6-(naphthalen-2-yl)imidazo[2,1-b]thiazole-5-carbaldehyde

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 6-(naphthalen-2-yl)imidazo[2,1-b]thiazole-5-carbaldehyde
• 英文别名: 6-(2-Naphthyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde；6-naphthalen-2-ylimidazo[2,1-b][1,3]thiazole-5-carbaldehyde
• 化学式: C₁₆H₁₀N₂OS
• mdl: MFCD04966915
• 分子量: 278.334
• InChiKey: BTTPNMZBPGOXNJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  62.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  6-(naphthalen-2-yl)imidazo[2,1-b]thiazole-5-carbaldehyde 在 sodium tetrahydroborate 、 溶剂黄146 作用下， 以 甲醇 、 乙醇 为溶剂， 生成 N-((6-(naphthalen-2-yl)imidazo[2,1-b]thiazol-5-yl)methyl)-2-phenylethan-1-amine
  参考文献：
  名称：

  Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies

  摘要：

  The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 mu M and E-MAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells. (C) 2019 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2019.06.031
• 作为产物：
  描述：

  2-溴代-2-乙酰基萘 在 三氯氧磷 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 22.0h， 生成 6-(naphthalen-2-yl)imidazo[2,1-b]thiazole-5-carbaldehyde
  参考文献：
  名称：

  DL5050, a Selective Agonist for the Human Constitutive Androstane Receptor

  摘要：

  The constitutive androstane receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear receptors, especially the closely related human pregnane X receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, 18 and 19 (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.

  DOI：

  10.1021/acsmedchemlett.9b00079

文献信息

• [EN] CAR AND NRF2 DUAL ACTIVATOR AGENTS FOR CYCLOPHOSPHAMIDE-BASED AND DOXORUBICIN-BASED TREATMENTS OF CANCER<br/>[FR] AGENTS ACTIVATEURS DOUBLES DE CAR ET NRF2 POUR DES TRAITEMENTS DU CANCER À BASE DE CYCLOPHOSPHAMIDE ET À BASE DE DOXORUBICINE
  申请人：UNIV MARYLAND

  公开号：WO2021178684A1

  公开（公告）日：2021-09-10

  The disclosure relates to selective small molecule dual activators of human constitutive androstane receptor (hCAR) and nuclear factor erythroid 2-related factor 2 (Nrf2), pharmaceutical compositions thereof, and use thereof for the treatment of hematologic malignancies and other cancers. The small molecule dual hCAR and Nrf2 activators in combination with CPA based chemotherapy regimen provides a synergistic effect to help promote cytoxicity of the cyclophosphamide (CPA) based and doxorubicin (DOX) based anticancer treatments including CHOP regimen (CPA, doxorubicin, vincristine, and prednisone) while reducing cardiotixocity associated with DOX.

  该公开涉及选择性的人类组成雄烷受体（hCAR）和核因子红细胞2相关因子2（Nrf2）的小分子双活化剂，其药物组合物以及用于治疗血液恶性肿瘤和其他癌症的用途。与CPA基础化疗方案结合使用的小分子双hCAR和Nrf2活化剂提供协同作用，有助于促进环磷酰胺（CPA）和多柔比星（DOX）为基础的抗癌治疗的细胞毒性，包括CHOP方案（CPA、多柔比星、长春碱和泼尼松），同时减少与DOX相关的心毒性。
• CAR ACTIVATOR AGENTS FOR CYCLOPHOSPHAMIDE-BASED TREATMENTS OF CANCER
  申请人：UNIVERSITY OF MARYLAND, BALTIMORE

  公开号：US20200352915A1

  公开（公告）日：2020-11-12

  The invention relates to selective small molecule human constitutive androstane receptor (hCAR) activators of Formula (I) or (II), pharmaceutical compositions thereof, and use thereof for the treatment of hematologic malignancies and other cancers. The small molecule hCAR activator in combination with CPA based chemotherapy regimen provides a synergistic effect to help promote cytoxicity of the cyclophosphamide (CPA) based anticancer treatments including CHOP regimen (CPA, doxorubicin, vincristine, and prednisone) by preferential induction of CYP2B6 over CYP3A4 and promoting the formation of therapeutically active CPA metabolite 4-OH-CPA.
• Human constitutive androstane receptor agonist DL5016: A novel sensitizer for cyclophosphamide-based chemotherapies
  作者：Dongdong Liang、Linhao Li、Caitlin Lynch、Bryan Mackowiak、William D. Hedrich、Yong Ai、Yue Yin、Scott Heyward、Menghang Xia、Hongbing Wang、Fengtian Xue

  DOI：10.1016/j.ejmech.2019.06.031

  日期：2019.10

  The DNA alkylating prodrug cyclophosphamide (CPA), alone or in combination with other agents, is one of the most commonly used anti-cancer agents. As a prodrug, CPA is activated by cytochrome P450 2B6 (CYP2B6), which is transcriptionally regulated by the human constitutive androstane receptor (hCAR). Therefore, hCAR agonists represent novel sensitizers for CPA-based therapies. Among known hCAR agonists, compound 6-(4-chlorophenyl)imidazo-[2,1-b]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl) oxime (CITCO) is the most potent and broadly utilized in biological studies. Through structural modification of CITCO, we have developed a novel compound DL5016 (32), which has an EC50 value of 0.66 mu M and E-MAX value of 4.9 when activating hCAR. DL5016 robustly induced the expression of hCAR target gene CYP2B6, at both the mRNA and protein levels, and caused translocation of hCAR from the cytoplasm to the nucleus in human primary hepatocytes. The effects of DL5016 were highlighted by dramatically enhancing the efficacy of CPA-based cytotoxicity to non-Hodgkin lymphoma cells. (C) 2019 Elsevier Masson SAS. All rights reserved.
• DL5050, a Selective Agonist for the Human Constitutive Androstane Receptor
  作者：Dongdong Liang、Linhao Li、Caitlin Lynch、Benjamin Diethelm-Varela、Menghang Xia、Fengtian Xue、Hongbing Wang

  DOI：10.1021/acsmedchemlett.9b00079

  日期：2019.7.11

  The constitutive androstane receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear receptors, especially the closely related human pregnane X receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, 18 and 19 (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.