1,1'-[[(pentane-1,5-diyl)dioxy]-bis(11S,11aS)-10-(allyloxycarbonyl)-11-hydroxy-7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-5-one] | 260418-31-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: 1,1'-[[(pentane-1,5-diyl)dioxy]-bis(11S,11aS)-10-(allyloxycarbonyl)-11-hydroxy-7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-5-one]
• 英文别名: prop-2-enyl (6S,6aS)-3-[5-[[(6S,6aS)-6-hydroxy-2-methoxy-8-methylidene-11-oxo-5-prop-2-enoxycarbonyl-6,6a,7,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methylidene-11-oxo-6,6a,7,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate
• CAS: 260418-31-3
• 化学式: C₄₁H₄₈N₄O₁₂
• 分子量: 788.852
• InChiKey: WCJQXSDAIPAJOA-FHMMRVKWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  57
• 可旋转键数：
  16
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  177
• 氢给体数：
  2
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  1,1'-[[(pentane-1,5-diyl)dioxy]-bis(11S,11aS)-10-(allyloxycarbonyl)-11-hydroxy-7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-5-one] 在 四氢吡咯 、 四(三苯基膦)钯 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 以75%的产率得到(11aS,11a'S)-8,8'-(pentane-1,5-diylbis(oxy))bis(7-methoxy-2-methylene-2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(11aH)-one)
  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：

  1,5-戊二醇 在 镍 吡啶 、 sodium hydroxide 、 草酰氯 、 potassium tert-butylate 、 四丁基氟化铵 、 乙酸酐 、 copper(II) nitrate 、 一水合肼 、 二甲基亚砜 、 三乙胺 、 N,N-二甲基甲酰胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 86.5h， 生成 1,1'-[[(pentane-1,5-diyl)dioxy]-bis(11S,11aS)-10-(allyloxycarbonyl)-11-hydroxy-7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepin-5-one]
  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
• US7265105B2
  申请人：——

  公开号：US7265105B2

  公开（公告）日：2007-09-04
• Linker Length Modulates DNA Cross-Linking Reactivity and Cytotoxic Potency of C8/C8‘ Ether-Linked C2-<i>exo</i>-Unsaturated Pyrrolo[2,1-<i>c</i>][1,4]benzodiazepine (PBD) Dimers
  作者：Stephen J. Gregson、Philip W. Howard、Darren R. Gullick、Anzu Hamaguchi、Kathryn E. Corcoran、Natalie A. Brooks、John A. Hartley、Terence C. Jenkins、Sejal Patel、Matthew J. Guille、David E. Thurston

  DOI：10.1021/jm030897l

  日期：2004.2.1

  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.