ET AL: "WNT SIGNALS ARE TRANSMITTED THROUGH N-TERMINALLY DEPHOSPHORYLATED BETA-CATENIN", EMBO REPORTS, vol. 3, no. 1, January 2002 (2002-01-01), pages 63 - 68, XP001205224STAAL F J T ET ALWNT SIGNALS ARE TRANSMITTED THROUGH N-TERMINALLY DEPHOSPHORYLATED BETA-CATENINEMBO REPORTS20020131636863R364L165L2R2366L2X34-37Y38XYWODARZ A ET AL: "MECHANISMS OF WNT SIGNALING IN DEVELOPMENT", ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, ANNUAL REVIEWS, PALO ALTO, CA, US, vol. 14, 1988, pages 59 - 88, XP001012698, ISSN: 1081-0706WODARZ A ET ALMECHANISMS OF WNT SIGNALING IN DEVELOPMENTANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, ANNUAL REVIEWS, PALO ALTO, CA, US1988141081-07065988A792803X34-37Y38XYNELSON W JAMES ET AL: "Convergence of Wnt, beta-catenin, and cadherin pathways.", SCIENCE. 5 MAR 2004, vol. 303, no. 5663, 5 March 2004 (2004-03-05), pages 1483 - 1487, XP002326328, ISSN: 1095-9203NELSON W JAMES ET ALConvergence of Wnt, beta-catenin, and cadherin pathways.SCIENCE. 5 MAR 20042004030530356631095-920314831487WPX34-37,39-41PXLÉVY LAURENCE ET AL: "Acetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction.", MOLECULAR AND CELLULAR BIOLOGY. APR 2004, vol. 24, no. 8, April 2004 (2004-04-01), pages 3404 - 3414, XP002326329, ISSN: 0270-7306LÉVY LAURENCE ET ALAcetylation of beta-catenin by p300 regulates beta-catenin-Tcf4 interaction.MOLECULAR AND CELLULAR BIOLOGY. APR 20042004042480270-730634043414WPX48,50PY49,51PXPYMIYAGISHI M ET AL: "Regulation of Lef-mediated transcription and p53-dependent pathway by associating beta-catenin with CBP/p300.", THE JOURNAL OF BIOLOGICAL CHEMISTRY. 10 NOV 2000, vol. 275, no. 45, 10 November 2000 (2000-11-10), pages 35170 - 35175, XP002326330, ISSN: 0021-9258MIYAGISHI M ET ALRegulation of Lef-mediated transcription and p53-dependent pathway by associating beta-catenin with CBP/p300.THE JOURNAL OF BIOLOGICAL CHEMISTRY. 10 NOV 200020001110275450021-92583517035175X48,50Y49,51XYGUSTERSON ROSALIND J ET AL: "The transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity.", THE JOURNAL OF BIOLOGICAL CHEMISTRY. 28 FEB 2003, vol. 278, no. 9, 28 February 2003 (2003-02-28), pages 6838 - 6847, XP002326331, ISSN: 0021-9258GUSTERSON ROSALIND J ET ALThe transcriptional co-activators CREB-binding protein (CBP) and p300 play a critical role in cardiac hypertrophy that is dependent on their histone acetyltransferase activity.THE JOURNAL OF BIOLOGICAL CHEMISTRY. 28 FEB 20032003022827890021-925868386847WDX48,50DXEP1054059A1VLAAMS INTERUNIV INST BIOTECH [BE]20001122WX52XCOWIN P: "Unraveling the cytoplasmic interactions of the cadherin superfamily.", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 8 NOV 1994, vol. 91, no. 23, 8 November 1994 (1994-11-08), pages 10759 - 10761, XP002326332, ISSN: 0027-8424COWIN PUnraveling the cytoplasmic interactions of the cadherin superfamily.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 8 NOV 19941994110891230027-84241075910761WY52,53YMUNEMITSU SUSAN ET AL: "Regulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor protein", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US, vol. 92, no. 7, 1995, pages 3046 - 3050, XP002160048, ISSN: 0027-8424MUNEMITSU SUSAN ET ALRegulation of intracellular beta-catenin levels by the adenomatous polyposis coli (APC) tumor-suppressor proteinPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF USA, NATIONAL ACADEMY OF SCIENCE. WASHINGTON, US19959270027-842430463050WX52,54Y53,55XYFILIPAK M ET AL: "Tumor necrosis factor inhibits the terminal event in mesenchymal stem cell differentiation", MEDLINE ABSTRACT, JOURNAL OF CELLULAR PHYSIOLOGY, vol. 137, no. 2, 1988, XP002904585FILIPAK M ET ALTumor necrosis factor inhibits the terminal event in mesenchymal stem cell differentiationMEDLINE ABSTRACT, JOURNAL OF CELLULAR PHYSIOLOGY19881372WX56XKIELMAN M F ET AL: "Apc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signaling", NATURE GENETICS, NATURE AMERICA, NEW YORK, US, vol. 32, no. 4, 20 December 2002 (2002-12-20), pages 594 - 605, XP002233454, ISSN: 1061-4036KIELMAN M F ET ALApc modulates embryonic stem-cell differentiation by controlling the dosage of beta-catenin signalingNATURE GENETICS, NATURE AMERICA, NEW YORK, US200212203241061-4036594605WX56XWO03068961A2AXORDIA LTD [GB], et al20030821the whole document, but see especially SEQ. ID NO 49 (for SEQ: ID NO 1 as claimed) and SEQ ID NO 2 (for SEQ ID NO 3 as claimed)X70-79,90-96,104-110,116-127,138-144,152-158XUS6063583AMONTMINY MARC R [US]20000516col. 13-30X70-79,90-96,104-110XWO9918124A1MERCK & CO INC [US], et al19990415Wsee esp. Fig. 7aX80-89,97-103,111-117XPATENT ABSTRACTS OF JAPAN vol. 1999, no. 05 31 May 1999 (1999-05-31)PATENT ABSTRACTS OF JAPAN19990531199905JPH1132767AAClaim 3, pp. 13-14, Seq. with 567 amino acidsX80-89,97-103,111-117,128-137,145-151,159-165XWO02065134A2UNIV DUNDEE [GB], et al20020822claim 9, SEQ: ID NO 9X80-89,97-103,111-117XWO9803652A2US HEALTH [US], et al19980129see the whole document. Specifically, Seq ID NO 3 and Seq. ID NO 9, also claims 1-16X80-89,97-103,111-117,128-137,145-151,159-165XEP1302104A1CHUGAI PHARMACEUTICAL CO LTD [JP], et al20030416seq. ID No. 1, example 1X128-137,145-151,159-165X

