2-氨基-N-[4-[5-(2-菲基)-3-(三氟甲基)-1H-吡唑-1-基]苯基]乙酰胺 | 742112-33-0

• 物质功能分类: 生物化工 - 抑制剂 - PI3K/Akt/mTOR抑制剂(PI3K/Akt/mTOR)
• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 中文名称: 2-氨基-N-[4-[5-(2-菲基)-3-(三氟甲基)-1H-吡唑-1-基]苯基]乙酰胺
• 中文别名: 达努塞替
• 英文名称: 2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide
• 英文别名: OSU-03012；AR-12；2-amino-N-(4-(5-(phenanthren-2-yl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)acetamide；2-amino-N-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide；PDK1 inhibitor AR-12
• CAS: 742112-33-0
• 化学式: C₂₆H₁₉F₃N₄O
• 分子量: 460.458
• InChiKey: YULUCECVQOCQFQ-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO 中≥23 mg/mL；不溶于水；不溶于乙醇

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  72.9
• 氢给体数：
  2
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

OSU-03012 (AR-12) 是一种有效的重组PDK-1抑制剂，在无细胞试验中IC50为5 μM，比OSU-02067的作用效果高2倍。

体外研究

OSU-03012诱导PC-3细胞凋亡，IC50为5 µM，并且降低免疫沉淀的p70S6K活性。Celecoxib完全抑制肿瘤细胞生长需要至少50 μM，而OSU-03012在浓度为3-5 μM时即可完全抑制多种肿瘤细胞生长。与作用于正常的胶质细胞相比，OSU-03012对神经胶质瘤细胞更有效地促进细胞死亡。OSU-03012和电离辐射共同使用会增加caspase非依赖性的细胞死亡。此外，它还能促进组织蛋白酶B从溶酶体中释放及AIF从线粒体中释放。

在蛋白激酶R类的内质网激酶-/-细胞中，OSU-03012的药效减弱，这与BID分裂下降有关，并且还阻断了组织蛋白酶B和AIF向细胞质中的释放。OSU-03012能够抑制甲状腺癌细胞（NPA, WRO, 和ARO细胞）的增殖和迁移，诱导凋亡，导致S期细胞增多而G2期细胞不增多。它是一种ATP竞争性抑制剂，在甲状腺癌细胞中抑制了PAK活性及AKT磷酸化。OSU-03012还能够抑制肝细胞癌细胞系（包括Huh7, Hep3B和HepG2）的生长，IC50<1 μM。在作用于Huh7细胞时，OSU-03012不抑制PDK1或AKT活性，也不诱导细胞凋亡，但能促进自噬，并导致活性氧（ROS）积累。

最新研究显示，OSU-03012能够增强(Bcr)-Abl 突变细胞系对imatinib诱导的凋亡的敏感性。

体内研究

按200 mg/kg剂量作用于Huh7移植瘤时，OSU-03012抑制了57.59%的肿瘤生长。在MDA-MB-435/LCC6移植瘤中使用OSU-03012后明显降低了EGFR蛋白表达，下降约48%，同时也阻止了YB-1结合到EGFR启动子上。口服处理HMS-97神经鞘移植瘤时，OSU-03012抑制其生长达到55%。

结论

综上所述，OSU-03012是一种高效的肿瘤抑制剂，在多种体外和体内实验中都展示了显著的治疗效果。

反应信息

• 作为产物：
  描述：

  4,4,4-三氟-1-(2-菲基)-1,3-丁烷二酮 在 盐酸 、 platinum(IV) oxide 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 乙酸乙酯 为溶剂， 生成 2-氨基-N-[4-[5-(2-菲基)-3-(三氟甲基)-1H-吡唑-1-基]苯基]乙酰胺
  参考文献：
  名称：

  Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus

  摘要：

  Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism. Examination of an in-house, celecoxib-based focused compound library in conjunction with structural modifications led to the identification of compound 46 as the lead agent with high antibacterial potency against a panel of Staphylococcus pathogens and different strains of MRSA. Moreover, this killing effect is bacteria-specific, as human cancer cells are resistant to 46. In addition, a single intraperitoneal administration of compound 46 at 30 mg/kg improved the survival of MRSA-infected C57BL/6 mice. In light of its high potency in eradicating MRSA in vitro and its in vivo activity, compound 46 and its analogues warrant continued preclinical development as a potential therapeutic intervention against MRSA. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.06.018

文献信息

• COMPOUNDS AND METHODS FOR TREATMENT AND PREVENTION OF FLAVIVIRUS INFECTION
  申请人：FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION, INC.

