folate-EDA-EDTA-Cys-OH | 1579248-68-2

• 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: folate-EDA-EDTA-Cys-OH
• CAS: 1579248-68-2
• 化学式: C₃₄H₄₄N₁₂O₁₃S
• 分子量: 860.862
• InChiKey: OSCNOPIIOYCASI-VXKWHMMOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.62
• 重原子数：
  60.0
• 可旋转键数：
  26.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  381.66
• 氢给体数：
  12.0
• 氢受体数：
  17.0

反应信息

• 作为反应物：
  描述：

  vinblastine pyridinyl disulfide 、 folate-EDA-EDTA-Cys-OH 在 碳酸氢钠 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 0.17h， 以49%的产率得到
  参考文献：
  名称：

  Folate–Vinca Alkaloid Conjugates for Cancer Therapy: A Structure–Activity Relationship

  摘要：

  Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.

  DOI：

  10.1021/bc400441s
• 作为产物：
  描述：

  folate-EDA-EDTA-Cys(Trt)-OH 在 三异丙基硅烷 、 三氟乙酸 作用下， 以 水 为溶剂， 反应 1.0h， 以91%的产率得到folate-EDA-EDTA-Cys-OH
  参考文献：
  名称：

  Folate–Vinca Alkaloid Conjugates for Cancer Therapy: A Structure–Activity Relationship

  摘要：

  Vintafolide is a potent folate-targeted vinca alkaloid small molecule drug conjugate (SMDC) that has shown promising results in multiple clinical oncology studies. Structurally, vintafolide consists of 4 essential modules: (1) folic acid, (2) a hydrophilic peptide spacer, (3) a disulfide-containing, self-immolative linker, and (4) the cytotoxic drug, desacetylvinblastine hydrazide (DAVLBH). Here, we report a structure-activity study evaluating the biological impact of (i) substituting DAVLBH within the vintafolide molecule with other vinca alkaloid analogues such as vincristine, vindesine, vinflunine, or vinorelbine; (ii) substituting the naturally (S)-configured Asp-Arg-Asp-Asp-Cys peptide with alternative hydrophilic spacers of varied composition; and (iii) varying the composition of the linker module. A series of vinca alkaloid-containing SMDCs were synthesized and purified by HPLC and LCMS. The SMDCs were screened in vitro against folate receptor (FR)-positive cells, and anti-tumor activity was tested against well-established subcutaneous FR-positive tumor xenografts. The cytotoxic and anti-tumor activity was directly compared to that produced by vintafolide. Among all the folate vinca alkaloid SMDCs tested, DAVLBH-containing SMDCs were active, while those constructed with vincristine, vindesine, or vinorelbine analogues failed to produce meaningful biological activity. Within the DAVLBH series, having a bioreleasable, self-immolative linker system was found to be critical for activity since multiple analogues constructed with thioether-based linkers all failed to produce meaningful activity both in vitro and in vivo. Substitutions of some or all of the natural amino acids within vintafolide's hydrophilic spacer module did not significantly change the in vitro or in vivo potency of the SMDCs. Vintafolide remains one of the most potent folate-vinca alkaloid SMDCs produced to date, and continued clinical development is warranted.

  DOI：

  10.1021/bc400441s