  摘要：

  公开号：

  WO2005021025A3

文献信息

• Comparison of various coupling reagents in solid-phase aza-peptide synthesis
  作者：Meeli Arujõe、Anu Ploom、Anton Mastitski、Jaak Järv

  DOI：10.1016/j.tetlet.2017.07.063

  日期：2017.8

  aza-peptide bond formation during conventional Fmoc SPPS. The kinetics of aza-peptide bond formation in the model peptide H-Ala-AzAla-Phe-NH2 was compared with various conventional amino acid activators. The reaction rates and yields were dependent on the activator structure. The reaction time of aza-peptide formation using oxyma-based agents was approximately 30 times longer than in typical peptide synthesis

  氮杂肽是有前途的药物前导，但是在常规的Fmoc SPPS期间，低产率的氮杂肽键形成阻碍了其特性的广泛研究。将模型肽H-Ala-AzAla-Phe-NH 2中氮杂肽键形成的动力学与各种常规氨基酸激活剂进行了比较。反应速率和产率取决于活化剂的结构。使用基于氧化酶的试剂形成氮杂肽的反应时间比典型肽合成中的反应时间长约30倍。因此，需要新的活化剂来增加活化的氨基酸的反应性，以在氮杂-肽键形成期间实现氨基脲部分的有效酰化。
• Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist
  作者：Mohamed Elsawy、Irina Tikhonova、Lorraine Martin、Brian Walker

  DOI：10.2174/0929866522666150622101626

  日期：2015.8.5

  The peptidic nature of anti-IAPs N-terminus Smac-derived peptides precludes their utilization as potential therapeutic anticancer agents. Recent advances in the development of novel Smacderived peptidomimetics and non-peptidic molecules with improved anti-IAPs activity and resistance to proteolytic cleavage have been reported and led to a number of candidates that are currently in clinical trials including LCL-161, SM-406/AT-406, GDC-0512/GDC-0917, and birinapant. As an attempt to improve the proteolytic stability of Smac peptides, we developed the Aza-peptide AzaAla- Val-Pro-Phe-Tyr-NH2 (2). Unlike unmodified peptide Ala-Val-Pro-Phe-Tyr-NH2 (1), analogue (2) exhibited resistance towards proteolytic cleavage by two aminopeptidases; LAP and DPP-IV, while retaining its IAP inhibitory activity. This was due to the altered planar geometry of the P1 residue side chain. Our findings showed that using aza-isosteres of bioactive peptide sequences imbue the residue with imperviousness to proteolysis; underscoring a potential approach for developing a new generation of Smac-derived Aza-peptidomimetics.

