16-Amino-5-bromo-4-hydroxy-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaen-11-one | 907602-23-7

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 大环内酰胺类
• 英文名称: 16-Amino-5-bromo-4-hydroxy-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaen-11-one
• CAS: 907602-23-7
• 化学式: C₁₇H₁₇BrN₂O₃
• 分子量: 377.238
• InChiKey: FRZBSKDYTIMNOE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  23
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  84.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  16-Amino-5-bromo-4-hydroxy-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaen-11-one 在 溶剂黄146 、 sodium nitrite 、 sodium azide 作用下， 反应 0.75h， 以66%的产率得到16-Azido-5-bromo-4-hydroxy-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaen-11-one
  参考文献：
  名称：

  Simplified Cyclic Analogues of Bastadin-5. Structure−Activity Relationships for Modulation of the RyR1/FKBP12 Ca²⁺ Channel Complex

  摘要：

  Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient SNAr macroetherification, and evaluated in an assay that measures [H-3]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (+/-)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 mu M), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 mu M) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.

  DOI：

  10.1021/jm050708u
• 作为产物：
  描述：

  methyl 3-(4-fluoro-3-nitrophenyl)propanoate 在 chromium dichloride 、 lithium hydroxide 、 4 A molecular sieve 、 三溴化硼 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.0h， 生成 16-Amino-5-bromo-4-hydroxy-2-oxa-10-azatricyclo[12.2.2.13,7]nonadeca-1(16),3,5,7(19),14,17-hexaen-11-one
  参考文献：
  名称：

  Simplified Cyclic Analogues of Bastadin-5. Structure−Activity Relationships for Modulation of the RyR1/FKBP12 Ca²⁺ Channel Complex

  摘要：

  Bastadin-5, a brominated macro-dilactam from the marine sponge Ianthella basta, enhances release of Ca2+ from stores within the sarcoplasmic reticulum (SR) of muscle and nonmuscle cells by modulating RyR1/FKBP12 complex. Analogues of bastadin-5 present desirable targets for SAR studies to shed light on the gating mechanism and locus of bastadin-5 binding on these heteromeric channels that mediate essential steps in early coupling of membrane excitation to Ca2+ signaling cascades. Simple, ring-constrained analogues of bastadin-5 were synthesized from substituted benzaldehydes in a convergent manner, featuring an efficient SNAr macroetherification, and evaluated in an assay that measures [H-3]-ryanodine that is known to correlate with the functional open state of the Ca2+ channel. The simplified 14-membered ring, atropisomeric analogue (+/-)-7, like bastadin-5, enhanced ryanodine binding to the RyR1/FKBP12 complex (EC50 11 mu M), however, unexpectedly, the corresponding achiral 18-membered ring analogue 14 potently inhibited binding (IC50 6 mu M) under the same conditions. Structure-activity relationships of both families of cyclic analogues showed activity in a ryanodine binding assay that varied with substitutions of the Br atom on the trisubstituted aryl ring by various functional groups. The most active analogues were those that conserved the dibromocatechol ether moiety that corresponds to the 'western edge' of the bastadin-5 structure. These data suggest that cyclic analogues of bastadin-5 interact with the channel complex in a complex manner that can either enhance or inhibit channel activity.

  DOI：

  10.1021/jm050708u