ethyl 7-bromo-4-hydroxy-2-naphthoate

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: ethyl 7-bromo-4-hydroxy-2-naphthoate
• 英文别名: ethyl 5-bromo-4-hydroxy-2-naphthoate；2-Naphthalenecarboxylic acid, 5-bromo-4-hydroxy-, ethyl ester；ethyl 5-bromo-4-hydroxynaphthalene-2-carboxylate
• 化学式: C₁₃H₁₁BrO₃
• 分子量: 295.133
• InChiKey: FRFBJJINIVPNBP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl 7-bromo-4-hydroxy-2-naphthoate 在 lithium hydroxide monohydrate 、 叠氮磷酸二苯酯 、 水 、 四丁基碘化铵 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.0h， 生成 tert-butyl (4-(benzyloxy)-5-bromonaphthalen-2-yl)carbamate
  参考文献：
  名称：

  一种新型、异常有效的 Duocarmycin 氨基甲酸酯前药，不释放残留副产物

  摘要：

  seco -CBI-吲哚2的独特杂环氨基甲酸酯前药据报道，不释放残留副产物的 duocarmycin 和 CC-1065 天然产物家族的一类可水解前药的新成员。前药设计为通过氨基甲酸酯的水解激活，释放游离药物，而不会裂解释放可追踪的外来基团。与先前检测的在体内快速裂解的氨基甲酸酯前药不同，发现环状氨基甲酸酯在化学和生物条件下对水解异常稳定，提供了非常有效的游离药物的缓慢、持续释放。前药的体内评估发现其功效超过母体药物，其疗效与毒性的治疗窗口远大于母体药物，

  DOI：

  10.1021/jm300330b
• 作为产物：
  描述：

  在 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以5.4 g的产率得到ethyl 7-bromo-4-hydroxy-2-naphthoate
  参考文献：
  名称：

  一种新型、异常有效的 Duocarmycin 氨基甲酸酯前药，不释放残留副产物

  摘要：

  seco -CBI-吲哚2的独特杂环氨基甲酸酯前药据报道，不释放残留副产物的 duocarmycin 和 CC-1065 天然产物家族的一类可水解前药的新成员。前药设计为通过氨基甲酸酯的水解激活，释放游离药物，而不会裂解释放可追踪的外来基团。与先前检测的在体内快速裂解的氨基甲酸酯前药不同，发现环状氨基甲酸酯在化学和生物条件下对水解异常稳定，提供了非常有效的游离药物的缓慢、持续释放。前药的体内评估发现其功效超过母体药物，其疗效与毒性的治疗窗口远大于母体药物，

  DOI：

  10.1021/jm300330b

文献信息

• [EN] CYCLIC PRODRUGS OF DUOCARMYCIN ANALOGS<br/>[FR] PROMÉDICAMENTS CYCLIQUES D'ANALOGUES DE DUOCARMYCINE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2013148631A1

  公开（公告）日：2013-10-03

  The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

  该发明提供了DNA-反应性类似物duocarmycin和CC-1065抗癌药物的前药，其中循环前药形式，如氨基甲酸酯，硫代氨基甲酸酯或氨基甲酸酰胺，可以在体内被患者水解，产生包含DNA烷基化基团和结合/靶向基团的生物活性剂。DNA-反应性基团是与异环丙环己酮融合的杂环基团，可以通过该发明的循环氨基甲酸酯前药的内源水解产生。在体内激活过程中，循环氨基甲酸酯前药不产生任何残留副产物。还提供了合成方法和生物学方法和数据。
• CYCLIC PRODRUGS OF DUOCARMYCIN ANALOGS
  申请人：The Scripps Research Institute

  公开号：US20150057270A1

  公开（公告）日：2015-02-26

  The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spiro-cyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