  公开号：US20180015153A1

  公开（公告）日：2018-01-18

  The present invention concerns the use of compounds for the treatment or prevention of Flavivirus infections, such as Zika virus infections. Aspects of the invention include methods for treating or preventing Flavivirus virus infection, such as Zika virus infection, by administering a compound or class of compound disclosed herein, such as a niclosamide compound, an emricasan compound, a cyclin-dependent kinase inhibitor, a proteasome inhibitor, or a combination of two or more of the foregoing, to a subject in need thereof; methods for inhibiting Flavivirus infections such as Zika virus infections in a cell in vitro or in vivo; pharmaceutical compositions; packaged dosage formulations; and kits for treating or preventing Flavivirus infections, such Zika virus infections.

  本发明涉及化合物用于治疗或预防黄病毒感染，如寨卡病毒感染。该发明的方面包括通过给予本文所披露的化合物或化合物类别，如尼克洛酰胺化合物、恩米卡珊化合物、细胞周期依赖性激酶抑制剂、蛋白酶体抑制剂或前述两种或更多的组合，治疗或预防黄病毒感染，如寨卡病毒感染的方法；在体外或体内抑制黄病毒感染，如寨卡病毒感染的方法；制药组合；包装剂量配方；以及用于治疗或预防黄病毒感染，如寨卡病毒感染的工具包。
• [EN] PDK-1/AKT SIGNALING INHIBITORS<br/>[FR] INHIBITEURS DE SIGNALISATION PDK-1/AKT
  申请人：UNIV OHIO STATE RES FOUND

  公开号：WO2005044130A1

  公开（公告）日：2005-05-19

  A new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of formula (I): wherein X is selected from the group consisting of alkyl and haloalkyl; Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl; and wherein Ar is optionally substituted with one or more radicals selected from the group consisting of halo, C1 C4 alkyl, C1 C4 haloalkyl, azido, C1 C4 azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof; and R is selected from the group consisting of nitrile, acetonitrile, ethylnitrile, propylnitrile, carboxamide, amidine, tetrazole, oxime, hydrazone, acetamidine, aminoacetamide, guanidine, and urea. Also provided are methods of using the compounds for the treatment and prevention of cancer in humans.

  一种新的磷脂酰肌醇依赖性激酶-1（PDK-1）抑制剂的化学式（I）：其中X选自烷基和卤代烷基组成的群体；Ar是从苯基、联苯基、萘基、蒽基、菲基组成的基团中选取的芳基基团；其中Ar可选择地被一个或多个从卤素、C1-C4烷基、C1-C4卤代烷基、叠氮化物、C1-C4叠氮基烷基、芳基、烷基芳基、卤代芳基、卤代烷基芳基等组成的基团取代；R选自腈、乙腈、乙腈、丙腈、羧酰胺、胺基、四唑、肟、醛肟、乙酰胺、氨基乙酰胺、胍、尿素等组成的群体。还提供了使用这些化合物用于人类癌症的治疗和预防的方法。
• ANTI-INFECTIVE AGENTS AGAINST INTRACELLULAR PATHOGENS
  申请人：Chen Ching-Shih

  公开号：US20090111799A1

  公开（公告）日：2009-04-30

  A new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of Formula I: wherein X wherein X is —CF 3 , Ar is selected from and R is selected from where R′ is L-Lys, D-Lys, β-Ala, L-Lue, L-Ile, Phe, SO 2 CH 2 CH 2 NH 2 , SO 2 NH 2 , Asn, Glu or Gyl, and R″ is methyl, ethyl, allyl, CH 2 CH 2 OH, CH 2 CN, CH 2 CH 2 CN, CH 2 CONH 2 ,

