1,1'-[[(propane-1,3-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] | 260417-97-8

• 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'-[[(propane-1,3-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'-[[(propane-1,3-diyl)dioxy]bis[2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene]-carbonyl]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxy-pyrrolidine]；1,1'-[[(propane-1,3-diyl)dioxy]bis[(2-amino-N-allyloxy-carbonyl-5-methoxy-1,4-phenylene)carbonyl]]bis[(2S,4R)-2-t-butyldimsilyloxymethyl-4-hydroxypyrrolidine]；prop-2-enyl N-[2-[(2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carbonyl]-5-[3-[4-[(2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carbonyl]-2-methoxy-5-(prop-2-enoxycarbonylamino)phenoxy]propoxy]-4-methoxyphenyl]carbamate
• CAS: 260417-97-8
• 化学式: C₄₉H₇₆N₄O₁₄Si₂
• 分子量: 1001.33
• InChiKey: CSFDNMBXRSLEEG-NUXXNWGHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.22
• 重原子数：
  69
• 可旋转键数：
  26
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  213
• 氢给体数：
  4
• 氢受体数：
  14

反应信息

• 作为反应物：
  描述：

  1,1'-[[(propane-1,3-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 、 potassium tert-butylate 、 氟化氢吡啶 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.5h， 生成 1,1'-[(propane-1,3-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
• 作为产物：
  描述：

  1',3'-bis(4-carboxy-2-methoxy-5-nitrophenoxy)propane 在 吡啶 、 草酰氯 、 TEA 、 镍 、 N,N-二甲基甲酰胺 、 肼 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 35.5h， 生成 1,1'-[[(propane-1,3-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：

  C2-C3 / C2'-C3'-内不饱和吡咯并[2,1-c] [1,4]苯并二氮杂二聚体的第一个实例的合成。

  摘要：

  我们报道了通过新的有效途径合成的C2-C3 / C2'-C3'-内不饱和吡咯并[2,1-c] [1,4]苯并二氮杂（PBD）二聚体16的第一个例子-C 3-内-不饱和增强与A环连接的PBD二聚体的细胞毒性和DNA结合亲和力，但程度小于C 2 / C 2'-外-不饱和。这种新的途径已允许制备多克数量的相关临床候选药物1，并应导致结构上更多样化的PBD二聚体类似物。

  DOI：

  10.1016/s0960-894x(01)00560-1

文献信息

• Synthesis of the first example of a c2-C3/C2′-C3′-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine dimer
  作者：Stephen J Gregson、Philip W Howard、Kathryn E Corcoran、Terence C Jenkins、Lloyd R Kelland、David E Thurston

  DOI：10.1016/s0960-894x(01)00560-1

  日期：2001.11

  We report the first example of a C2-C3/C2'-C3'-endo unsaturated pyrrolo[2,1-c][1,4]benzodiazepine (PBD) dimer 16 synthesised through a new and efficient route, thus establishing that C2-C3-endo unsaturation enhances both cytotoxicity and DNA-binding affinity in A-Ring-linked PBD dimers but to a lesser extent than C2/C2'-exo-unsaturation. This new route has allowed the preparation of multi-gram quantities

  我们报道了通过新的有效途径合成的C2-C3 / C2'-C3'-内不饱和吡咯并[2,1-c] [1,4]苯并二氮杂（PBD）二聚体16的第一个例子-C 3-内-不饱和增强与A环连接的PBD二聚体的细胞毒性和DNA结合亲和力，但程度小于C 2 / C 2'-外-不饱和。这种新的途径已允许制备多克数量的相关临床候选药物1，并应导致结构上更多样化的PBD二聚体类似物。
• [EN] PYRROLOBENZODIAZEPINE DERIVATIVES, COMPOSITIONS COMPRISING THE SAME AND METHODS RELATED THERETO<br/>[FR] DERIVES DE PYRROLOBENZODIAZEPINE, COMPOSITIONS COMPRENANT CES DERIVES ET METHODES S'Y RAPPORTANT
  申请人：US GOV HEALTH & HUMAN SERV

  公开号：WO2005040170A3

  公开（公告）日：2005-06-30
• Pyrrolobenzodiazepines
  申请人：Spirogen Limited

  公开号：EP1193270B1

  公开（公告）日：2003-05-14
• 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.