GENZ-644282抑制剂 | 529488-28-6

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 中文名称: GENZ-644282抑制剂
• 英文名称: 2,3-dimethoxy-12-(2-(methylamino)ethyl)[1,3]dioxolo[4',5':4,5]-benzo[1,2-h]benzo[c][1,6]naphthyridin-13(12H)-one
• 英文别名: 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N-methylamino)ethyl]-5H-dibenzo[c,h]1,6-naphthyridin-6-one；Gen-644282；Genz-644282；16,17-dimethoxy-21-[2-(methylamino)ethyl]-5,7-dioxa-11,21-diazapentacyclo[11.8.0.02,10.04,8.014,19]henicosa-1(13),2,4(8),9,11,14,16,18-octaen-20-one
• CAS: 529488-28-6
• 化学式: C₂₂H₂₁N₃O₅
• 分子量: 407.426
• InChiKey: BAORCAMWLWRZQG-UHFFFAOYSA-N

物化性质

• 熔点：
  254-257℃ (Decomposition)
• 沸点：
  665.5±55.0 °C(Predicted)
• 密度：
  1.344±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  82.2
• 氢给体数：
  1
• 氢受体数：
  7

安全信息

• 危险性防范说明：
  P261,P264,P270,P271,P280,P301+P312,P302+P352,P304+P340,P305+P351+P338,P330,P332+P313,P337+P313,P362,P403+P233,P405,P501
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  2-8℃

制备方法与用途

用途

GENZ-644282 用于合成 ARC-111 类似物，以改善母体化合物的抗肿瘤活性。

生物活性

Genz-644282 是一种非喜树碱类的拓扑异构酶 I (Topo I) 抑制剂，表现出较强的细胞毒性。其平均 IC50 值为 1.2 nM（范围为 0.2 nM 至 21.9 nM）。Genz-644282 可用于癌症研究。

靶点

Target	Value
Topo I (细胞外测定)	1.2 nM

反应信息

• 作为反应物：
  描述：

  GENZ-644282抑制剂 在 哌啶 、 2,6-二甲基吡啶 、 1-羟基苯并三唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 [4-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-5-(carbamoylamino)pentanoyl]amino]phenyl]methyl N-[2-(16,17-dimethoxy-20-oxo-5,7-dioxa-11,21-diazapentacyclo[11.8.0.02,10.04,8.014,19]henicosa-1(13),2,4(8),9,11,14,16,18-octaen-21-yl)ethyl]-N-methylcarbamate
  参考文献：
  名称：

  [EN] TOPOISOMERASE POISONS
  [FR] POISONS DE TOPOISOMÉRASE

  摘要：

  本文提供的是式(I)的化合物及其盐。还提供了包括式(I)的化合物的药物组合物，制备式(I)的化合物的方法，制备式(I)的有用中间体，以及使用式(I)的化合物治疗疾病（如癌症、细菌感染或真菌感染）的治疗方法。

  公开号：

  WO2017176648A1
• 作为产物：
  描述：

  2'-氨基-4',5'-亚甲二氧基苯乙酮 在 钯 palladium diacetate 、 甲酸 、 sodium hydride 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 、 silver carbonate 、 三氯氧磷 、 苯酚 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 42.5h， 生成 GENZ-644282抑制剂
  参考文献：
  名称：

  5-(2-Aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones:  Variation of N-Alkyl Substituents Modulates Sensitivity to Efflux Transporters Associated with Multidrug Resistance

  摘要：

  5H-8,9-Dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3-methylenedioxydibenzo [c, h]-[1,6]naphthyridin-6-one (ARC-111) has potent TOP1-targeting activity and pronounced antitumor activity. Several analogues of ARC-111 were synthesized with NH2, N-alkyl, N,N-dialkyl, pyrrolidinyl, piperidinyl, and piperazinyl substituents at the 2-position of the 5-ethyl group. The relative TOP1-targeting activity and cytotoxicity of these structural analogues were assessed in RPMI8402 and P388 tumor cells and their camptothecin-resistant variants CPT-K5 and P388/CPT45, respectively. Potent TOP1-targeting activity was retained within a series of mono N-alkyl analogues that included NHCH2CH3, NHCH(CH3)(2), and NHC(CH3)(3). TOP1-targeting activity was diminished by the presence of a N-benzyl moiety. In a comparison of a series of N-alkyl-N-isopropyl analogues, activity decreased in the order CH3 > CH2CH3 > CH(CH3)(2). Cytotoxicity in RPMI8402 and P388 did correlate with TOP1-targeting activity. Cytotoxic activity was also determined in KB3-1 cells and its variants KB/V-1 and KBH5.0. As KB/V-1 cells overexpress MDR1 and KBH5.0 cells overexpress BCRP, decreased cytotoxicity in these cell lines relative to the parent cell line is indicative of compounds that are substrates for these efflux transporters. In view of their diminished cytotoxicity in KB/V-1 cells, it appears that the likely demethylated metabolites of ARC-111, i.e., where NH2 or NHCH3 replaces the N(CH3)(2) at the 2-position of the 5-ethyl substituent, are substrates for MDR1. In contrast, no significant difference in cytotoxicity among these three cell lines was observed with other N-alkyl analogues, including NHC2H5, NHCH(CH3)(2), NHC(CH3)(3), N(CH3)(2), N(CH2CH3)(2), NCH3(CH(CH)(3))(2)), and either the pyrrolidinyl or the piperidinyl analogues. The 2-(piperazinyl) analogues were associated with diminished cytotoxicity in KB/V-1 cells, suggesting that the second basic amino substituent is associated with their recognition as substrates by MDR1. Comparative studies on the antitumor activity of ARC-111 and its N-demethylated derivatives (the NHCH3 and NH2 analogues) against SJ-BT45 medulloblastoma xenografts in scid mice revealed that the secondary amine metabolite is at least as active as ARC-111 in vivo, although the primary amine derivative was significantly less potent.

