N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid | 1218772-52-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid
• CAS: 1218772-52-1
• 化学式: C₃₅H₄₉N₃O₉
• 分子量: 655.789
• InChiKey: JTSMYBBWEZRZAF-JGCGQSQUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.87
• 重原子数：
  47.0
• 可旋转键数：
  21.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  161.52
• 氢给体数：
  4.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid 、 4-[N-(2,4-二氨基-6-蝶啶甲基)-N-甲氨基]苯甲酸半盐酸盐n水 、 芴甲氧羰基-L-谷氨酸 1-叔丁酯 、 N-芴甲氧羰基-L-苯丙氨酸五氟苯酯 、 三氟乙酸 在 1-羟基苯并三唑 、 N,N'-二异丙基碳二亚胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以18%的产率得到
  参考文献：
  名称：

  Synthesis and optimization of hyaluronic acid–methotrexate conjugates to maximize benefit in the treatment of osteoarthritis

  摘要：

  We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like syno-viocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.053
• 作为产物：
  描述：

  、 9-芴甲基-N-琥珀酰亚胺基碳酸酯 在 碳酸氢钠 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 9.0h， 以1.71 g的产率得到N-{1-[3-(2-{2-[3-(9H-fluoren-9-ylmethoxycarbonylamino)propoxy]ethoxy}ethoxy)propylcarbamoyl]-2,2-dimethylpropyl}succinamic acid
  参考文献：
  名称：

  Synthesis and optimization of hyaluronic acid–methotrexate conjugates to maximize benefit in the treatment of osteoarthritis

  摘要：

  We previously reported that a conjugate of hyaluronic acid (HA) and methotrexate (MTX) could be a prototype for future osteoarthritis drugs having the efficacy of the two clinically validated agents but with a reduced risk of the systemic side effects of MTX by using HA as the drug delivery carrier. To identify a clinical candidate, we attempted optimization of a lead, conjugate 1. Initially, in fragmentation experiments with cathepsins, we optimized the peptide part of HA-MTX conjugates to be simpler and more susceptible to enzymatic cleavage. Then we optimized the peptide, the linker, the molecular weight, and the binding ratio of the MTX of the conjugates to inhibit proliferation of human fibroblast-like syno-viocytes in vitro and knee swelling in rat antigen-induced monoarthritis in vivo. Consequently, we found conjugate 30 (DK226) to be a candidate drug for the treatment of osteoarthritis. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.053