O²-chloromethyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate | 960231-74-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: O²-chloromethyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
• 英文别名: (Z)-2-(chloromethoxy)-1-(pyrrolidin-1-yl)diazene 1-oxide；(Z)-chloromethoxyimino-oxido-pyrrolidin-1-ylazanium
• CAS: 960231-74-7
• 化学式: C₅H₁₀ClN₃O₂
• 分子量: 179.606
• InChiKey: XSGNNXPOOVOEEC-CLFYSBASSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  11
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  53.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-乙酰-L-苯丙氨酸 、 O²-chloromethyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate 在 caesium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以60%的产率得到O2-(Nα-acetyl-L-phenylalanine)methyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  Synthesis of peptide-diazeniumdiolate conjugates: towards enzyme activated antitumor agents

  摘要：

  The development of NO donors with site-specific and time-controlled properties is of great interest. We have designed a novel prodrug class as possible agents against metastatic prostate cancer by coupling a diazeniumdiolate to the terminal carboxyl groups of amino acids or peptides, such as Ser-Ser-Tyr-Tyr, Ser-Ser-Phe-Tyr, and Gly-Ile-Ser-Ser-Phe-Tyr. These prodrugs can be activated by alpha -chymotrypsin or prostate specific antigen and are potentially potent compounds for prostatic cancer. (C) 2001 Published by Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4039(01)00263-5
• 作为产物：
  描述：

  O²-methylthiomethyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate 在 磺酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 O²-chloromethyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate
  参考文献：
  名称：

  来自diazen-1-ium-1,2-glycate一氧化氮供体和ROS诱导剂plumbagin的新型抗癌杂种：设计，合成和生物学评估。

  摘要：

  高水平的一氧化氮（NO）和活性氧（ROS）可能在癌细胞中充当促凋亡信号。在这项研究中，我们将一类重要的NO供体diazeniumdiolates（NONOates）与天然的铅蛋白（PL）结合在一起，而后者主要是出色的ROS诱导剂。本文中，总共合成了12种新颖的lumbagin / NONOate杂种，并评估了它们对一组人类癌细胞系（MDA-MB-231，A549，HepG2和HCT-116细胞）和两个正常人类细胞（ HK-2和WRL-68电池）。其中，与上述母体化合物相比，化合物10a和10b显示出比其母体化合物优越的效力（IC 50值为3.48-6.68μM），但是对正常细胞的抑制作用较弱。根据其选择性的细胞毒性，10a和10b在癌细胞中释放的NO水平高于正常细胞。此外，与母体化合物plumbagin相比，有效的化合物10a以浓度依赖的方式诱导A549细胞凋亡，并导致更多的ROS产生。

  DOI：

  10.1016/j.ejmech.2018.04.047

文献信息

• PROSTAGLANDIN CONJUGATES AND DERIVATIVES FOR TREATING GLAUCOMA AND OCULAR HYPERTENSION
  申请人：NOVARTIS AG

  公开号：US20160108012A1

  公开（公告）日：2016-04-21

  Prostaglandin conjugates and derivatives and methods for their use to treat glaucoma and/or lower intraocular pressure are disclosed. Additionally, ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma and elevated intraocular pressure are disclosed. Such compositions comprise an effective amount of prostaglandin conjugates or derivatives of the present invention.

  本发明公开了用于治疗青光眼和/或降低眼内压的前列腺素共轭物和衍生物以及其使用方法。此外，本发明还公开了用于治疗眼部疾病如青光眼和眼内压升高的眼科药物组合物。这些组合物包括本发明的前列腺素共轭物或衍生物的有效量。
• Novel (E)-2-(aryl)-3-(4-methanesulfonylphenyl)acrylic ester prodrugs possessing a diazen-1-ium-1,2-diolate moiety: Design, synthesis, cyclooxygenase inhibition, and nitric oxide release studies
  作者：Khaled R.A. Abdellatif、Ying Dong、Qiao-Hong Chen、Morshed Alam Chowdhury、Edward E. Knaus

  DOI：10.1016/j.bmc.2007.07.021

  日期：2007.11

  hybrid nitric oxide-releasing anti-inflammatory drugs (11) possessing a 1-(N,N-diethylamino)diazen-1-ium-1,2-diolate, or 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate, nitric oxide (.NO) donor moiety attached via a one-carbon methylene spacer to the carboxylic acid group of (E)-3-(4-methanesulfonylphenyl)-2-(phenyl)acrylic acids were synthesized. These ester prodrugs (11) all exhibited in vitro inhibitory

