10-{3-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-propyl}-2-trifluoromethyl-10H-phenothiazine | 66421-98-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻嗪类
• 英文名称: 10-{3-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-propyl}-2-trifluoromethyl-10H-phenothiazine
• 英文别名: 10-(3-{4-[2-(Piperidin-1-yl)ethyl]piperazin-1-yl}propyl)-2-(trifluoromethyl)-10H-phenothiazine；10-[3-[4-(2-piperidin-1-ylethyl)piperazin-1-yl]propyl]-2-(trifluoromethyl)phenothiazine
• CAS: 66421-98-5
• 化学式: C₂₇H₃₅F₃N₄S
• 分子量: 504.663
• InChiKey: ZPBNZKWNUNRBDE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  38.3
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  10-(3-氯丙基)-2-(三氟甲基)-10H-吩噻嗪 在 盐酸 、 氯化亚砜 、 sodium iodide 作用下， 以 氯仿 、 丁酮 为溶剂， 反应 27.0h， 生成 10-{3-[4-(2-piperidin-1-yl-ethyl)-piperazin-1-yl]-propyl}-2-trifluoromethyl-10H-phenothiazine
  参考文献：
  名称：

  潜在的中枢神经系统抗肿瘤药-吩噻嗪II：氟吩嗪类似物。

  摘要：

  发现氟奋乃静对腹膜内L-1210和P-388白血病小鼠肿瘤模型具有中等程度的可再现活性。在腹膜内L-1210，P-388和B16黑色素瘤系统以及脑内L-1210中制备了氟奋乃静的7种醚衍生物和8种化合物，其中末端侧链羟基被胺官能团取代。和上皮细胞母细胞瘤脑肿瘤模型。虽然没有观察到实质性的脑内活性，但七种衍生物在腹膜内L-1210或P-388系统中具有可再现的活性。几个给出的T / C值为150％。没有观察到B16黑色素瘤活性。还测试了这些化合物在培养过程中针对L-1210，P-388和KB细胞的细胞毒性。胺类等排体虽然几乎没有体内活性，

  DOI：

  10.1002/jps.2600670209

文献信息

• NUPR1 INHIBITION FOR TREATING CANCER
  申请人：INSTITUT NATIONAL DE SANTE ET DE LA RECHERCHE MEDICALE (INSERM)

  公开号：US20210137938A1

  公开（公告）日：2021-05-13

  The present invention relates to the treatment of a tumor selected from the group consisting of pancreatic cancer, liver cancer, melanoma, colon cancer, glioblastoma, osteosarcoma, prostate cancer and breast cancer, more particularly pancreatic cancer. The inventors found a novel family compounds of formula (I) able to treat a variety of cancers by inhibiting NUPR1, a stress-inducible 82-amino-acid-long, intrinsically disordered member of the AT-hook family of chromatin proteins. Thus, the present invention relates to a compound of formula (I) for its use in the treatment of a tumor selected from the group consisting of pancreatic cancer, liver cancer, melanoma, colon cancer, glioblastoma, osteosarcoma, prostate cancer and breast cancer. In particular, the inventors tested compounds of formula (I) on four well characterized primary pancreatic cancer-derived cells 02.063 and LIPC (Basal subtype), Foic8b (derived from a liver metastasis) and HN14 (Classical subtype), as well as on other cellular lines derived from different tumors, i.e. U87 (glioblastoma), A375 and B16 (melanoma), U20S and SaOS (osteosarcoma), HT29, SK-CO-1 and LS174T (colon cancer), HepG2 (hepatocarcinoma), PC3 (prostate) and MDA-MB-231 (breast cancer). The compounds per se are also claimed.
• [EN] TARGETING THE NLS REGION OF NUPR1 PROTEIN TO TREAT CANCER<br/>[FR] CIBLAGE DE LA RÉGION NLS DE LA PROTÉINE NUPR1 POUR TRAITER LE CANCER
  申请人：INST NAT SANTE RECH MED

  公开号：WO2021105384A1

  公开（公告）日：2021-06-03

  The present invention relates to the treatment of cancer. NUPR1 is a 82-residue-long nuclear intrinsically disordered protein (IDP) that plays an important role in pancreatic ductal adenocarcinoma (PDAC) as well as other cancers since its genetic inactivation induces tumors growth arrest. The inventors have recently developed an efficient multidisciplinary strategy by combining biophysical, biochemical, bioinformatic and biological approaches for a molecular screening to select potential drug candidates against NUPR1. A family of TFP-derived compounds has been produced and the most active one, named ZZW-115, has more than 10 times efficient antitumor activity than TFP. More importantly, they demonstrated that targeting the NLS region (nuclear location signal region) of NUPR1 protein with small compounds, like TFP and TFP-derived compounds, could be an efficient method to treat patients with cancers. Thus, the invention relates to a compound which targets a region comprising the region consisting of amino acids 63-78 of SEQ ID NO:1 for use in the treatment of a cancer in a subject in need thereof.
• [EN] COMBINATION COMPRISING NUPR1 INHIBITORS TO TREAT CANCER<br/>[FR] ASSOCIATION COMPRENANT DES INHIBITEURS DE NUPR1 POUR TRAITER LE CANCER
  申请人：INST NAT SANTE RECH MED

  公开号：WO2021105391A1

  公开（公告）日：2021-06-03

  The present invention relates to the treatment of cancer. NUPR1 is a nuclear intrinsically disordered protein (IDP) of 82 amino acids long that play an important role in pancreatic ductal adenocarcinoma (PDAC) as well as other cancers since its genetic inactivation by genetic or pharmacological approaches induces tumors growth arrest and/or regression. The inventors recently developed an efficient multidisciplinary strategy by combining biophysical, biochemical, bioinformatic and biological approaches for a molecular screening to select potential drug candidates against NUPR1. A family of TFP-derived compounds was produced and the most active one, named ZZW-115, showed more than 10 times efficient antitumor activity on a large panel of primary PDAC-derived cells and several non-pancreatic cancer cells. More, they showed that treatment with ZZW-115 sensitizes cancer cells to genotoxic-induced DNA damage. Thus, the present invention relates to a combination of an inhibitor of NUPR1 and a genotoxic treatment for use in the treatment of a cancer in a subject in need thereof. Particularly, the invention is defined by its claims.
• Potential CNS Antitumor Agents—Phenothiazines II: Fluphenazine Analogs
  作者：Tadashi Hirata、Geoffrey Peng、John S. Driscoll

  DOI：10.1002/jps.2600670209

  日期：1978.2

  Fluphenazine was found to possess moderate reproducible activity against the intraperitoneal L-1210 and P-388 leukemia murine tumor models. Seven ether derivatives of fluphenazine and eight compounds in which the terminal side-chain hydroxyl group was replaced by an amine function were prepared and evaluated in the intraperitoneal L-1210, P-388, and B16 melanoma systems as well as the intracerebral

  发现氟奋乃静对腹膜内L-1210和P-388白血病小鼠肿瘤模型具有中等程度的可再现活性。在腹膜内L-1210，P-388和B16黑色素瘤系统以及脑内L-1210中制备了氟奋乃静的7种醚衍生物和8种化合物，其中末端侧链羟基被胺官能团取代。和上皮细胞母细胞瘤脑肿瘤模型。虽然没有观察到实质性的脑内活性，但七种衍生物在腹膜内L-1210或P-388系统中具有可再现的活性。几个给出的T / C值为150％。没有观察到B16黑色素瘤活性。还测试了这些化合物在培养过程中针对L-1210，P-388和KB细胞的细胞毒性。胺类等排体虽然几乎没有体内活性，