benzhydryl 7β-(2-(thien-2-yl)acetamido)-3-<<<<(4-methylbenzoyl)hydrazino>carbonyl>oxy>methyl>-3-cephem-4-carboxylate 1β-sulfoxide | 139607-37-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酰胺类
• 英文名称: benzhydryl 7β-(2-(thien-2-yl)acetamido)-3-<<<<(4-methylbenzoyl)hydrazino>carbonyl>oxy>methyl>-3-cephem-4-carboxylate 1β-sulfoxide
• 英文别名: benzhydryl 7β-[2-(thien-2-yl)acetamido]-3-[({[(4-methylbenzoyl)hydrazino]carbonyl}oxy)methyl]-3-cephem-4-carboxylate 1β-sulfoxide；benzhydryl (5S,6R,7R)-3-[[(4-methylbenzoyl)amino]carbamoyloxymethyl]-5,8-dioxo-7-[(2-thiophen-2-ylacetyl)amino]-5λ4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 139607-37-7
• 化学式: C₃₆H₃₂N₄O₈S₂
• 分子量: 712.804
• InChiKey: LHXZDEJYDOCKMK-NDMHKISOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.67
• 重原子数：
  50.0
• 可旋转键数：
  10.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  160.21
• 氢给体数：
  3.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  benzhydryl 7β-(2-(thien-2-yl)acetamido)-3-<<<<(4-methylbenzoyl)hydrazino>carbonyl>oxy>methyl>-3-cephem-4-carboxylate 1β-sulfoxide 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.75h， 以68%的产率得到7β-(2-(thien-2-yl)acetamido)-3-<<<<(4-methylbenzoyl)hydrazino>carbonyl>oxy>methyl>-3-cephem-4-carboxylic acid 1β-sulfoxide
  参考文献：
  名称：

  Synthesis of acylhydrazido-substituted cephems. Design of cephalosporin-vinca alkaloid prodrugs: substrates for an antibody targeted enzyme

  摘要：

  Cephalosporin 20 substituted at the C-3' position with the potent oncolytic agent desacetylvinblastine hydrazide (3) was synthesized as a potential prodrug for the treatment of solid tumors. The design of this novel prodrug was based on the knowledge that hydrolysis of a cephalosporin's beta-lactam bond can result in the expulsion of the C-3' substituent. Proper selection of the linkage used to join the cephem to the vinca, e.g., 8 vs 20, provided a releasable form of the drug as well as a chemically stable prodrug. We envisioned the conversion of prodrug to free vinca to be mediated by an immunoconjugate, consisting of a beta-lactamase enzyme covalently attached to a monoclonal antibody, which has been prelocalized at the tumor. Treatment of candidate prodrugs with the P99 beta-lactamase enzyme isolated from Enterobacter cloacae 265A efficiently catalyzed their conversion to the free drug form. A study of model compounds 11 and 18 indicated that cephem 1-beta-sulfoxide 18 was a better substrate for the enzyme than its sulfide counterpart 11. This finding prompted the synthesis of cephem sulfoxide 20 which was efficiently accomplished via condensation of desacetylvinblastine hydrazide with the cephalothin derived cephem 3'-p-nitrophenyl carbonate 15.

  DOI：

  10.1021/jo00034a027
• 作为产物：
  描述：

  二苯基重氮甲烷 在 4-二甲氨基吡啶 、 N,N-二异丙基乙胺 吡啶 、 2,6-二甲基吡啶 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 丙酮 、 乙腈 为溶剂， 反应 18.0h， 生成 benzhydryl 7β-(2-(thien-2-yl)acetamido)-3-<<<<(4-methylbenzoyl)hydrazino>carbonyl>oxy>methyl>-3-cephem-4-carboxylate 1β-sulfoxide
  参考文献：
  名称：

  Synthesis of acylhydrazido-substituted cephems. Design of cephalosporin-vinca alkaloid prodrugs: substrates for an antibody targeted enzyme

  摘要：

  Cephalosporin 20 substituted at the C-3' position with the potent oncolytic agent desacetylvinblastine hydrazide (3) was synthesized as a potential prodrug for the treatment of solid tumors. The design of this novel prodrug was based on the knowledge that hydrolysis of a cephalosporin's beta-lactam bond can result in the expulsion of the C-3' substituent. Proper selection of the linkage used to join the cephem to the vinca, e.g., 8 vs 20, provided a releasable form of the drug as well as a chemically stable prodrug. We envisioned the conversion of prodrug to free vinca to be mediated by an immunoconjugate, consisting of a beta-lactamase enzyme covalently attached to a monoclonal antibody, which has been prelocalized at the tumor. Treatment of candidate prodrugs with the P99 beta-lactamase enzyme isolated from Enterobacter cloacae 265A efficiently catalyzed their conversion to the free drug form. A study of model compounds 11 and 18 indicated that cephem 1-beta-sulfoxide 18 was a better substrate for the enzyme than its sulfide counterpart 11. This finding prompted the synthesis of cephem sulfoxide 20 which was efficiently accomplished via condensation of desacetylvinblastine hydrazide with the cephalothin derived cephem 3'-p-nitrophenyl carbonate 15.

  DOI：

  10.1021/jo00034a027