  一种新的磷脂酰肌醇依赖激酶-1（PDK-1）抑制剂的化学式I：其中X为—CF3，Ar从中选择，R从中选择，其中R′为L-赖氨酸，D-赖氨酸，β-丙氨酸，L-亮氨酸，L-异亮氨酸，苯丙氨酸，SO2CH2CH2NH2，SO2NH2，天冬氨酸，谷氨酸或甘氨酸，R″为甲基，乙基，烯丙基，CH2CH2OH，CH2CN，CH2CH2CN，CH2CONH2。
• PDK-1/Akt signaling inhibitors
  申请人：Chen Ching-Shih

  公开号：US20060079566A1

  公开（公告）日：2006-04-13

  A new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of formula I: wherein X is selected from the group consisting of alkyl and haloalkyl; Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl; and wherein Ar is optionally substituted with one or more radicals selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, azido, C 1 -C 4 azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof; and R is selected from the group consisting of nitrile, acetonitrile, ethylnitrile, propylnitrile, carboxamide, amidine, tetrazole, oxime, hydrazone, acetamidine, aminoacetamide, guanidine, and urea. Also provided are methods of using the compounds for the treatment and prevention of cancer in humans.

  一种新的磷脂酰肌醇依赖性激酶-1（PDK-1）抑制剂，化学式为I：其中X选自烷基和卤代烷基；Ar是选自苯基，联苯基，萘基，蒽基，菲基和芴基的芳基基团；其中Ar可选地被一个或多个选自卤素，C1-C4烷基，C1-C4卤代烷基，叠氮基，C1-C4叠氮烷基，芳基，烷基芳基，卤代芳基，卤代烷基芳基和其组合的基团取代；而R选自腈，乙腈，丙腈，羧酰胺，胍，四唑，肟，腙，乙酰胍，氨基乙酰胺，胍，尿素等基团。还提供了使用该化合物治疗和预防人类癌症的方法。
• PDK-1/AKT SIGNALING INHIBITORS
  申请人：Chen Ching-Shih

  公开号：US20080269309A1

  公开（公告）日：2008-10-30

  Use of a new class of phosphoinositide-dependent kinase-1 (PDK-1) inhibitors of formula I for inducing apoptosis in unwanted rapidly proliferating cells, for treating, inhibiting, or delaying the onset of cancer, and for preventing restenosis in a subject that has undergone an angioplasty or stent: wherein X is selected from the group consisting of alkyl and haloalkyl; Ar is an aryl radical selected from the group consisting of phenyl, biphenyl, naphthyl, anthryl, phenanthryl, and fluorenyl; and wherein Ar is optionally substituted with one or more radicals selected from the group consisting of halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, azido, C 1 -C 4 azidoalkyl, aryl, akylaryl, haloaryl, haloalkylaryl, and combinations thereof; and R is selected from the group consisting of nitrile, acetonitrile, ethylnitrile, propylnitrile, carboxamide, amidine, tetrazole, oxime, hydrazone, acetamidine, aminoacetamide, guanidine, and urea.

  使用一种新的磷脂酰肌醇依赖性激酶-1（PDK-1）抑制剂（I式）用于诱导不需要的快速增殖细胞凋亡，用于治疗、抑制或延迟癌症发生，并用于预防经过血管成形术或支架的患者再狭窄：其中X选自烷基和卤代烷基的群体；Ar是选自苯基、联苯基、萘基、蒽基、菲基和芴基的芳基基团；其中Ar可选地被一个或多个选自卤素、C1-C4烷基、C1-C4卤代烷基、叠氮基、C1-C4叠氮基烷基、芳基、烷基芳基、卤代芳基、卤代烷基芳基和其组合的基团取代；R选自腈、乙腈、乙腈、丙腈、羧酰胺、胍、四唑、肟、酰肟、氨基乙酰胺、胍、尿素的群体。