N-[(benzyloxy)carbonyl]-L-alanyl-L-alanyl-L-asparagine

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[(benzyloxy)carbonyl]-L-alanyl-L-alanyl-L-asparagine
• 英文别名: Carbobenzoxy-l-alanyl-alanyl-asparagine；(2S)-4-amino-4-oxo-2-[[(2S)-2-[[(2S)-2-(phenylmethoxycarbonylamino)propanoyl]amino]propanoyl]amino]butanoic acid
• 化学式: C₁₈H₂₄N₄O₇
• 分子量: 408.411
• InChiKey: CQRQJXPXRKIHDZ-GVXVVHGQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  177
• 氢给体数：
  5
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-[(benzyloxy)carbonyl]-L-alanyl-L-alanyl-L-asparagine 、 盐酸多柔比星 在 N-甲基吗啉 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.13h， 生成 N-benzyloxycarbonyl-Ala-Ala-Asn-Doxorubicin
  参考文献：
  名称：

  Synthesis and Evaluation of a CBZ-AAN-Dox Prodrug and itsin vitroEffects on SiHa Cervical Cancer Cells Under Hypoxic Conditions

  摘要：

  Although doxorubicin (Dox) is widely used in clinical treatment for solid tumors, it causes many side‐effects such as heart and kidney damage, bone marrow suppression, and drug resistance. Legumain is a lysosomal protease that is elevated and associated with an invasive and metastatic phenotype in a number of solid tumors. In this study, we designed and synthesized a Dox prodrug, N‐benzyloxycarbonyl‐Ala‐Ala‐Asn‐Doxorubicin (CBZ‐AAN‐Dox), with 94% purity. Single substrate kinetic assays demonstrated hLegumain‐specific enzymatic cleavage and activation of the prodrug in vitro, and this enzymatic cleavage of the prodrug substrate was more sensitive in acidic conditions, releasing more than 70% of Dox after 24 h. Treatment of tumor cells with our prodrug demonstrated a much higher IC50 value, significantly enhanced uptake of the prodrug, and considerably less cellular toxicity compared to Dox treatment alone. Our study presents a novel prodrug, CBZ‐AAN‐Dox, to potentially increase both the safety and efficacy of clinical treatment of tumors by exploiting the tumor's innate expression of legumain.

  DOI：

  10.1111/cbdd.12525
• 作为产物：
  描述：

  N-(苄氧羰基)-L-丙氨酰-L-丙氨酸 、 L-天冬酰胺叔丁酯 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 三氟乙酸 作用下， 生成 N-[(benzyloxy)carbonyl]-L-alanyl-L-alanyl-L-asparagine
  参考文献：
  名称：

  PRODRUGS OF CYTOTOXIC ACTIVE AGENTS HAVING ENZYMATICALLY CLEAVABLE GROUPS

  摘要：

  该发明涉及通式(Ia)的新型前药或结合物，其中细胞毒性药物，例如动力蛋白抑制剂，被腿蛋白酶可切割基团掩蔽，从而释放药物，并且涉及使用这些前药或结合物用于治疗和/或预防疾病，以及使用这些前药或结合物用于生产用于治疗和/或预防疾病的药物，特别是治疗和/或预防高增殖和/或血管生成异常的疾病，例如癌症。

  公开号：

  US20190077752A1

文献信息

• ANTIBODY DRUG CONJUGATES (ADCS) AND ANTIBODY PRODRUG CONJUGATES (APDCS) WITH ENZYMATICALLY CLEAVABLE GROUPS
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：US20180169256A1

  公开（公告）日：2018-06-21

  The present invention relates to novel binder-prodrug conjugates (APDCs) where binders are conjugated with inactive precursor compounds of kinesin spindle protein inhibitors, and to antibody-drug conjugates ADCs and to processes for producing these APDCs and ADCs.

  这项发明涉及新型结合物-前药偶联物（APDCs），其中结合物与动力蛋白纺锤体抑制剂的非活性前体化合物偶联，以及抗体药物偶联物ADCs以及制备这些APDCs和ADCs的方法。
• Site specific homogeneous with KSP inhibitors
  申请人：BAYER PHARMA AKTIENGESELLSCHAFT

  公开号：US10973923B2

  公开（公告）日：2021-04-13

  The invention relates to site specific homogeneous binder drug conjugates of kinesin spindle protein inhibitors, to active metabolites of these conjugates, to processes for preparing these conjugates, to the use of these conjugates for the treatment and/or prophylaxis of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.

  本发明涉及驱动蛋白纺锤体蛋白抑制剂的位点特异性均质粘合剂药物共轭物，涉及这些共轭物的活性代谢物，涉及制备这些共轭物的工艺，涉及使用这些共轭物治疗和/或预防疾病，涉及使用这些共轭物制备治疗和/或预防疾病的药物，特别是过度增殖性和/或血管生成性疾病，例如癌症。这种治疗可以作为单一疗法进行，也可以与其他药物或进一步的治疗措施结合使用。
• Antibody drug conjugates (ADCS) and antibody prodrug conjugates (APDCS) with enzymatically cleavable groups
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：US11123439B2

  公开（公告）日：2021-09-21

  The present invention relates to novel binder-prodrug conjugates (APDCs) where binders are conjugated with inactive precursor compounds of kinesin spindle protein inhibitors, and to antibody-drug conjugates ADCs and to processes for producing these APDCs and ADCs.

  本发明涉及新型粘合剂-药物共轭物（APDCs），其中粘合剂与驱动蛋白纺锤体蛋白抑制剂的非活性前体化合物共轭；本发明还涉及抗体-药物共轭物 ADCs 以及生产这些 APDCs 和 ADCs 的工艺。
• [EN] TARGETED CONJUGATES OF KSP INHIBITORS<br/>[FR] CONJUGUÉS HOMOGÈNES SPÉCIFIQUES AU SITE AVEC INHIBITEURS DE KSP
  申请人：BAYER PHARMA AG

  公开号：WO2016207090A3

  公开（公告）日：2017-02-16
• ANTIKÖRPER-WIRKSTOFF-KONJUGATE (ADCS) VON KSP-INHIBITOREN MIT AGLYCOSYLIERTEN ANTI-TWEAKRANTIKÖRPERN
  申请人：Bayer Pharma Aktiengesellschaft

  公开号：EP3233127A1

  公开（公告）日：2017-10-25