brostallicin

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: brostallicin
• 英文别名: PNU-166196；N-(5-{[(5-{[(5-{[(2-{[amino(imino)methyl]amino}ethyl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)amino]carbonyl}-1-methyl-1H-pyrrol-3-yl)-4-[(2-bromoacryloyl)amino]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride；2-[[4-[[4-[[4-[[4-(2-Bromoprop-2-enoylamino)-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]ethyl-(diaminomethylidene)azanium;chloride；2-[[4-[[4-[[4-[[4-(2-bromoprop-2-enoylamino)-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]-1-methylpyrrole-2-carbonyl]amino]ethyl-(diaminomethylidene)azanium;chloride
• 化学式: C₃₀H₃₅BrN₁₂O₅*ClH
• 分子量: 760.05
• InChiKey: IPKHXIAPPAKHTB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.07
• 重原子数：
  49
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  230
• 氢给体数：
  8
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  偏端霉素A盐酸盐 在 4-二甲氨基吡啶 、 lithium hydroxide 、 碳酸氢钠 、 sodium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 68.75h， 生成 brostallicin
  参考文献：
  名称：

  Syntheses of brostallicin starting from distamycin A

  摘要：

  Two syntheses of brostallicin, a DNA minor groove binder now undergoing phase II studies, starting from distamycin A are described. One approach is based upon the selective hydrolysis via imide activation of the C-terminus amide. Besides employing traditional solution-phase synthesis, the convenient use of a polymer-supported reagent is also discussed. The other one is based upon the Curtius rearrangement of the C-terminus side chain of a convenient intermediate, easily prepared in two steps by straightforward functional group manipulation of distamycin A. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(02)01733-1

文献信息

• Cytotoxic α-Halogenoacrylic Derivatives of Distamycin A and Congeners
  作者：Italo Beria、Pier Giovanni Baraldi、Paolo Cozzi、Marina Caldarelli、Cristina Geroni、Sergio Marchini、Nicola Mongelli、Romeo Romagnoli

  DOI：10.1021/jm031051k

  日期：2004.5.1

  action of many antitumor agents involves DNA damage, either by direct binding of the drug to DNA or to DNA-binding proteins. However, most of the DNA-interacting agents have only a limited degree of sequence specificity, which implies that they may hit all the cellular genes. DNA minor groove binders, among which the derivatives of distamycin A play an important role, could provide significant improvement

  许多抗肿瘤药的作用机制都涉及DNA损伤，这可能是由于药物与DNA或与DNA结合蛋白的直接结合而引起的。但是，大多数DNA相互作用剂仅具有有限程度的序列特异性，这意味着它们可能击中所有细胞基因。DNA小沟结合剂（其中双霉素A的衍生物起着重要作用）由于与富含胸腺嘧啶-腺嘌呤（TA）的序列具有很高的选择性，可以显着改善癌症的治疗，增加基因特异性。我们现在报告和讨论合成的，体外和体内活性以及二霉素A的α-卤代丙烯酰胺基衍生物的一些机理特征。这项工作的最终结果是选择brostallicin 17（PNU-166196）。Brostallicin，目前处于II期临床试验中，与广谱霉素衍生物塔木斯汀相比，它具有广谱的抗肿瘤活性和更高的凋亡作用。与临床测试的DNA小沟结合剂相比，brostallicin的重要体外毒理学特征是对人类造血祖细胞的骨髓毒性与对肿瘤细胞的细胞毒性之间的比率非常高。brostall
• Acryloyl substituted distamycin derivatives, process for preparing them, and their use as antitumor and antiviral agents
  申请人：Pharmacia & Upjohn S.p.A.

  公开号：US20030023031A1

  公开（公告）日：2003-01-30

  According to the invention, there is provided a method of manufacturing a medicament for use in the treatment of cancer or viral infections which comprises obtaining a cancer treating effective amount of a compound of formula (I), 1 and combining the compound of formula (I) with at least one pharmaceutically acceptable excipient, and wherein the cancer treating effective amount of a compound of formula I is an acryloyl substituted distamycin derivative in which n, R 1 and R 2 , R 3 , B, are defined herein or a pharmaceutically acceptable salt thereof to produce a medicament for use in the treatment of cancer or viral infections.

  根据本发明，提供了一种制造治疗癌症或病毒感染的药物的方法，该方法包括获取公式（I）化合物的治疗癌症有效量，1并将公式（I）化合物与至少一种药用可接受的赋形剂结合，其中公式I化合物的治疗癌症有效量是一种丙烯酰基取代的二氨基链霉素衍生物，其中n，R1和R2，R3，B在此定义，或其药用可接受盐，以制备用于治疗癌症或病毒感染的药物。
• Pharmaceutical compositions comprising acryloyl distamycin derivatives and topoisomerase I and II inhibitors
  申请人：——

  公开号：US20030162722A1

  公开（公告）日：2003-08-28

  The present invention provides the combined use of acryloyl distamycin derivatives, in particular &agr;-bromo- and &agr;-chloro-acryloyl distamycin derivatives of formula (I), as set forth in the specification, and an antineoplastic topoisomerase I or II inhibitor, in the treatment of tumors. Also provided is the use of the said combinations in the treatment or prevention of metastasis or in the treatment of tumors by inhibition of angiogenesis.

  本发明提供了丙烯酰基二霉素衍生物，特别是式(I)的&agr;-溴-和&agr;-氯-丙烯酰基二霉素衍生物（如说明书所述）与抗肿瘤拓扑异构酶I或II抑制剂在治疗肿瘤中的联合使用。还提供了上述组合物在治疗或预防转移或通过抑制血管生成治疗肿瘤中的用途。
• Combined therapy against tumors comprising substituted acryloyl distamycin derivatives and alkylating agents
  申请人：——

  公开号：US20030180383A1

  公开（公告）日：2003-09-25

  Compounds which are &agr;-halogenoacryloyl distamycin derivatives of formula (I) wherein R 1 is a bromine or chlorine atom; R 2 is a distamycin or distamycin-like framework as set forth in the specification; or a pharmaceutically acceptable salt thereof; are cytotoxic agents particularly effective in the treatment of tumors over expressing GSH/GSTs system and which are poorly responsive or even resistant to conventional antitumor therapies.

  式 (I) 的&agr;-卤代丙烯酰基多柔霉素衍生物的化合物，其中 R 1 是溴原子或氯原子；R 2 或其药学上可接受的盐；是治疗过度表达 GSH/GSTs 系统、对传统抗肿瘤疗法反应不佳甚至耐药的肿瘤特别有效的细胞毒剂。
• Antitumor theraphy comprising distamycin derivatives
  申请人：——

  公开号：US20040006023A1

  公开（公告）日：2004-01-08

  The present invention relates to an administration schedule comprising the intravenous administration of a &agr;-halogen-acryloyl distamycin derivative, or a pharmaceutically acceptable salt thereof. The above administration allows the treatment of a variety of tumors in mammals.

  本发明涉及一种给药方案，包括静脉注射一种&agr;-卤代-丙烯酰基多柔霉素衍生物或其药学上可接受的盐。上述给药方法可治疗哺乳动物的多种肿瘤。