4-(10-(allyloxycarbonyl)-7-methoxy-5-oxo-11-(tetrahydro-2H-pyran-2-yloxy)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanoic acid | 1314533-98-6

• 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: 4-(10-(allyloxycarbonyl)-7-methoxy-5-oxo-11-(tetrahydro-2H-pyran-2-yloxy)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanoic acid
• 英文别名: 4-(((11aS)-10-((allyloxy)carbonyl)-7-methoxy-5-oxo-11-((tetrahydro-2H-pyran-2-yl)oxy)-2,3,5,10,11,11a-hexahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)butanoic acid；(11aS)-8-(3-Carboxy-propoxy)-7-methoxy-5-oxo-11-(tetrahydropyran-2-yloxy)-2,3,11,11a-tetrahydro-1H,5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carboxylic acid allyl ester；4-[[(6aS)-2-methoxy-6-(oxan-2-yloxy)-11-oxo-5-prop-2-enoxycarbonyl-6a,7,8,9-tetrahydro-6H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoic acid
• CAS: 1314533-98-6
• 化学式: C₂₆H₃₄N₂O₉
• 分子量: 518.564
• InChiKey: QDPWXVUDFIQEQQ-KETPHWKMSA-N

物化性质

• 熔点：
  72 °C
• 沸点：
  726.7±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  37
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  124
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-(10-(allyloxycarbonyl)-7-methoxy-5-oxo-11-(tetrahydro-2H-pyran-2-yloxy)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanoic acid 在 四氢吡咯 、 四(三苯基膦)钯 、 三苯基膦 作用下， 反应 0.5h， 以72%的产率得到C₁₇H₂₀N₂O₅
  参考文献：
  名称：

  GC-Targeted C8-Linked Pyrrolobenzodiazepine–Biaryl Conjugates with Femtomolar in Vitro Cytotoxicity and in Vivo Antitumor Activity in Mouse Models

  摘要：

  DNA binding 4-(1-methyl-1H-pyrrol-3-yl)-benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-kappa B with its cognate DNA binding sequence.

  DOI：

  10.1021/jm301882a
• 作为产物：
  描述：

  allyl (11aS)-11-hydroxy-7-methoxy-8-(4-methoxy-4-oxobutoxy)-5-oxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate 在 对甲苯磺酸 、 sodium hydroxide 作用下， 以 甲醇 、 水 、 乙酸乙酯 为溶剂， 生成 4-(10-(allyloxycarbonyl)-7-methoxy-5-oxo-11-(tetrahydro-2H-pyran-2-yloxy)-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-8-yloxy)butanoic acid
  参考文献：
  名称：

  新型的广谱抗生素，含有吡咯并苯二氮杂卓环，具有抗多药耐药革兰氏阴性菌的活性。

  摘要：

  迫切需要找到对多药耐药（MDR）革兰氏阴性病原体具有活性的新抗生素类别，因为抗生素的生产线基本上是空的。具有C8连接的脂族杂环的改性吡咯并苯并二氮杂卓可提供一类新型的广谱抗菌剂，其对包括世界卫生组织优先病原体在内的MDR革兰氏阴性细菌具有活性。构效关系确定第三环对于革兰氏阴性活性特别重要。除铜绿假单胞菌外，对于MDR革兰氏阴性，先导化合物的最低抑菌浓度范围为0.125至2 mg / L，对于MDR革兰氏阳性菌种，最低抑菌浓度为0.03至1 mg / L。铅化合物可快速杀菌，可在4小时内将活菌数减少> 5 log鲍曼不动杆菌和肺炎克雷伯菌。铅化合物在基于凝胶的测定中抑制DNA促旋酶，IC 50为3.16±1.36 mg / L。这项研究为开发新型广谱抗生素提供了一种新的化学支架，可以帮助补充抗生素。

  DOI：

  10.1021/acs.jmedchem.0c00328

文献信息

• [EN] POLYCYCLIC AMIDES AS CYTOTOXIC AGENTS<br/>[FR] AMIDES POLYCYCLIQUES SERVANT D'AGENTS CYTOTOXIQUES
  申请人：FEMTOGENIX LTD

  公开号：WO2020049286A1

  公开（公告）日：2020-03-12

  The invention relates to a compound of formula (I): or pharmaceutically acceptable salts, solvates, tautomers, stereoisomers or mixtures thereof; wherein the fused ring moiety is a non-alkylating moiety; and wherein the compounds are useful as medicaments, in particular for use as a drug in an antibody-drug conjugate and in the treatment of a proliferative disease, a bacterial infection, a malarial infection and inflammation.

