N-(p-benzoic acid)-3,4-dibromomaleimide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-(p-benzoic acid)-3,4-dibromomaleimide
• 英文别名: 3,4-dibromomaleimide-N-(p-benzoic acid)；N-(p-benzoic acid)-2,3-dibromomalemide；Pbenz-dbrmd；4-(3,4-dibromo-2,5-dioxopyrrol-1-yl)benzoic acid
• 化学式: C₁₁H₅Br₂NO₄
• 分子量: 374.973
• InChiKey: HNIHLGFMEFERQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  74.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(p-benzoic acid)-3,4-dibromomaleimide 在 sodium acetate 、 2-乙氧基-1-乙氧碳酰基-1,2-二氢喹啉 作用下， 以 甲醇 、 乙腈 为溶剂， 反应 1.5h， 生成 3,4-di-(N-(tert-butoxycarbonyl)-L-cysteine methyl ester)maleimide-N-(prop-2-yn-1-yl)-p-benzamide
  参考文献：
  名称：

  Optimisation of the dibromomaleimide (DBM) platform for native antibody conjugation by accelerated post-conjugation hydrolysis

  摘要：

  描述了Dibromomaleimide (DBM)试剂，这些试剂在共轭后快速水解，代表了一种优化的平台，用于均匀和稳定的抗体共轭。

  DOI：

  10.1039/c7ob00220c
• 作为产物：
  描述：

  2,3-二氯顺酐 、 对氨基苯甲酸 在 溶剂黄146 作用下， 120.0 ℃ 、101.33 kPa 条件下， 反应 0.67h， 以79%的产率得到N-(p-benzoic acid)-3,4-dibromomaleimide
  参考文献：
  名称：

  Next generation maleimides enable the controlled assembly of antibody–drug conjugates via native disulfide bond bridging

  摘要：

  高度均一的ADCs是通过在曲妥珠单抗中高效地连接链间二硫键，使用下一代马来酰亚胺而生成的。

  DOI：

  10.1039/c4ob01550a

文献信息

• [EN] TYPE III DEIODINASE INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE LA DÉSIODINASE DE TYPE III ET LEURS UTILISATIONS
  申请人：HADASIT MED RES SERVICE

  公开号：WO2015140792A1

  公开（公告）日：2015-09-24

  The present invention relates to compounds that inhibit the activity of Type III deiodinase (DIO3). The present invention further relates to methods for treating or preventing depression, depression associated with other psychiatric or general medical diseases or conditions, condition amenable to treatment with known anti-depressants and cancer, particularly by using the compounds of the invention.

  本发明涉及抑制第三型去碘酶（DIO3）活性的化合物。本发明还涉及治疗或预防抑郁症、与其他精神疾病或一般医学疾病相关的抑郁症、适合使用已知抗抑郁药物治疗的疾病或状况，以及癌症的方法，特别是通过使用本发明的化合物。
• Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment
  作者：Dotan Moskovich、Yael Finkelshtein、Adi Alfandari、Amit Rosemarin、Tzuri Lifschytz、Avivit Weisz、Santanu Mondal、Harinarayana Ungati、Aviva Katzav、Debora Kidron、Govindasamy Mugesh、Martin Ellis、Bernard Lerer、Osnat Ashur-Fabian

  DOI：10.1038/s41388-021-02020-z

  日期：2021.11.3

  The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (ES-2 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and ES-2 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian cancer and potentially other DIO3-dependent malignancies.

  碘甲腺原氨酸脱碘酶3型（DIO3）可使甲状腺激素（T3）的抑癌作用失活，从而导致癌症增殖。我们最近证实，DIO3 参与了高级别浆液性卵巢癌（HGSOC）的进展。在此，我们提供了 DIO3 高表达与患者低生存率之间的联系，这与 Ki67、PAX8、CA-125 和 CCNE1 等常见疾病标志物相似。这些观察结果表明，DIO3 是一个合理的抑制靶点。我们利用 DIO3 模拟物，开发出以二溴马来酸酐（DBRMD）为核心支架的原创 DIO3 抑制剂。在 DIO3 阳性的 HGSOC 细胞（ES-2 和 KURAMOCHI）中，PBENZ-DBRMD 和 ITYR-DBRMD 这两种化合物可减少细胞数量，诱导细胞凋亡，并降低细胞增殖，但在 DIO3 阴性的正常卵巢细胞（CHOK1）和去除了 DIO3 或其底物 T3 的 ES-2 中却没有这种效果。在 HGSOC 异种移植模型中进一步证实了这种药物对肿瘤的强效抑制作用，而且安全性很高。抗肿瘤作用是通过下调一系列促癌蛋白介导的，其中大部分蛋白已知会受到 T3 的抑制。总之，利用特异性靶向 DIO3 酶的小分子，我们为卵巢癌和其他潜在的 DIO3 依赖性恶性肿瘤提供了一种新的治疗模式。
• Chemical Modification of Antibodies
  申请人：UCL Business PLC

  公开号：US20150031861A1

  公开（公告）日：2015-01-29

  The present invention relates to antibodies and antibody fragments, one or more of whose native inter-chain disulfide bridges have been replaced with a specific bridging moiety. The bridging moiety can be selectively targeted to inter-chain disulfide bonds within the antibody or antibody fragment, enabling the construction of more homogenously modified products such as antibody-drug conjugates.

  本发明涉及抗体和抗体片段，其中一个或多个原生的链间二硫键已被一种特定的桥接基团所取代。该桥接基团可以选择性地靶向抗体或抗体片段内的链间二硫键，从而实现构建更均质修饰产品，如抗体-药物结合物。
• Type III deiodinase inhibitors and uses thereof
  申请人：HADASIT MEDICAL RESEARCH SERVICES AND DEVELOPMENT LTD.

  公开号：US11091434B2

  公开（公告）日：2021-08-17

  The present invention relates to compounds that inhibit the activity of Type III deiodinase (DIO3). The present invention further relates to methods for treating or preventing depression, depression associated with other psychiatric or general medical diseases or conditions, condition amenable to treatment with known anti-depressants and cancer, particularly by using the compounds of the invention.

  本发明涉及抑制 III 型脱碘酶（DIO3）活性的化合物。本发明进一步涉及治疗或预防抑郁症、与其他精神或普通疾病或病症相关的抑郁症、可接受已知抗抑郁药治疗的病症和癌症的方法，特别是通过使用本发明的化合物。
• 3,4-BROMO OR -SULFONATE SUBSTITUTED 1H-PYRROLE-2,5-DIONE DERIVATIVES AS TYPE III DEIODINASE (DIO3) INHIBITORS FOR TREATING DEPRESSIONS AND CANCER
  申请人：HADASIT MEDICAL RESEARCH SERVICES AND DEVELOPMENT LTD.

  公开号：EP3119768B1

  公开（公告）日：2019-07-31