  一类新的杂合释放一氧化氮的消炎药（11），具有1-（N，N-二乙氨基）重氮-1-1,2-二醇盐或1-（吡咯烷-1-基）重氮-1-1,2-羟基二醇盐，一氧化碳（.NO）供体基团，通过一个碳亚甲基间隔基连接到（E）-3-（4-甲磺酰基苯基）-2-（苯基）的羧酸基团上合成丙烯酸。这些酯类前药（11）均表现出对环氧合酶2（COX-2）同工酶的体外抑制活性（IC（50）= 0.94-31.6 microM范围）。与磷酸盐缓冲液（PBS）在pH 7.4（3.2-11.3％范围）孵育后，所有化合物均释放出NO。相比之下，当在大鼠血清中孵育这些杂化酯前药时，释放的.NO百分比显着更高（48.6-75.3％范围）。这些孵化研究表明，两者都有。NO和母体抗炎药（E）-3-（4-甲磺酰基苯基）-2-（苯基）丙烯酸会在体内被非特异性血清酯酶裂解后释放。O（2）-[（E）-2-（4-乙酰氨基苯基）-3-（4-甲磺酰基苯基）丙烯酰氧基甲基]
• Prostaglandin conjugates and derivatives for treating glaucoma and ocular hypertension
  申请人：Novartis AG

  公开号：US10016441B2

  公开（公告）日：2018-07-10

  Prostaglandin conjugates and derivatives and methods for their use to treat glaucoma and/or lower intraocular pressure are disclosed. Additionally, ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma and elevated intraocular pressure are disclosed. Such compositions comprise an effective amount of prostaglandin conjugates or derivatives of the present invention.

  本研究公开了前列腺素轭合物和衍生物及其用于治疗青光眼和/或降低眼内压的方法。此外，还公开了用于治疗青光眼和眼压升高等眼科疾病的眼科药物组合物。此类组合物包含有效量的本发明前列腺素共轭物或衍生物。
• Novel Nonsteroidal Antiinflammatory Drugs Possessing a Nitric Oxide Donor Diazen-1-ium-1,2-diolate Moiety:  Design, Synthesis, Biological Evaluation, and Nitric Oxide Release Studies
  作者：Carlos Velázquez、P. N. Praveen Rao、Edward E. Knaus

  DOI：10.1021/jm050211k

  日期：2005.6.1

  A novel group of hybrid nitric oxide-releasing nonsteroidal antiinflammatory drugs ((NO)-N-center dot-NSAIDs) possessing a 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (11, 13, 15) or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (12,14,16) moiety attached via a one-carbon methylene spacer to the carboxylic acid group of the traditional NSAIDs aspirin, ibuprofen, and indomethacin were synthesized. Although none of these ester prodrugs (11-16) exhibited in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50 > 100 mu M), all of the compounds (11-16) significantly decreased carrageenan-induced rat paw edema. In this regard, the ester prodrugs 11-16 showed equipotent antiinflammatory activities in vivo to that of the parent drugs aspirin, ibuprofen, and indomethacin. All of the compounds released nitric oxide upon incubation with either phosphate buffer solution at pH 7.4 (14-16% range) or porcine liver esterase (16-19% range), but the percentage of (NO)-N-center dot released was up to sixfold higher (93%) when these ester prodrugs were incubated with guinea pig serum. These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo cleavage by nonspecific serum esterases. The simultaneous release of aspirin and nitric oxide from the (NO)-N-center dot-aspirin prodrugs constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. The data acquired in an in vivo ulcer index (UI) assay showed that for this group of ester prodrugs, particularly the (NO)-N-center dot-aspirins (11, 12) and (NO)-N-center dot-ibuprofens (13, 14), no lesions were observed (UI 0) when compared to the parent drugs aspirin (UI 57, 250 mg/kg po dose), ibuprofen (UI 45, 250 mg/kg po dose), or indomethacin (UI = 34, 30 mg/kg po dose) at equivalent doses. Accordingly, these hybrid (NO)-N-center dot-NSAID prodrugs possessing a diazen-1-ium-1,2-diolate moiety, represent a new approach for the rational design of antiinflammatory drugs with reduced gastric ulcerogenicity.
• Synthesis and cytotoxicity of 5-fluorouracil/diazeniumdiolate conjugates
  作者：Tingwei Bill Cai、Xiaoping Tang、Janet Nagorski、Paul G Brauschweiger、Peng George Wang

  DOI：10.1016/j.bmc.2003.09.003

  日期：2003.11

  5-Fluorouracil/diazeniumdiolate conjugates were first synthesized, and showed greater cytotoxicities than 5-fluorouracil for DU 145 human prostate and HeLa cancer cells. (C) 2003 Elsevier Ltd. All rights reserved.