GWL-78 | 909415-27-6

• 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: GWL-78
• 英文别名: Ahj9FJ6lhp；methyl 4-[[4-[4-[[(6aS)-2-methoxy-11-oxo-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]butanoylamino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carboxylate
• CAS: 909415-27-6
• 化学式: C₃₀H₃₄N₆O₇
• 分子量: 590.636
• InChiKey: AYJUTKQNHHVYAL-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  43
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  146
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  methyl 4-(4-formyl-2-methoxy-5-nitrophenoxy)butanoate 在 palladium on activated charcoal 四氢吡咯 、 吡啶 、 4-二甲氨基吡啶 、 sodium hydroxide 、 potassium permanganate 、 四(三苯基膦)钯 、 草酰氯 、 氢气 、 对甲苯磺酸 、 二甲基亚砜 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 丙酮 为溶剂， -40.0~70.0 ℃ 、275.79 kPa 条件下， 反应 65.25h， 生成 GWL-78
  参考文献：
  名称：

  Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(N-methylpyrrole) Conjugates

  摘要：

  A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXW(z) (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/ nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.

  DOI：

  10.1021/jm051199z

文献信息

• [EN] PYRROLOBENZODIAZEPINE DERIVATIVES AS INHIBITORS OF NF-KAPPA B FOR THE TREATMENT OF PROLIFERATIVE DISEASES<br/>[FR] DÉRIVÉS DE PYRROLOBENZODIAZÉPINE UTILES EN TANT QU'INHIBITEURS DE NF-KAPPA B POUR LE TRAITEMENT DE MALADIES PROLIFÉRATIVES
  申请人：KING S COLLEGE LONDON

  公开号：WO2020152462A1

  公开（公告）日：2020-07-30

  The invention relates to a compound of formula (I) or salts, solvates, stereoisomers, tautomers or combinations thereof, wherein the dotted lines indicate the optional presence of a double bond between C1 and C2 or C2 and C3; and R1 and R2 are either (i) R1 and R2 together form a double bond; (ii) R1 is H and R2 is OH; or (iii) R1 is H and R2 is OC1-6 alkyl; Y is N-RB, S or O; Y1 is N or C-R8; q is o or 1; Het is where the carbonyl of the Het group is attached to the Y- & Y1-containing heterocyclic ring; Y2 is N-RB, S or O; Y3 is N or C-R10; Y4 is N-RB, S or O; Y5 is N or C-R10; Rx is H, RB, (CH2)m-ORB, halo, (CH2)m-NHRB and CO2RB; and each RB is independently selected from H, C1-6 alkyl and C1-6 haloalkyl. The invention also describes pharmaceutical compositions, and kits comprising compounds of formula (I) and their use for treating proliferative diseases such as multiple myeloma or chronic lymphocytic leukaemia and as NF-κΒ inhibitors.

  该发明涉及公式（I）的化合物或其盐、溶剂合物、立体异构体、互变异构体或它们的组合，其中虚线表示C1和C2或C2和C3之间的双键的可选存在；R1和R2要么（i）R1和R2一起形成双键；（ii）R1为H且R2为OH；或（iii）R1为H且R2为OC1-6烷基；Y为N-RB、S或O；Y1为N或C-R8；q为0或1；Het是Het基团的羰基连接到含有Y和Y1的杂环环上；Y2为N-RB、S或O；Y3为N或C-R10；Y4为N-RB、S或O；Y5为N或C-R10；Rx为H、RB、（CH2）m-ORB、卤素、（CH2）m-NHRB和CO2RB；每个RB独立选择自H、C1-6烷基和C1-6卤代烷基。该发明还描述了制药组合物和包含公式（I）化合物的试剂盒，以及它们在治疗增殖性疾病如多发性骨髓瘤或慢性淋巴细胞白血病以及作为NF-κΒ抑制剂的用途。
• WO2007/39752
  申请人：——

  公开号：——

  公开（公告）日：——
• Design, Synthesis, and Biophysical and Biological Evaluation of a Series of Pyrrolobenzodiazepine−Poly(<i>N</i>-methylpyrrole) Conjugates
  作者：Geoff Wells、Christopher R. H. Martin、Philip W. Howard、Zara A. Sands、Charles A. Laughton、Arnaud Tiberghien、Chi Kit Woo、Luke A. Masterson、Marissa J. Stephenson、John A. Hartley、Terence C. Jenkins、Steven D. Shnyder、Paul M. Loadman、Michael J. Waring、David E. Thurston

  DOI：10.1021/jm051199z

  日期：2006.9.1

  A novel series of methyl ester-terminated C8-linked pyrrolobenzodiazepine (PBD)-poly(N-methylpyrrole) conjugates (50a-f) has been synthesized and their DNA interaction evaluated by thermal denaturation, DNA footprinting, and in vitro transcription stop assays. The synergistic effect of attaching a PBD unit to a polypyrrole fragment is illustrated by the large increase in DNA binding affinity (up to 50-fold) compared to the individual PBD and pyrrole components. 50a-f were found to bind mainly to identical DNA sequences but with apparent binding site widths increasing with molecular length and the majority of sites conforming to the consensus motif 5'-XGXW(z) (z = 3 +/- 1; W = A or T; X = any base but preferably a purine). They also provided robust sequence-selective blockade of transcription at sites corresponding approximately to their DNA footprints. 50a-f were shown to have good cellular/ nuclear penetration properties, and a degree of correlation between cytotoxicity and DNA-binding affinity was observed.