3-(2-氯乙基)-4-氧代-3H-咪唑并(5,1-d)-1,2,3,5-四嗪-8-羧酸 | 113942-32-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑四嗪类
• 中文名称: 3-(2-氯乙基)-4-氧代-3H-咪唑并(5,1-d)-1,2,3,5-四嗪-8-羧酸
• 英文名称: 3-(2-chloroethyl)-3,4-dihydro-4-oxoimidazo<5,1-d><1,2,3,5>tetrazine-8-carboxylic acid
• 英文别名: 3-(2-chloroethyl)-4-oximidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxylic acid；3-(2-chloroethyl)-4-oxoimidazo<5,1-d>-1,2,3,5-tetrazine-8-carboxylic acid；3-(2-chloroethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4-oxo-8-carboxylic acid；3-(2-chloroethyl)-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid；3-(2-Chloroethyl)-4-oxoimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid
• CAS: 113942-32-8
• 化学式: C₇H₆ClN₅O₃
• 分子量: 243.609
• InChiKey: FOGTXLLWVRUBDH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(2-氯乙基)-4-氧代-3H-咪唑并(5,1-d)-1,2,3,5-四嗪-8-羧酸 在 氯化亚砜 、 N,N-二甲基甲酰胺 作用下， 反应 5.0h， 生成 3-(2-Chloro-ethyl)-4-oxo-3,4-dihydro-imidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid propyl ester
  参考文献：
  名称：

  Antitumor imidazotetrazines. 20. Preparation of the 8-acid derivative of mitozolomide and its utility in the preparation of active antitumor agents

  摘要：

  The preparation of 3-(2-chlorethyl)-4-oxo-3H-imidazo[5,1-d]-1,2,3,5- tetrazine-8-carboxylic acid, a key derivative of mitozolomide in our exploration of the structure-activity relationships of this class of antitumor agents, is described. The facile conversion to the 8-carbonyl chloride gave a derivative that reacted preferentially with nucleophiles at the 8-position rather than at the reactive 4-oxo group, allowing the preparation of a wide range of ester, thioester, amide (including an amide derived from an amino acid), hydroxamic acid, hydrazide and sulfoximide, azide and diazoacetyl derivatives. The in vivo activity is presented of a range of these compounds against TLX5 lymphoma and L1210 leukemia cell lines.

  DOI：

  10.1021/jm00167a018
• 作为产物：
  描述：

  米托唑胺 在 硫酸 、 sodium nitrite 作用下， 以 水 为溶剂， 以70%的产率得到3-(2-氯乙基)-4-氧代-3H-咪唑并(5,1-d)-1,2,3,5-四嗪-8-羧酸
  参考文献：
  名称：

  固定在树脂上的异羟肟酸 (HAIR)：用于合成双靶向 HDAC 抑制剂和 HDAC 降解剂 (PROTAC) 的工具箱。

  摘要：

  通过多靶点药物抑制多个癌症相关途径是现代抗癌药物发现中的一种新兴方法。在这里，基于组蛋白脱乙酰酶抑制剂 (HDACi) 和烷化剂之间已确立的协同作用，我们提出了一系列使用药效团连接策略的烷化 HDACi 的发现。为了并行合成目标化合物，我们开发了一种有效的固相支持方案，使用固定在树脂上的异羟肟酸（HAIR）作为稳定且通用的构建块来制备功能化 HDACi。最有前途的化合物3 n在细胞凋亡诱导、半胱天冬酶 3/7 激活和 DNA 损伤 (γ-H2AX) 形成方面的活性明显高于任一活性成分单独的活性总和。此外，为了证明我们预装树脂的实用性，HAIR 方法成功扩展到概念验证蛋白水解靶向嵌合体 (PROTAC) 的合成，该嵌合体可有效降解组蛋白脱乙酰酶。

  DOI：

  10.1002/anie.202006725

文献信息

• Tetrazines
  申请人：MAY & BAKER LIMITED

  公开号：EP0252682A2

  公开（公告）日：1988-01-13

  Tetrazines of the formula: wherein R¹ represents cycloalkyl, optionally substituted alkyl, alkenyl or alkynyl, A¹ represents nitrogen or -CR³= wherein R³ represents hydrogen or a substituent, A² represents nitrogen or, when A¹ represents nitrogen, A² represents nitrogen or a group -CR³= as hereinbefore defined, Z¹ represents oxygen or sulphur, and R² represents a cyano or azidocarbonyl group or a group of the formula -COZ²R⁹, -CONHOR⁹, -CONHNR⁹R¹⁰, -CONHNHCOOR⁹, -CONHNHCONHR⁹ -COCR¹¹=N₂, -CONHR¹² or -CON=S(O)R¹³R¹⁴ wherein Z² is oxygen or sulphur and R⁹ and R¹⁰ each represents hydrogen, alkyl which may carry an optionally substituted phenyl substituent, or represents optionally substituted phenyl, R¹¹ represents hydrogen or alkyl, and R¹² represents optionally substituted alkyl and R¹³ and R¹⁴ each represent alkyl, and when R¹, R², or R³ represents or contains an acidic group, salts thereof are useful as pharmaceuticals; processes for their preparation and new intermediates are described.