  该发明涉及公式(I)的化合物；或其药学上可接受的盐、溶剂合物、互变异构体、立体异构体或它们的混合物；其中融合环基团是非烷基化基团；这些化合物可用作药物，特别是用作抗体药物结合物中的药物，以及用于治疗增殖性疾病、细菌感染、疟疾感染和炎症。
• PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF
  申请人：Mersana Therapeutics, Inc.

  公开号：US20170369453A1

  公开（公告）日：2017-12-28

  The present disclosure relates generally to derivatives of pyrrolobenzodiazepines and antibody-drug conjugates thereof and to methods of using these conjugates as therapeutics and/or diagnostics.

  本公开涉及吡咯苯并二氮杂苯并二氮杂二环己烯衍生物及其抗体药物结合物，以及使用这些结合物作为治疗和/或诊断的方法。
• C8-Linked Pyrrolobenzodiazepine Monomers with Inverted Building Blocks Show Selective Activity against Multidrug Resistant Gram-Positive Bacteria
  作者：Paolo Andriollo、Charlotte K. Hind、Pietro Picconi、Kazi S. Nahar、Shirin Jamshidi、Amrit Varsha、Melanie Clifford、J. Mark Sutton、Khondaker Miraz Rahman

  DOI：10.1021/acsinfecdis.7b00130

  日期：2018.2.9

  block orientations on antibacterial activity and obtain structure activity relationship (SAR) information, four novel structures were synthesized in which the building blocks of previously reported compounds were inverted, and their antibacterial activity was studied. The compounds showed minimum inhibitory concentrations (MICs) in the range of 0.125–32 μg/mL against MDR Gram-positive strains with a bactericidal

  抗菌素耐药性已成为全球关注的主要问题。开发用于治疗由多药耐药性（MDR）病原体引起的感染的新型抗菌剂是当务之急。吡咯并苯二氮卓类（PBD）是一类有前途的抗菌剂，最初是从自然资源中发现和分离的。最近，C8连接的PBD联芳基共轭物已被证明对某些MDR革兰氏阳性菌株具有活性。为了探索结构单元取向对抗菌活性的作用并获得结构活性关系（SAR）信息，合成了四个新颖的​​结构，其中先前报道的化合物的结构单元被颠倒了，并研究了它们的抗菌活性。化合物的最低抑菌浓度（MIC）在0范围内。125-32μg/ mL，具有杀菌作用的MDR革兰氏阳性菌株。结果表明，酰胺键的一次反转降低了活性，而两次反转恢复了针对MDR病原体的活性。所有倒置的化合物都不能稳定DNA，并且缺乏真核毒性。这些化合物抑制DNA旋转酶在体外，在生化分析中，最有效的化合物对野生型和突变型DNA促旋酶均具有同等活性。所观察到的该化合物对具有等价回
• Effects of Systematic Shortening of Noncovalent C8 Side Chain on the Cytotoxicity and NF-κB Inhibitory Capacity of Pyrrolobenzodiazepines (PBDs)
  作者：David B. Corcoran、Thomas Lewis、Kazi S. Nahar、Shirin Jamshidi、Christopher Fegan、Chris Pepper、David E. Thurston、Khondaker Miraz. Rahman

  DOI：10.1021/acs.jmedchem.8b01849

  日期：2019.2.28

  of JJN-3 cells to the synthesized molecules. Although shortening the noncovalent interactive element of 13 had a less than expected effect upon compound cytotoxicity due to reduced DNA interaction, the transcription factor inhibitory capacity of the molecule was notably altered. This study suggests that a relatively short noncovalent side chain at the C8 position of PBD is sufficient to confer cytotoxicity

