1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] | 260418-27-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine]
• 英文别名: 1,1'-[[(pentane-1,5-diyl)dioxy]bis[2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene]-carbonyl]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine]
• CAS: 260418-27-7
• 化学式: C₅₁H₈₀N₄O₁₄Si₂
• 分子量: 1029.39
• InChiKey: ORJYUTCKIHAMGU-DNMDQSTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.0
• 重原子数：
  71.0
• 可旋转键数：
  24.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  213.12
• 氢给体数：
  4.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] 在 草酰氯 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 以75%的产率得到1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S)-2-t-butyldimethylsilyloxymethyl-4-oxo-pyrrolidine]
  参考文献：
  名称：

  Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8‘ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers

  摘要：

  A C2/C2'-exo-unsaturated pyrrolo [2, 1-c] [1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)(n)O-C8' diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., > 3400-fold in IGROV1 ovarian cells) and interstrand DNA cross-linking reactivity (> 10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand cross-linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b cross-links DNA with > 10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced DeltaT(m) shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5'-GAT(1-2)C cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)(2) is also reported.

  DOI：

  10.1021/jm030897l
• 作为产物：
  描述：

  (3R,5S)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-3-ol 在 镍 吡啶 、 一水合肼 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 7.5h， 生成 1,1'-[[(pentane-1,5-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine]
  参考文献：
  名称：

  Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8‘ Ether-Linked C2-exo-Unsaturated Pyrrolo[2,1-c][1,4]benzodiazepine (PBD) Dimers

  摘要：

  A C2/C2'-exo-unsaturated pyrrolo [2, 1-c] [1,4]benzodiazepine (PBD) dimer 4b (DRG-16) with a C8-O(CH2)(n)O-C8' diether linkage (n = 5) has been synthesized that shows markedly superior in vitro cytotoxic potency (e.g., > 3400-fold in IGROV1 ovarian cells) and interstrand DNA cross-linking reactivity (> 10-fold) compared to the shorter homologue 4a (SJG-136; n = 3). In contrast, for the C-ring unsubstituted series, the corresponding n = 5 dimer (3c) is generally less cytotoxic and has a lower interstrand cross-linking reactivity compared to its shorter n = 3 homologue (3a). Dimer 4b cross-links DNA with > 10-fold efficiency compared to 4a, and also inhibits the activity of the restriction endonuclease BamH1 more efficiently than either 3a or 4a. The C2-exo-unsaturated PBD dimers 4a,b are not only more effective than their C-ring saturated counterparts in terms of induced DeltaT(m) shift, but they also exert this effect more rapidly. Thus, while 3a and 3c exert 68 and 35% of their maximum effect immediately upon interaction with DNA, this level increases to 76 and 97% for 4a and 4b, respectively. Molecular modeling shows a rank order of 4b (n = 5) > 4a (n = 3) > 3a (n = 3) > 3c (n = 5) in terms of binding energy toward duplexes containing embedded target 5'-GAT(1-2)C cross-link sequences, reflecting the superior fit of the C2-exo-unsaturated rather than saturated C-rings of the PBD dimers. A novel synthesis of core synthetic building blocks for PBD dimers via stepwise Mitsunobu reaction and nitration with Cu(NO3)(2) is also reported.

  DOI：

  10.1021/jm030897l

文献信息

• Pyrrolobenzodiazepines
  申请人：Spirogen Limited

  公开号：EP1193270B1

  公开（公告）日：2003-05-14