  本发明提供了DNA反应性类似物duocarmycin和CC-1065抗癌剂的前药，其中循环前药形式，如氨基甲酸酯，硫代氨基甲酸酯或氨基甲酰亚胺，可以在体内被患者水解，生成相应的生物活性剂，包括DNA烷基化基团和结合/靶向基团。DNA反应性基团是γ-螺环己酮与杂环基团融合而成，可以通过本发明的循环氨基甲酸酯前药的内源性水解产生。循环氨基甲酸酯前药在体内激活时不产生残留副产品。本发明还提供了合成方法、生物学方法和数据。
• Cyclic prodrugs of duocarmycin analogs
  申请人：The Scripps Research Institute

  公开号：US09139596B2

  公开（公告）日：2015-09-22

  The invention provides prodrugs of DNA-reactive analogs of duocarmycin and CC-1065 anticancer agents, wherein a cyclic prodrug form, such as carbamate, thionocarbamate, or carbamimidate, can be hydrolyzed by the patient in vivo to yield a respective bioactive agent comprising a DNA-alkylating moiety and a binding/targeting moiety. The DNA-reactive moiety is a γ-spirocyclohexenone fused to a heterocyclyl group which can be produced by endogenous hydrolysis of a cyclic carbamate prodrug of the invention. The cyclic carbamate prodrug produces no residual byproduct during activation in vivo. Methods of synthesis and biological methods and data are also provided.

  该发明提供了DNA反应性类似物Duocarmycin和CC-1065抗癌剂的前药，其中环状前药形式，如氨基甲酸酯，硫酸氨基甲酸酯或氨基甲酰胺酯，可以在体内被患者水解，生成包含DNA烷基化基团和结合/靶向基团的相应生物活性剂。DNA反应性基团是γ-螺环己酮融合到杂环基团中，可以通过该发明的环状氨基甲酸酯前药的内源性水解产生。环状氨基甲酸酯前药在体内激活过程中不产生任何残留副产物。还提供了合成方法和生物方法和数据。
• Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Cyano-1,2,9,9a-tetrahydrocyclopropa[<i>c</i>]benz[<i>e</i>]indol-4-one Alkylation Subunit:  Hammett Quantitation of the Magnitude of Electronic Effects on Functional Reactivity
  作者：Dale L. Boger、Nianhe Han、Christine M. Tarby、Christopher W. Boyce、Hui Cai、Qing Jin、Paul A. Kitos

  DOI：10.1021/jo9605298

  日期：1996.1.1

  The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in efforts that establish the magnitude of potential electronic effects on the functional reactivity of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors followed by 5-exo-trig aryl radical-alkene cyclization for synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation for introduction of the activated cyclopropane. The most concise approach provided the CCBI subunit and its immediate precursor in 14-15 steps in superb overall conversions (15-20%). Resolution of an immediate CCBI precursor and its incorporation into both enantiomers of 34-39, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-CCBI (25) revealed that introduction of the C7 nitrile slowed the rate of solvolysis but only to a surprisingly small extent. Classical Hammett quantitation of the effect provided a remarkably small rho (-0.3), indicating an exceptionally small C7 substituent electronic effect on functional reactivity. Additional kinetic studies of acid-catalyzed nucleophilic addition proved inconsistent with C4 carbonyl protonation as the slow and rate-determining step but consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction, This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. Consistent with past studies, a direct relationship between solvolysis stability and cytotoxic potency was observed with the CCBI-derived agents providing the most potent analogs in the CBI series, and these observations were related to the predictable Hammett substituent effects. For the natural enantiomers, this unusually small electronic effect on functional reactivity had no perceptible effect on their DNA alkylation selectivity. Similar effects of the C7 cyano substituent on the unnatural enantiomers were observed, and they proved to be 4-10x more effective than the corresponding CBI-based unnatural enantiomers and 4-70x less potent than the CCBI natural enantiomers.
• US9139596B2
  申请人：——

  公开号：US9139596B2

  公开（公告）日：2015-09-22