  C8连接的吡咯并苯并二氮杂（PBD）共轭物（13）的非共价元素的系统性缩短导致C8-PBD单体的19个成员库的合成。通过膜联蛋白V测定法阐明了使分子具有细胞毒性所必需的13的关键元素。在JJN-3细胞暴露于合成分子后，通过基于酶联免疫吸附法的核NF-κB测量，还探索了缩短分子非共价元素对转录因子抑制能力的影响。尽管由于减少的DNA相互作用，缩短13的非共价相互作用元件对化合物细胞毒性的作用小于预期，但该分子的转录因子抑制能力却发生了显着变化。这项研究表明，在PBD的C8位置相对较短的非共价侧链足以赋予细胞毒性。缩短的PBD单体由于其强大的细胞毒性和类似药物的性质而提供了一种新的ADC有效负载支架。
• [EN] PYRROLOBENZODIAZEPINES<br/>[FR] PYRROLOBENZODIAZÉPINES
  申请人：UCL BUSINESS PLC

  公开号：WO2013164592A1

  公开（公告）日：2013-11-07

  A compound of formula (I) or a salt or solvate thereof, wherein the dotted double bond indicates the presence of a single or double bond between C2 and C3; R2 is selected from -H, -OH, =O, =CH2, -CN, -R, OR, halo, dihalo, =CHR, =CHRR', -O- SO2-R, CO2R and COR; R7 is selected from H, R, OH, OR, SH, SR, NH2, NHR, NRR', nitro, Me3Sn and halo; where R and R' are independently selected from optionally substituted C1-7 alkyl, C3-20 heterocyclyl and C5-20 aryl groups; R10 and R11 either together form a double bond, or are selected from H and QRQ respectively, where Q is selected from O, S and NH and RQ is H or C1-7 alkyl or H and SOxM, where x is 2 or 3, and M is a monovalent pharmaceutically acceptable cation; A is selected from (A1), (A2), (A3), (A4) or (A5) where X1 and Y1 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; X2 and Y2 are selected from: CH and NH; CH and NMe; N and NMe; CH and S; N and S; N and O; and CH and O, respectively; Z1 is selected from O and S; Z2 is selected from CH and N; F is selected from a single bond and –(E-F1)m-; each E is independently selected from a single bond, and –C(=O)-NH-; each F1 is independently a C3-20 heteroarylene group; m is 1, 2 or 3; G is selected from hydrogen, C1-4alkyl, -C(=O)-O-C1-4alkyl, -(CH2)n-C3-20 heterocycloalkyl, and –O-(CH2)n-C3-20 heterocycloalkyl group; each n is 0-4; provided that A2 is not A2', where X1 and Y1 of A2' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and provided that A3 is not A3', where X2 and Y2 of A3' are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; B is either a single bond or (B1), where X and Y of B1 are selected from: CH and NMe; COH and NMe; CH and S; N and NMe; N and S, respectively; and R1 is C1-4 alkyl.

  化合物的化学式(I)或其盐或溶剂化合物，其中点虚线表示C2和C3之间存在单键或双键；R2选自-H、-OH、=O、=CH2、-CN、-R、OR、卤素、二卤素、=CHR、=CHRR'、-O-SO2-R、CO2R和COR；R7选自H、R、OH、OR、SH、SR、NH2、NHR、NRR'、硝基、Me3Sn和卤素；其中R和R'分别独立选自可选择的取代C1-7烷基、C3-20杂环烷基和C5-20芳基；R10和R11要么一起形成双键，要么分别选自H和QRQ，其中Q选自O、S和NH，RQ为H或C1-7烷基或H和SOxM，其中x为2或3，M为一价的药用可接受阳离子；A选自(A1)、(A2)、(A3)、(A4)或(A5)，其中X1和Y1选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；X2和Y2选自：CH和NH；CH和NMe；N和NMe；CH和S；N和S；N和O；以及CH和O，依此类推；Z1选自O和S；Z2选自CH和N；F选自单键和-(E-F1)m-；每个E独立选自单键和-C(=O)-NH-；每个F1独立为C3-20杂芳基；m为1、2或3；G选自氢、C1-4烷基、-C(=O)-O-C1-4烷基、-(CH2)n-C3-20杂环烷基和-O-(CH2)n-C3-20杂环烷基；每个n为0-4；条件是A2不是A2'，其中A2'的X1和Y1选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；条件是A3不是A3'，其中A3'的X2和Y2选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；B要么是单键，要么是(B1)，其中B1的X和Y选自：CH和NMe；COH和NMe；CH和S；N和NMe；N和S，依此类推；R1为C1-4烷基。