N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hydroxylamine | 1384933-15-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并噻唑类
• 英文名称: N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hydroxylamine
• 英文别名: 2-(4-hydroxylamino-3-methylphenyl)-5-fluorobenzothiazole
• CAS: 1384933-15-6
• 化学式: C₁₄H₁₁FN₂OS
• 分子量: 274.319
• InChiKey: DIIJOKNPHUUHHU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.21
• 重原子数：
  19.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  45.15
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hydroxylamine 在 乙二胺四乙酸 作用下， 以 aq. phosphate buffer 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 2.08h， 生成
  参考文献：
  名称：

  Bioactivation of Fluorinated 2-Aryl-benzothiazole Antitumor Molecules by Human Cytochrome P450s 1A1 and 2W1 and Deactivation by Cytochrome P450 2S1

  摘要：

  Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (SF 203) and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of SF 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and the formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two-step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O-demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity.

  DOI：

  10.1021/tx3001994
• 作为产物：
  描述：

  bis[4-fluoro-2-(3-methyl-4-nitrobenzoyl)aminophenyl] disulfide 在 10% Pd/C 、 对甲苯磺酸 、 一水合肼 、 三苯基膦 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 26.0h， 生成 N-(4-(5-fluorobenzo[d]thiazol-2-yl)-2-methylphenyl)hydroxylamine
  参考文献：
  名称：

  Bioactivation of Fluorinated 2-Aryl-benzothiazole Antitumor Molecules by Human Cytochrome P450s 1A1 and 2W1 and Deactivation by Cytochrome P450 2S1

  摘要：

  Both 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (SF 203) and 5-fluoro-2-(3,4-dimethoxyphenyl)-benzothiazole (GW 610) contain the benzothiazole pharmacophore and possess potent and selective in vitro antitumor properties. Prior studies suggested the involvement of cytochrome P450 (P450) 1A1 and 2W1-mediated bioactivation in the antitumor activities and P450 2S1-mediated deactivation of 5F 203 and GW 610. In the present study, the biotransformation pathways of 5F 203 and GW 610 by P450s 1A1, 2W1, and 2S1 were investigated, and the catalytic parameters of P450 1A1- and 2W1-catalyzed oxidation were determined in steady-state kinetic studies. The oxidations of SF 203 catalyzed by P450s 1A1 and 2W1 yielded different products, and the formation of a hydroxylamine was observed for the first time in the latter process. Liquid chromatography-mass spectrometry (LC-MS) analysis with the synthetic hydroxylamine and also a P450 2W1/5F 203 incubation mixture indicated the formation of dGuo adduct via a putative nitrenium intermediate. P450 2W1-catalyzed oxidation of GW 610 was 5-fold more efficient than the P450 1A1-catalyzed reaction. GW 610 underwent a two-step oxidation process catalyzed by P450 1A1 or 2W1: a regiospecific O-demethylation and a further hydroxylation. Glutathione (GSH) conjugates of 5F 203 and GW 610, presumably through a quninoneimine and a 1,2-quinone intermediate, respectively, were detected. These results demonstrate that human P450s 1A1 and 2W1 mediate 5F 203 and GW 610 bioactivation to reactive intermediates and lead to GSH conjugates and a dGuo adduct, which may account for the antitumor activities of 5F 203 and GW 610 and also be involved in cell toxicity. P450 2S1 can catalyze the reduction of the hydroxylamine to the amine 5F 203 under anaerobic conditions and, to a lesser extent, under aerobic conditions, thus attenuating the anticancer activity.

  DOI：

  10.1021/tx3001994

文献信息

• Chemistry of Ring-Substituted 4-(Benzothiazol-2-yl)phenylnitrenium Ions from Antitumor 2-(4-Aminophenyl)benzothiazoles
  作者：Yang Zhang、Mrinal Chakraborty、Christian G. Cerda-Smith、Ryan N. Bratton、Natalie E. Maurer、Ethan M. Senser、Michael Novak

  DOI：10.1021/jo400826f

  日期：2013.7.19

  long-lived (530 ns) nitrenium ion 11a by hydrolysis or photolysis in water. In this study, azide trapping shows that 9b–g generate 11b–g via rate-limiting N–O heterolysis. Ion lifetimes, estimated from azide/solvent selectivities, range from 250 to 1150 ns with identical lifetimes for 11a and 11f. Differences in biological activity of the amines are likely not due to differences in the chemistry of the cations

  2-(4-氨基苯基)苯并噻唑的环取代衍生物1a , 1b – g正在开发中作为抗肿瘤剂。一种衍生物1f已作为前药2f Phortress (NSC 710305)进入 1 期临床试验。这些胺被 CYP450 1A1 激活，显然转化为羟胺8a - g，它们很可能被代谢成酯，这些酯电离成负责细胞损伤的氮烯离子。之前我们展示了9a，即8a的乙酸酯，产生长寿命 (530 ns) 氮鎓离子11a在水中水解或光解。在这项研究中，叠氮化物捕集显示，图9b -克生成11B -克通过限速N-O heterolysis。根据叠氮化物/溶剂选择性估计的离子寿命范围为 250 到 1150 ns，11a和11f 的寿命相同。胺的生物活性的差异可能不是由于阳离子化学的差异，而是由于单个胺的代谢活化/失活的差异。与氮烯离子不同，酯的寿命强烈依赖于 3'-Me 取代基。含有 3'-Me 的酯 ( 9b , 9f , 9g)