  式中的四嗪： 其中 R¹ 代表环烷基、任选取代的烷基、烯基或炔基，A¹ 代表氮或-CR³= 其中 R³ 代表氢或取代基，A² 代表氮或当 A¹ 代表氮时、Z¹ 代表氧或硫，R² 代表氰基或叠氮羰基或式-COZ²R⁹、-CONHOR⁹、-CONHNR⁹R¹⁰、-CONHNHCOOR⁹、-CONHNHCONHR⁹ -COR¹=N₂的基团、-CONHR¹²或-CON=S(O)R¹³R¹⁴，其中 Z² 是氧或硫，R⁹和 R¹⁰ 各自代表氢、可带有任选取代的苯基取代基的烷基或代表任选取代的苯基、 R¹¹代表氢或烷基，R¹²代表任选取代的烷基，R¹³和R¹⁴各自代表烷基，当R¹、R²或R³代表或含有酸性基团时，其盐可用作药物；描述了其制备工艺和新的中间体。
• Antitumor Imidazotetrazines. 41. Conjugation of the Antitumor Agents Mitozolomide and Temozolomide to Peptides and Lexitropsins Bearing DNA Major and Minor Groove-Binding Structural Motifs
  作者：Jill Arrowsmith、Sharon A. Jennings、Alan S. Clark、Malcolm F. G. Stevens

  DOI：10.1021/jm020936d

  日期：2002.12.1

  Carboxylic acids derived from the amido groups of the antitumor agents mitozolomide and temozolomide have been conjugated to simple amino acids and peptides by carbodiimide coupling. Solid-state peptide synthesis has been applied to link the acids to DNA major groove-binding peptidic motifs known to adopt alpha-helical conformations. Attachment of the acids to pyrrole and imidazole polyamidic lexitropsins gave a series of potential DNA minor groove- binding ligands. In vitro biological evaluation of a limited number of these novel conjugates failed to demonstrate any enhanced growth-inhibitory activity compared to the unconjugated drugs; sites of alkylation at tracts of multiple guanines were also unaffected. Attachment of additional residues at C-8 of the imidazotetrazines did not perturb the chemistry of activation of the bicyclic nucleus, and biological sequelae can be rationalized by invoking the liberation of a common, diffusible, reactive chemical intermediate, the methanediazonium ion.
• Synthesis and antibacterial activity of dual-action agents of a β-lactam antibiotic with cytotoxic agent mitozolomide or temozolomide
  作者：Yongfeng Wang、Peter Lambert、Linxiang Zhao、Danni Wang

  DOI：10.1016/s0223-5234(01)01331-9

  日期：2002.4

  Dual-action agents 5a-f and 12a-f. a beta-lactam antibiotic combined with a cytotoxic agent. mitozolomide (Meto) or temozolomide (Temo). were synthesised. The antibacterial activity (MICs) of the dual-action agents has been determined against a panel of bacteria including several beta-lactamase producing strains. The tests showed 5a-f active against the non-p-lactamase producing methicillin sensitive Staphylococcus aureus (MSSA) strains. however, little synergistic effect between the P-lactam and the cytotoxic agent was observed. 12a-f demonstrated some synergistic effect against bacteria. 12a. in particular. is active against ampicillin resistant (beta-lactamase-producing) strains of Serratia marcescens. (C) 2002 Published by editions scientifiques et medicales Elsevier SAS.
• Walsh; Ross; Routledge, Pharmaceutical Sciences, 1996, vol. 2, # 1, p. 33 - 38
  作者：Walsh、Ross、Routledge、Wallis、Fraser

  DOI：——

  日期：——
• 10.24820/ark.5550190.p011.182dummy2
  作者：Bradshaw, Tracey D.、Foreiter, Magdalena B.、Lewis, William、Moody, Christopher J.、Stevens, Malcolm F. G.、Summers, Helen S.

  DOI：10.24820/ark.5550190.p011.182dummy2

  日期：——