  DOI：

  10.1021/jm049447z

文献信息

• [EN] METHODS FOR TREATING HEMATOLOGICAL MALIGNANCIES<br/>[FR] MÉTHODES DE TRAITEMENT DE MALIGNITÉS HÉMATOLOGIQUES
  申请人：GENZYME CORP

  公开号：WO2012015875A1

  公开（公告）日：2012-02-02

  The invention provides methods and pharmaceutical compositions for treating certain hematological cancers.

  这项发明提供了治疗特定血液系统癌症的方法和药物组合物。
• [EN] METHODS FOR TREATING GASTRIC AND PANCREATIC MALIGNANCIES<br/>[FR] MÉTHODES DE TRAITEMENT DE MALIGNITÉS GASTRIQUES ET PANCRÉATIQUES
  申请人：GENZYME CORP

  公开号：WO2012015901A1

  公开（公告）日：2012-02-02

  The invention provides methods and pharmaceutical compositions for treating pancreatic cancer or gastric cancer or a metastasis thereof.

  该发明提供了治疗胰腺癌或胃癌或其转移的方法和药物组合物。
• Synthesis of N-substituted 5-[2-(N-alkylamino)ethyl]dibenzo[c,h][1,6]naphthyridines as novel topoisomerase I-targeting antitumor agents
  作者：Wei Feng、Mavurapu Satyanarayana、Liang Cheng、Angela Liu、Yuan-Chin Tsai、Leroy F. Liu、Edmond J. LaVoie

  DOI：10.1016/j.bmc.2008.09.002

  日期：2008.10

  Several N-alkyl and N,N-dialkyl 5H-8,9-dimethoxy-5-(2-aminoethyl)-2,3-methylenedioxydibenzo[c,h][1,6]naphthyridin -6-ones have been identified as topoisomerase I-targeting agents with potent antitumor activity. In the present study, the impact on biological activity of substitution of a trifluoromethyl, cyano, aminocarbonyl, or ethynyl group on a N-methyl substituent of N,N-dimethyl-, N-methyl-N-ethyl-

  几个N-烷基和N，N-二烷基5H-8,9-二甲氧基-5-（2-氨基乙基）-2,3-亚甲基二氧基二苯并[c，h] [1,6]萘啶-6-被鉴定为具有强大的抗肿瘤活性的拓扑异构酶I靶向剂。在本研究中，对三氟甲基，氰基，氨基羰基或乙炔基取代对N，N-二甲基-，N-甲基-N-乙基-和N-甲基的生物活性的影响评估了-N-异丙基5H-8,9-二甲氧基-5-（2-氨基乙基）-2,3-亚甲基二氧基二苯并[c，h] [1,6]萘啶-6-。
• [DE] NEU SPIROBENZOFURANLACTAME UND IHRE DERIVATE, VERFAHREN ZU IHRER HERSTELLUNG UND VERWENDUNG DERSELBEN<br/>[EN] NOVEL SPIROBENZOFURANLACTAMS AND THE DERIVATIVES THEREOF, METHODS FOR THE PRODUCTION THEREOF, AND USE THEREOF<br/>[FR] NOUVEAUX SPIROBENZOFURANELACTAMES ET SES DERIVES, PROCEDES POUR LES PRODUIRE ET LEUR UTILISATION
  申请人：AVENTIS PHARMA GMBH

  公开号：WO2004055021A1

  公开（公告）日：2004-07-01

  Die vorliegende Erfindung betrifft Spirobenzofuranlactam-Derivate der Formel (I), die von dem Mikroorganismus Stachybotris atra ST002348, DSM 14952, während der Fermentation gebildet werden, Verfahren zu deren Herstellung, deren Verwendung zur Herstellung eines Arzneimittels, Spirobenzofuranlactam-Derivate enthaltende Arzneimittel sowie den Mikroorganismus Stachybotris atra ST002348, DSM 14952.

  该发明涉及公式（I）的Spirobenzofuranlactam衍生物，它们由Stachybotris atra ST002348，DSM 14952微生物在发酵过程中形成，制备方法，用于制备药物的使用，含有Spirobenzofuranlactam衍生物的药物以及Stachybotris atra ST002348，DSM 14952微生物。
• Multivalent constructs for therapeutic and diagnostic applications
  申请人：——

  公开号：US20040210041A1

  公开（公告）日：2004-10-21

  The invention provides compositions and methods for therapeutic and diagnostic applications.

  这项发明提供了用于治疗和诊断应用的组合物和方法。