phenyl 2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetate | 1613697-47-4

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 喜树碱
• 英文名称: phenyl 2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetate
• CAS: 1613697-47-4
• 化学式: C₈₆H₁₀₈N₁₆O₁₇S₅
• 分子量: 1798.23
• InChiKey: FXKIKBRMKKXBFN-PBXBDECWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  124
• 可旋转键数：
  58
• 环数：
  12.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  528
• 氢给体数：
  8
• 氢受体数：
  31

反应信息

• 作为产物：
  描述：

  (S)-4-ethyl-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-4-yl 2-(2-((1-azido-13-oxo-3,6,9-trioxa-12-azaheptadecan-16-yl)disulfaneyl)phenyl)acetate 、 在 copper(ll) sulfate pentahydrate 、 维生素 C 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 4.0h， 以54%的产率得到phenyl 2-[2-[[5-[2-[[4-[2-[2-[2-[2-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethylamino]-6-[[1-[2-[2-[2-[2-[4-[[2-[2-[[(19S)-19-ethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4,6,8,10,15(20)-heptaen-19-yl]oxy]-2-oxoethyl]phenyl]disulfanyl]pentanoylamino]ethoxy]ethoxy]ethoxy]ethyl]triazol-4-yl]methylamino]-1,3,5-triazin-2-yl]amino]ethylamino]-5-oxopentan-2-yl]disulfanyl]phenyl]acetate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluations of Tumor-Targeting Dual-Warhead Conjugates for a Taxoid–Camptothecin Combination Chemotherapy

  摘要：

  Novel tumor-targeting dual-warhead conjugates, 2 (DW-1) and 3 (DW-2), which consist of a next-generation taxoid, 1 (SB-T-1214), and camptothecin as two warheads, self-immolative disulfide linkers for drug release, biotin as the tumor-targeting moiety, and 1,3,5-triazine as the tripod splitter module, were designed and synthesized. The potency of 2 was evaluated against MX-1, MCF-7, ID8, L1210FR (BR+, biotin receptor overexpressed) and WI38 (BR-, normal) cell lines in the absence and presence of glutathione (GSH), which is an endogenous thiol that triggers drug release inside the cancer cells. With the GSH and resuspension protocol, 2 exhibited IC50 values of 3.22-9.80 nM against all BR+ cancer cell lines, and 705 nM against WI38. Thus, there was a two orders of magnitude higher selectivity to cancer cells. Also, a clear cooperative effect was observed for the taxoid-camptothecin combination when two drugs were delivered to the cancer cells specifically in the form of a dual-warhead conjugate.

  DOI：

  10.1021/jm500631u