1,1'-[[(propane-1,3-diyl)dioxy]-bis[(2-nitro-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] | 260417-95-6

• 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-nitro-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-nitro-5-methoxy-1,4-phenylene]carbonyl]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine]；1,1'-[[(propane-1,3-yl)dioxy]bis[(2-nitro-5-methoxy-1,4-phenylene)carbonyl]]bis[(2S,4R)-2-t-butyldimethylsilyloxy-methyl-4-hydroxypyrrolidine]
• CAS: 260417-95-6
• 化学式: C₄₁H₆₄N₄O₁₄Si₂
• 分子量: 893.149
• InChiKey: MNKJMHACYZFYGC-QUAHOIDUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.56
• 重原子数：
  61.0
• 可旋转键数：
  18.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  222.74
• 氢给体数：
  2.0
• 氢受体数：
  14.0

反应信息

• 作为反应物：
  描述：

  1,1'-[[(propane-1,3-diyl)dioxy]-bis[(2-nitro-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S,4R)-2-t-butyldimethylsilyloxymethyl-4-hydroxypyrrolidine] 在 吡啶 、 草酰氯 、 TEA 、 potassium tert-butylate 、 镍 、 二甲基亚砜 、 肼 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 6.0h， 生成 1,1'-[[(propane-1,3-diyl)dioxy]-bis[(2-amino-N-allyloxycarbonyl-5-methoxy-1,4-phenylene)carbonyl]]-bis[(2S)-2-t-butyldimethylsilyloxymethyl-4-methylidene-2,3-dihydropyrrole]
  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
• 作为产物：
  描述：

  Cbz-L-羟脯氨酸 在 palladium on activated charcoal 锂硼氢 、 硫酸 、 氢气 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 20.0 ℃ 、344.74 kPa 条件下， 反应 29.5h， 生成 1,1'-[[(propane-1,3-diyl)dioxy]-bis[(2-nitro-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

• Synthesis and in vitro evaluation of SG3227, a pyrrolobenzodiazepine dimer antibody-drug conjugate payload based on sibiromycin
  作者：Gary C. Kemp、Arnaud C. Tiberghien、Neki V. Patel、Francois D'Hooge、Sanjay M. Nilapwar、Lauren R. Adams、Simon Corbett、David G. Williams、John A. Hartley、Philip W. Howard

  DOI：10.1016/j.bmcl.2017.01.074

  日期：2017.3

  pyrrolobenzodiazepine dimer payload, SG3227, was rationally designed based on the naturally occurring antitumour compound sibiromycin. SG3227 was synthesized from a dimeric core in an efficient fashion. An unexpected room temperature Diels-Alder reaction occurred during the final step of the synthesis and was circumvented by use of an iodoacetamide conjugation moiety in place of a maleimide. The payload was successfully

  基于天然存在的抗肿瘤化合物西比霉素，合理设计了一种新型的吡咯并苯并二氮杂卓二聚体有效负载SG3227。SG3227是由二聚体核心以高效方式合成的。在合成的最后步骤中发生了意想不到的室温Diels-Alder反应，并通过使用碘乙酰胺共轭部分代替马来酰亚胺来规避。有效载荷已成功偶联至曲妥珠单抗，所得ADC在体外对表达HER2的人类癌细胞系表现出强大的活性。
• [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
• EP3604311
  申请人：——

  公开号：——

  公开（公告）日：——
• Pyrrolobenzodiazepines
  申请人：Spirogen Limited

  公开号：EP1193270B1

  公开（公告）日：2003-05-14