3,4-bis(benzyloxy)-5-(((3R,7R,11R)-7,11-bis(2,3-bis-(benzyloxy)benzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecan-3-yl)carbamoyl)benzoic acid | 1407510-73-9

• 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: 3,4-bis(benzyloxy)-5-(((3R,7R,11R)-7,11-bis(2,3-bis-(benzyloxy)benzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecan-3-yl)carbamoyl)benzoic acid
• CAS: 1407510-73-9
• 化学式: C₇₃H₆₃N₃O₁₇
• 分子量: 1254.31
• InChiKey: LFHORORBWPYAGJ-UPMPAGDASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.2
• 重原子数：
  93.0
• 可旋转键数：
  25.0
• 环数：
  10.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  258.88
• 氢给体数：
  4.0
• 氢受体数：
  16.0

反应信息

• 作为反应物：
  描述：

  3,4-bis(benzyloxy)-5-(((3R,7R,11R)-7,11-bis(2,3-bis-(benzyloxy)benzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecan-3-yl)carbamoyl)benzoic acid 、 1-氨基-11-叠氮-3,6,9-三氧杂十一烷 在 N,N-二异丙基乙胺 、 ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以77%的产率得到N1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-4,5-bis-(benzyloxy)-N3-((3R,7R,11R)-7,11-bis(2,3-bis(benzyloxy)benzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecan-3-yl)isophthalamide
  参考文献：
  名称：

  Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

  摘要：

  The design, synthesis, and characterization of enterobactin antibiotic conjugates, hereafter Ent-Amp/Amx, where the beta-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent beta-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

  DOI：

  10.1021/ja503911p
• 作为产物：
  描述：

  N,N′-((3R,7R,11R)-11-(2,3-bis(benzyloxy)-5-formylbenzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecane-3,7-diyl)bis-(2,3-bis(benzyloxy)benzamide) 在 sodium chlorite 、 氨基磺酸 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 0.5h， 以89%的产率得到3,4-bis(benzyloxy)-5-(((3R,7R,11R)-7,11-bis(2,3-bis-(benzyloxy)benzamido)-2,6,10-trioxo-1,5,9-trioxacyclododecan-3-yl)carbamoyl)benzoic acid
  参考文献：
  名称：

  Siderophore-Mediated Cargo Delivery to the Cytoplasm of Escherichia coli and Pseudomonas aeruginosa: Syntheses of Monofunctionalized Enterobactin Scaffolds and Evaluation of Enterobactin–Cargo Conjugate Uptake

  摘要：

  The design and syntheses of monofunctionalized enterobactin (Ent, L- and D-isomers) scaffolds where one catecholate moiety of enterobactin houses an alkene, aldehyde, or carboxylic acid at the C5 position are described. These molecules are key precursors to a family of 10 enterobactin-cargo conjugates presented in this work, which were designed to probe the extent to which the Gram-negative ferric enterobactin uptake and processing machinery recognizes, transports, and utilizes derivatized enterobactin scaffolds. A series of growth recovery assays employing enterobactin-deficient E. coli ATCC 33475 (ent-) revealed that six conjugates based on L-Ent having relatively small cargos promoted E. coli growth under iron limiting conditions whereas negligible-to-no growth recovery was observed for four conjugates with relatively large cargos. No growth recovery was observed for the enterobactin receptor deficient strain of E. coli H1187 (fepA-) or the enterobactin esterase deficient derivative of E. coli K-12 JW0576 (fes-), or when the D-isomer of enterobactin was employed These results demonstrate that the E. coli ferric enterobactin transport machinery identifies and delivers select cargo-modified scaffolds to the E. coli cytoplasm. Pseudomonas aeruginosa PAO1 K648 (pvd-, pch-) exhibited greater promiscuity than that of E. coli for the uptake and utilization of the enterobactin-cargo conjugates, and growth promotion was observed for eight conjugates under iron-limiting conditions. Enterobactin may be utilized for delivering molecular cargos via its transport machinery to the cytoplasm of E. coli and P. aeruginosa thereby providing a means to overcome the Gram-negative outer membrane permeability barrier.

  DOI：

  10.1021/ja3077268