  抗 IAP N 末端 Smac 衍生肽的肽性质阻碍了它们的利用 作为潜在的治疗性抗癌药物。新型 Smacogenic 开发的最新进展 具有改善的抗 IAP 活性和耐药性的肽模拟物和非肽分子 已报道了蛋白水解裂解，并导致了目前正在研究的许多候选物 临床试验包括 LCL-161、SM-406/AT-406、GDC-0512/GDC-0917 和 birinapant。作为一种尝试 为了提高 Smac 肽的蛋白水解稳定性，我们开发了 Aza 肽 AzaAla- Val-Pro-Phe-Tyr-NH2 (2)。与未修饰的肽 Ala-Val-Pro-Phe-Tyr-NH2 (1) 不同，类似物 (2) 表现出抗性 通过两种氨肽酶进行蛋白水解切割； LAP 和 DPP-IV，同时保留其 IAP 抑制活性。这 这是由于 P1 残基侧链的平面几何形状发生了改变。我们的研究结果表明，使用生物活性的氮杂电子等排体 肽序列使残基不被蛋白水解作用；强调了一种潜在的发展方法 新一代 Smac 衍生的 Aza 肽模拟物。
• Reverse-turn mimetics and method relating thereto
  申请人：Choongwae Pharma Corporation

  公开号：US20040072831A1

  公开（公告）日：2004-04-15

  Conformationally constrained compounds which mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

  本发明揭示了构象限制化合物，其模仿生物活性肽和蛋白质的反转区域的二级结构。这种反转区域模拟结构在广泛的领域中具有实用性，包括用作诊断和治疗剂。本发明还揭示了含有此类反转区域模拟结构的文库，以及筛选相同以识别生物活性成员的方法。本发明还涉及使用这种化合物来抑制或治疗由Wnt信号通路调节的疾病，如癌症，特别是结直肠癌，与血管成形术相关的再狭窄，多囊肾病，异常血管生成疾病，类风湿性关节炎疾病，结节性硬化症，阿尔茨海默病，多毛或脱发或溃疡性结肠炎。
• Modulation of beta-catenin/TCF-activated transcription
  申请人：Kahn Michael

  公开号：US20050059628A1

  公开（公告）日：2005-03-17

  The present invention provides compounds and methods for modulating transcription activated by β-catenin/TCF, such as the selective inhibition of genes targeted by the Wnt/β-catenin pathway.

  本发明提供了化合物和方法，用于调节由β-连环蛋白/TCF激活的转录，例如选择性抑制Wnt/β-连环蛋白途径靶向的基因。
• REVERSE-TURN MIMETICS AND METHOD RELATING THERETO
  申请人：Moon Sung Hwan

  公开号：US20100029630A1

  公开（公告）日：2010-02-04

  Conformationally constrained compounds that mimic the secondary structure of reverse-turn regions of biologically active peptides and proteins are disclosed. Such reverse-turn mimetic structures have utility over a wide range of fields, including use as diagnostic and therapeutic agents. Libraries containing the reverse-turn mimetic structures of this invention are also disclosed as well as methods for screening the same to identify biologically active members. The invention also relates to the use of such compounds for inhibiting or treating disorders modulated by Wnt-signaling pathway, such as cancer, especially colorectal cancer, restenosis associated with angioplasty, polycystic kidney disease, aberrant angiogenesis disease, rheumatoid arthritis disease, tuberous sclerosis complex, Alzheimer's disease, excess hair growth or loss, or ulcerative colitis.

  本文揭示了具有构象约束的化合物，其模拟生物活性肽和蛋白质的反转区域的二级结构。这种反转区域模拟结构在广泛的领域中具有实用性，包括用作诊断和治疗剂。本发明还揭示了包含这种反转区域模拟结构的文库，以及筛选这些文库以识别具有生物活性成员的方法。本发明还涉及使用这些化合物来抑制或治疗由Wnt信号通路调节的疾病，例如癌症，特别是结肠直肠癌，与血管成形术相关的再狭窄，多囊肾病，异常血管生成疾病，类风湿性关节炎疾病，结节性硬化症，阿尔茨海默病，过度生长或脱发，或溃疡性结肠炎。