chloromethylthalidomide | 359869-12-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: chloromethylthalidomide
• 英文别名: 2-(1-chloromethyl-2,6-dioxo-piperidine-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione；2-(1-chloromethyl-2,6-dioxo-piperidin-3-yl)-1,3-dihydro-2H-isoindole-1,3-dione；(R,S)-2-(1-(chloromethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione；2-(1-(chloromethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione；N-chloromethylthalidomide
• CAS: 359869-12-8
• 化学式: C₁₄H₁₁ClN₂O₄
• 分子量: 306.705
• InChiKey: ZATAZLBMVNRYOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.0
• 重原子数：
  21.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  74.76
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  chloromethylthalidomide 在 sodium azide 、 potassium iodide 作用下， 以 丙酮 为溶剂， 反应 30.0h， 生成 (R,S)-2-(1-(azidomethyl)-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  参考文献：
  名称：

  Synthesis and immunological activity of water-soluble Thalidomide prodrugs

  摘要：

  A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxy methyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300 mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k '. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the Vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00342-4
• 作为产物：
  描述：

  沙利度胺 在 氯化亚砜 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 chloromethylthalidomide
  参考文献：
  名称：

  Synthesis and immunological activity of water-soluble Thalidomide prodrugs

  摘要：

  A series of new water-soluble thalidomide prodrugs was prepared. All compounds were derivatized on the nitrogen of the glutarimide ring. Esters of natural amino acids and succinic acid derivatives have been introduced by reaction with the hydroxymethyl thalidomide 2. Nicotinic acid derivatives were prepared from halomethyl derivatives. Additionally, a methoxy methyl derivative and a carboxymethyl derivative were prepared directly from thalidomide. Most compounds showed a very large increase in water solubility compared to thalidomide itself (0.012 mg/mL). The amorphous hydrochlorides of the N-methylalanine ester 8, valine ester 9, and glycylglycine ester 10, respectively, were the most soluble compounds showing solubility greater than 300 mg/mL, which equals an increase greater than 15,000-fold. The lipophilicity of the prodrugs has been determined by their HPLC capacity factors k '. The stability of selected compounds was determined. The hydrolysis rates follow pseudo-first order kinetics. In order to assess the immunological activity, the prodrugs were tested using tumor necrosis factor-alpha and interleukin-2 inhibition assays. Selected compounds were additionally investigated on their abililty to inhibit the local Shwartzman reaction, an assay to determine the Vascular permeability. The prodrugs retained high effectiveness in the inhibition of TNF-alpha release. Our results indicated that the more stable prodrugs exhibited higher activity in the immunological assays. Some compounds showed higher activity than thalidomide itself, suggesting a high affine binding to the pharmacophore. In conclusion, the prodrugs exhibited high water solubility and high activity and might therefore be used in therapeutic applications. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00342-4

文献信息

• Synthesis and Evaluation of Thalidomide and Phthalimide Esters as Antitumor Agents
  作者：Magdy A. H. Zahran、Yasmin G. Abdin、Amany M. A. Osman、Amira M. Gamal-Eldeen、Roba M. Talaat、Erik B. Pedersen

  DOI：10.1002/ardp.201400073

  日期：2014.9

  A series of thalidomide and phthalimide ester analogs were efficiently synthesized from N‐chloromethylthalidomide, N‐chloromethylphthalimide, and N‐(2‐bromoethyl)phthalimide derivatives with various biologically important carboxylic acids. The synthesized compounds were purified and characterized by various chromatographic and spectroscopic techniques. The antitumor activity of all the synthesized

