cis,cis,trans-[Pt(IV)(NH3)2(Cl)2(O2CNHC16H23)(O2CCH2CH2COOH)] | 1612259-09-2

• 英文名称: cis,cis,trans-[Pt(IV)(NH3)2(Cl)2(O2CNHC16H23)(O2CCH2CH2COOH)]
• 英文别名: cis,cis,trans-[Pt(IV)(NH₃)₂(Cl)₂(O₂CNHC₁₆H₂₃)(O₂CCH₂CH₂COOH)]
• CAS: 1612259-09-2
• 化学式: C₂₁H₄₅Cl₂N₃O₆Pt
• 分子量: 701.591
• InChiKey: VLBSZTIQHMCEGE-UHFFFAOYSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  None
• 重原子数：
  None
• 可旋转键数：
  None
• 环数：
  None
• sp3杂化的碳原子比例：
  None
• 拓扑面积：
  None
• 氢给体数：
  None
• 氢受体数：
  None

反应信息

• 作为反应物：
  描述：

  cis,cis,trans-[Pt(IV)(NH3)2(Cl)2(O2CNHC16H23)(O2CCH2CH2COOH)] 、 C.I.酸性橙108 在 HATU 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以76%的产率得到cis,cis,trans-[Pt(IV)(NH₃)₂(Cl)₂(O₂CNHC₁₆H₂₃)(O₂CCH₂CH₂CONHCH₂CH₂OH)]
  参考文献：
  名称：

  Pt(IV) 前药优先靶向吲哚胺-2,3-双加氧酶，提供增强的卵巢癌免疫化疗

  摘要：

  吲哚胺-2,3-双加氧酶（IDO）是人类肿瘤中的一种免疫抑制酶，其表达可导致免疫逃避和肿瘤耐受。因此，IDO是肿瘤免疫治疗靶点，目前有几种IDO抑制剂正在进行临床试验。 IDO抑制剂可以增强常见癌症化疗药物的疗效。在这里，我们研究 Pt(IV)-(D)-1-甲基色氨酸缀合物 1 和 2 在癌症“免疫化疗”中的联合免疫调节和 DNA 交联触发细胞凋亡。化合物 2 能有效杀死激素依赖性、顺铂耐药的人卵巢癌细胞，通过自分泌信号环 IDO-AHR-IL6 的转录失调来抑制 IDO，从而阻断犬尿氨酸的产生并促进 T 细胞增殖。此外，1和2在小鼠中表现出低毒性并且在血液中稳定。据我们所知，该结构是第一个具有免疫检查点阻断特性的 Pt 候选药物。

  DOI：

  10.1021/jacs.5b10182
• 作为产物：
  描述：

  十六烷基异氰酸酯 、 cis,cis-[Pt(IV)(NH3)2(Cl)2(OH)(O2CCH2CH2COOH)] 以 N,N-二甲基甲酰胺 为溶剂， 以39.9%的产率得到cis,cis,trans-[Pt(IV)(NH3)2(Cl)2(O2CNHC16H23)(O2CCH2CH2COOH)]
  参考文献：
  名称：

  Pt(IV) 前药优先靶向吲哚胺-2,3-双加氧酶，提供增强的卵巢癌免疫化疗

  摘要：

  吲哚胺-2,3-双加氧酶（IDO）是人类肿瘤中的一种免疫抑制酶，其表达可导致免疫逃避和肿瘤耐受。因此，IDO是肿瘤免疫治疗靶点，目前有几种IDO抑制剂正在进行临床试验。 IDO抑制剂可以增强常见癌症化疗药物的疗效。在这里，我们研究 Pt(IV)-(D)-1-甲基色氨酸缀合物 1 和 2 在癌症“免疫化疗”中的联合免疫调节和 DNA 交联触发细胞凋亡。化合物 2 能有效杀死激素依赖性、顺铂耐药的人卵巢癌细胞，通过自分泌信号环 IDO-AHR-IL6 的转录失调来抑制 IDO，从而阻断犬尿氨酸的产生并促进 T 细胞增殖。此外，1和2在小鼠中表现出低毒性并且在血液中稳定。据我们所知，该结构是第一个具有免疫检查点阻断特性的 Pt 候选药物。

  DOI：

  10.1021/jacs.5b10182

文献信息

• COMPLEXES COMPRISING A PLATINUM COMPOUND AND AN IMMUNE CHECKPOINT INHIBITOR AND RELATED METHODS
  申请人：Massachusetts Institute of Technology

  公开号：US20170129911A1

  公开（公告）日：2017-05-11

  Complexes comprising a platinum compound and an immune checkpoint inhibitor, and related methods, are generally provided. In some embodiments, the immune checkpoint inhibitor is an inhibitor for indoleamine-2,3-dioxygenase.

  一般提供了包括铂化合物和免疫检查点抑制剂的复合物，以及相关方法。在某些实施例中，免疫检查点抑制剂是吲哌酸-2,3-二氧化酶的抑制剂。
• Pt(IV) Prodrugs Designed to Bind Non-Covalently to Human Serum Albumin for Drug Delivery
  作者：Yao-Rong Zheng、Kogularamanan Suntharalingam、Timothy C. Johnstone、Hyunsuk Yoo、Wei Lin、Jamar G. Brooks、Stephen J. Lippard

  DOI：10.1021/ja5038269

  日期：2014.6.18

  Albumin is the most abundant protein in human serum and drugs that are administered intravenously inevitably interact with it. We present here a series of platinum(IV) prodrugs designed specifically to enhance interaction with human serum albumin (HSA) for drug delivery. This goal is achieved by asymmetrically functionalizing the axial ligands of the prodrug so as to mimic the overall features of a fatty acid. Systematic variation of the length of the aliphatic tail tunes the cellular uptake and, consequently, the cytotoxicity of cis,cis,trans-[Pt(NH3)2Cl2(O2CCH2CH2COOH)(OCONHR)], 4, where R is a linear alkyl group. Investigation of an analogue bearing a fluorophore conjugated to the succinate ligand confirmed that these compounds are reduced by biological reductants with loss of the axial ligands. Intracellular release of cisplatin from 4 was further confirmed by observing the characteristic effects of cisplatin on the cell cycle and morphology following treatment with the prodrug. The most potent member of series 4, for which R is a hexadecyl chain, interacts with HSA in a 1:1 stoichiometry to form the platinum-protein complex 7. The interaction is non-covalent and extraction with octanol completely removes the prodrug from an aqueous solution of HSA. Construct 7 is robust and can be isolated following fast protein liquid chromatography. The nature of the tight interaction was investigated computationally, and these studies suggest that the prodrug is buried below the surface of the protein. Consequently, complexation to HSA is able to reduce the rate of reduction of the prodrug by ascorbate. The lead compound from series 4 also exhibited significant stability in whole human blood, attributed to its interaction with HSA. This favorable redox profile, in conjunction with the established nonimmunogenicity, biocompatibility, and enhanced tumor accumulation of HSA, produces a system that holds significant therapeutic potential.