N,N''-(9H-fluorene-2,7-diyl)bis(3-chlorobenzenesulfonamide) | 1161880-44-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: N,N''-(9H-fluorene-2,7-diyl)bis(3-chlorobenzenesulfonamide)
• 英文别名: 3-chloro-N-[7-[(3-chlorophenyl)sulfonylamino]-9H-fluoren-2-yl]benzenesulfonamide
• CAS: 1161880-44-9
• 化学式: C₂₅H₁₈Cl₂N₂O₄S₂
• 分子量: 545.467
• InChiKey: FQQFAGBHFSNKJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,7-二氨基芴 、 3-氯苯磺酰氯 在 吡啶 、 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 生成 N,N''-(9H-fluorene-2,7-diyl)bis(3-chlorobenzenesulfonamide)
  参考文献：
  名称：

  Improved, Selective, Human Intestinal Carboxylesterase Inhibitors Designed to Modulate 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) Toxicity

  摘要：

  CPT-11 is an antitumor prodrug that is-hydrolyzed by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I poison. However, the dose limiting, toxicity delays diarrhea that is thought to arise, in part, from activation of the prodrug by a human intestinal CE (hiCE). Therefore, we have sought to identify selective inhibitors of hiCE that may have utility in modulating drug toxicity. We have evaluated one such class of molecules (benzene sulfonamides) and developed QSAR models for inhibition of this protein. Using these predictive models, we have synthesized a panel of fluorene analogues that are selective for hiCE, demonstrating no cross reactivity to the human liver CE, hCE1, or toward human cholinesterases, and have K-i values as low as 14 nM. These compounds prevented hiCE-mediated hydrolysis of the drug and the potency of enzyme inhibition correlated with the clogP of the molecules. These studies will allow the development and application of hiCE-specific inhibitors designed to selectively modulate drug hydrolysis in vivo.

  DOI：

  10.1021/jm9001296

文献信息

• Improved, Selective, Human Intestinal Carboxylesterase Inhibitors Designed to Modulate 7-Ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) Toxicity
  作者：Latorya D. Hicks、Janice L. Hyatt、Shana Stoddard、Lyudmila Tsurkan、Carol C. Edwards、Randy M. Wadkins、Philip M. Potter

  DOI：10.1021/jm9001296

  日期：2009.6.25

  CPT-11 is an antitumor prodrug that is-hydrolyzed by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I poison. However, the dose limiting, toxicity delays diarrhea that is thought to arise, in part, from activation of the prodrug by a human intestinal CE (hiCE). Therefore, we have sought to identify selective inhibitors of hiCE that may have utility in modulating drug toxicity. We have evaluated one such class of molecules (benzene sulfonamides) and developed QSAR models for inhibition of this protein. Using these predictive models, we have synthesized a panel of fluorene analogues that are selective for hiCE, demonstrating no cross reactivity to the human liver CE, hCE1, or toward human cholinesterases, and have K-i values as low as 14 nM. These compounds prevented hiCE-mediated hydrolysis of the drug and the potency of enzyme inhibition correlated with the clogP of the molecules. These studies will allow the development and application of hiCE-specific inhibitors designed to selectively modulate drug hydrolysis in vivo.