(Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)phenyl ester

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚酯
• 英文名称: (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)phenyl ester
• 英文别名: (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid 4-(thioxo-5H-[1,2]dithiol-3-yl)-phenyl ester；[4-(5-sulfanylidenedithiol-3-yl)phenyl] 2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfinylphenyl)methylidene]inden-1-yl]acetate
• 化学式: C₂₉H₂₁FO₃S₄
• 分子量: 564.746
• InChiKey: SYLBPHQDUFEMEI-CFRMEGHHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.2
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  145
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-(4-羟基-苯基)-[1,2]二硫醇-3-硫酮 、 Sulindac 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 生成 (Z)-5-fluoro-2-methyl-1-[[4-(methylsulfinyl)phenyl]methylene]-1H-indene-3-acetic acid 4-(5-thioxo-5H-[1,2]dithiol-3-yl)phenyl ester
  参考文献：
  名称：

  Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid

  摘要：

  Background and purpose:Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti‐angiogenic properties, we investigated the activities of a new class of anti‐inflammatory drugs containing dithiolethione moieties (S‐NSAIDs) and S‐valproate.Experimental approach:Anti‐angiogenic activities of S‐NSAIDS, S‐valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.Key results:Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser78 phosphorylation of hsp27, a known molecular target of anti‐angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S‐NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H2S. In contrast to the parent drugs, S‐NSAIDs, S‐valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3‐dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S‐NSAIDs, remarkably, lacked this activity.Conclusions and implication:S‐NSAIDs and S‐valproate have potent anti‐angiogenic activities mediated by their dithiole moieties. The novel properties of S‐NSAIDs and S‐valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.British Journal of Pharmacology (2007) 151, 142–151. doi:10.1038/sj.bjp.0707198

  DOI：

  10.1038/sj.bjp.0707198

文献信息

• WO2006/134489
  申请人：——

  公开号：——

  公开（公告）日：——
• Sulindac Derivatives for Treatment of Cancer
  申请人：Sparatore Anna

  公开号：US20080207751A1

  公开（公告）日：2008-08-28

  The present invention relates to novel non steroidal anti-inflammatory compounds (NSAIDs) derivatives of sulindac, for the treatment/prevention, alone or in combination, of cancer.
• Modulation of angiogenesis by dithiolethione-modified NSAIDs and valproic acid
  作者：J S Isenberg、Y Jia、L Field、L A Ridnour、A Sparatore、P Del Soldato、A L Sowers、G C Yeh、T W Moody、D A Wink、R Ramchandran、D D Roberts

  DOI：10.1038/sj.bjp.0707198

  日期：2007.5

  Background and purpose:Angiogenesis involves multiple signaling pathways that must be considered when developing agents to modulate pathological angiogenesis. Because both cyclooxygenase inhibitors and dithioles have demonstrated anti‐angiogenic properties, we investigated the activities of a new class of anti‐inflammatory drugs containing dithiolethione moieties (S‐NSAIDs) and S‐valproate.Experimental approach:Anti‐angiogenic activities of S‐NSAIDS, S‐valproate, and the respective parent compounds were assessed using umbilical vein endothelial cells, muscle and tumor tissue explant angiogenesis assays, and developmental angiogenesis in Fli:EGFP transgenic zebrafish embryos.Key results:Dithiolethione derivatives of diclofenac, valproate, and sulindac inhibited endothelial cell proliferation and induced Ser78 phosphorylation of hsp27, a known molecular target of anti‐angiogenic signaling. The parent drugs lacked this activity, but dithiolethiones were active at comparable concentrations. Although dithiolethiones can potentially release hydrogen sulphide, NaSH did not reproduce some activities of the S‐NSAIDs, indicating that the dithioles regulate angiogenesis through mechanisms other than release of H2S. In contrast to the parent drugs, S‐NSAIDs, S‐valproate, NaSH, and dithiolethiones were potent inhibitors of angiogenic responses in muscle and HT29 tumor explants assessed by 3‐dimensional collagen matrix assays. Dithiolethiones and valproic acid were also potent inhibitors of developmental angiogenesis in zebrafish embryos, but the S‐NSAIDs, remarkably, lacked this activity.Conclusions and implication:S‐NSAIDs and S‐valproate have potent anti‐angiogenic activities mediated by their dithiole moieties. The novel properties of S‐NSAIDs and S‐valproate to inhibit pathological versus developmental angiogenesis suggest that these agents may have a role in cancer treatment.British Journal of Pharmacology (2007) 151, 142–151. doi:10.1038/sj.bjp.0707198