| 1429328-79-9

• 分子结构分类: 有机化合物 - 有机杂环化合物
• CAS: 1429328-79-9
• 化学式: C₆₃H₁₀₁N₉O₂₅
• 分子量: 1384.54
• InChiKey: HYUORQQSDOSCHS-SAFPHONASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.12
• 重原子数：
  97.0
• 可旋转键数：
  18.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  453.66
• 氢给体数：
  13.0
• 氢受体数：
  27.0

反应信息

• 作为反应物：
  描述：

  [(η⁶-p-cym)RuCl(PPh₃)₂][PF₆] 、 在 三乙胺 、 lithium chloride 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.67h， 生成
  参考文献：
  名称：

  Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

  摘要：

  A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(eta(6)-p-cym)RuCl(PPh3)(2)](+), allowing the assembly of the target conjugates The guanidinylated analogue was easily prepared from the neomycin ruthenium conjugate by reaction with N,N'-di-Boc-N ''-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix assisted laser desorption-ionization time (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 approximate to 80 mu M), whereas the neamine conjugate (4) was inactive (IC50 approximate to 200 mu M). However, the guanidinylated analogue of the neomycin ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 mu M in DU-145 and IC50 = 11.33 mu M in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 >> 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 mu M for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 mu M for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

  DOI：

  10.1021/mp300723b
• 作为产物：
  描述：

  hexa-N-Boc deoxy-neomycin-5’’-amine 、 4-(1H-咪唑-1-基)苯甲酸 在 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.08h， 以35%的产率得到
  参考文献：
  名称：

  Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

  摘要：

  A straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino- and guanidinoglycosides, as potential RNA targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(eta(6)-p-cym)RuCl(PPh3)(2)](+), allowing the assembly of the target conjugates The guanidinylated analogue was easily prepared from the neomycin ruthenium conjugate by reaction with N,N'-di-Boc-N ''-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semipreparative high-performance liquid chromatography (HPLC) and characterized by electrospray ionization (ESI) and matrix assisted laser desorption-ionization time (MALDI-TOF) mass spectrometry (MS) and NMR spectroscopy. The cytotoxicity of the compounds was tested in MCF-7 (breast) and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, the neomycin-ruthenium conjugate (2) displayed moderate antiproliferative activity in both cancer cell lines (IC50 approximate to 80 mu M), whereas the neamine conjugate (4) was inactive (IC50 approximate to 200 mu M). However, the guanidinylated analogue of the neomycin ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC50 = 7.17 mu M in DU-145 and IC50 = 11.33 mu M in MCF-7). Although the same ranking in antiproliferative activity was found in the nontumorigenic cell line (3 >> 2 > 4), IC50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g., IC50 = 49.4 mu M for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC50 = 12.75 mu M for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher antiproliferative activity of 3. Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

  DOI：

  10.1021/mp300723b