  一系列沙利度胺和邻苯二甲酰亚胺酯类似物由 N-氯甲基沙利度胺、N-氯甲基邻苯二甲酰亚胺和 N-（2-溴乙基）邻苯二甲酰亚胺衍生物与各种重要的生物学羧酸有效合成。合成的化合物通过各种色谱和光谱技术进行纯化和表征。所有合成化合物对人肝癌和乳腺癌细胞的抗肿瘤活性都进行了筛选，结果表明邻苯二甲酰亚胺酯 6a 是对 MCF7 细胞毒性最好的化合物，而所有测试化合物对 HepG2 细胞均表现出非细胞毒性作用。化合物5a、6a和7a具有免疫抑制作用，而化合物5c、5d、6c、6d、7c和7d显示免疫刺激作用。同时，
• Efforts toward elucidating Thalidomide’s molecular target: an expedient synthesis of the first Thalidomide biotin analogue
  作者：Scott G. Stewart、Carlos J. Braun、Marta E. Polomska、Mahdad Karimi、Lawrence J. Abraham、Keith A. Stubbs

  DOI：10.1039/c0ob00060d

  日期：——

  Herein we describe the synthesis of the first Thalidomide–biotin analogue in order to initiate investigations into the unknown molecular mode of action of Thalidomide. In this manner we describe the attachment of biotin tether through the Huisgen 1,3-dipolar cycloaddition or “click” synthetic methodology.

  在这里，我们描述了第一种沙利度胺-生物素类似物的合成，以启动对沙利度胺未知分子作用机制的研究。我们采用Huisgen 1,3-双极环加成或“点击”合成方法，描述了生物素连接体的结合。
• Design, synthesis and antitumor evaluation of novel thalidomide dithiocarbamate and dithioate analogs against Ehrlich ascites carcinoma-induced solid tumor in Swiss albino mice
  作者：Magdy A.-H. Zahran、Tarek A.-R. Salem、Rehab M. Samaka、Hussein S. Agwa、Ayman R. Awad

  DOI：10.1016/j.bmc.2008.09.071

  日期：2008.11

  A series of 16 novel thalidomide sulfur analogs containing one and two sulfur atoms 2 and 4-18, respectively, were designed and synthesized. These compounds were screened for in vitro antitumor activity against Ehrlich ascites carcinoma (EAC) cell line and exhibited potent cytotoxic activity. On the bases of the obtained results for in vitro cytotoxic activity, thalidomide sulfur analogs containing two sulfur atoms 8, 9, 13 and 14 were selected and tested in vivo against EAC-induced solid tumor in female mice compared to thalidomide 1 as well as its analog 2 and exhibited a highly significant reduction in tumor volume (TV). Results illustrated the antioxidative activity of these compounds as the level of hepatic lipid peroxidation decreased and levels of antioxidant enzymes like superoxide dismutase (SOD) and catalase were elevated. The histopathological investigations revealed that thalidomide sulfur analogs 2, 8, 9, 13 and 14 have antimitotic, apoptotic and necrotic activities against solid tumor. These compounds lead to increase of Fas-L expression. The immunohistochemical studies showed a decrease in Ki67 and vascular endothelial growth factor (VEGF) staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate and angiogenic process associated with tumor growth. Compounds 9 and 13 were the most potent compounds in tumor necrosis without liver necrosis. At the same time, treatment with compound 9 resulted in liver degeneration. (C) 2008 Elsevier Ltd. All rights reserved.
• DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL INDOLE-THALIDOMIDE HYBRIDS ANALOGS
  作者：Magdy Zahran

  DOI：10.21608/ejchem.2020.23685.2408

  日期：2020.3.13

  A series of novel Indole-Thalidomide hybrids were designed and synthesized in a good yield to improve and develop higher potency and selective anti-tumor agents. By two steps alkylation of Indole with Thalidomide then react the product with different active methylene groups. Their anti-proliferative evaluation activities against HCT 116 (colon cancer cell line), HepG2 (liver cancer cell line) and MCF-7 (breast cancer cell line). In vitro were tested by using Sulforhodamine-B stain (SRB) assay. The chemical structures of all synthesized analogs were elucidated on the basis of their spectral IR, H-1 NMR, C-13 NMR, Mass spectroscopy and element analysis. The result of the present work indicated all new analogs showed good activity toward all the tested cell lines, analog 8 has broad-spectrum anticancer activity toward all the tested cancer cell lines, followed by analog 2. The apoptosis evaluation for new analogs on Caspase-3, Bcl2 and Bax shown the best activity for analogs 2 and 8, so that the two analogs were histopathologically investigated.