(5S,8S)-8-((S)-2-((S)-2-((S)-2-((R)-2-aminopropanamido)-N-methylpropanamido)-3-(4-methoxyphenyl)propanamido)propanamido)-36-methoxy-7-oxo-2-oxa-6-aza-1(1,4),3(1,3)-dibenzenacyclononaphane-5-carboxylic acid hydrochloride | 138571-41-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (5S,8S)-8-((S)-2-((S)-2-((S)-2-((R)-2-aminopropanamido)-N-methylpropanamido)-3-(4-methoxyphenyl)propanamido)propanamido)-36-methoxy-7-oxo-2-oxa-6-aza-1(1,4),3(1,3)-dibenzenacyclononaphane-5-carboxylic acid hydrochloride
• CAS: 138571-41-2
• 化学式: C₃₉H₄₈N₆O₁₀*ClH
• 分子量: 797.305
• InChiKey: UOQFJVZNIMLHBL-HHKLHWMWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  56.0
• 可旋转键数：
  13.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  227.72
• 氢给体数：
  6.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  (5S,8S)-8-((S)-2-((S)-2-((S)-2-((R)-2-aminopropanamido)-N-methylpropanamido)-3-(4-methoxyphenyl)propanamido)propanamido)-36-methoxy-7-oxo-2-oxa-6-aza-1(1,4),3(1,3)-dibenzenacyclononaphane-5-carboxylic acid hydrochloride 在 二苯基磷酸 、 碳酸氢钠 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.0h， 生成 N¹⁵,N²⁹-desmethyl RA-VII
  参考文献：
  名称：

  Synthesis of N29-desmethyl RA-VII. Identification of the pharmacophore of RA-I-VII and deoxybouvardin and reassignment of the subunit functional roles

  摘要：

  N29-Desmethyl RA-VII was prepared in efforts that address the key structural and conformational features of the agent that contribute to its antitumor activity.

  DOI：

  10.1021/jo00031a001
• 作为产物：
  描述：

  (5S,8S)-36-methoxy-8-((6R,9S,12S,15S)-12-(4-methoxybenzyl)-N,2,2,6,9,11,15-heptamethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-amido)-7-oxo-2-oxa-6-aza-1(1,4),3(1,3)-dibenzenacyclononaphane-5-carboxylic acid 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 以100%的产率得到(5S,8S)-8-((S)-2-((S)-2-((S)-2-((R)-2-aminopropanamido)-N-methylpropanamido)-3-(4-methoxyphenyl)propanamido)propanamido)-36-methoxy-7-oxo-2-oxa-6-aza-1(1,4),3(1,3)-dibenzenacyclononaphane-5-carboxylic acid hydrochloride
  参考文献：
  名称：

  N-Desmethyl Derivatives of Deoxybouvardin and RA-VII: Synthesis and Evaluation

  摘要：

  The synthesis of the complete set of seven N-desmethyl derivatives of RA-VII (8) are described. Thus, the synthesis of the four 14-membered cycloisodityrosine derivatives 21-24 and their coupling with the two tetrapeptides 32 and 33 followed by formation of the 18-membered ring with macrocyclization provided the full set of seven desmethyl derivatives 14-20 of RA-VII (8). The solution phase conformational properties of 8 and 14-20 were examined by 1D and 2D H-1 NMR to reveal the role of N-methylation on the key conformational aspects of the natural agents. In contrast to each of the simple cycloisodityrosine derivatives 21-24 which adopt a single, rigid solution conformation possessing a secondary or tertiary trans amide central to the 14-membered ring, the natural agents including 8 adopt a single predominant solution conformation (83-88%) that corresponds closely to the X-ray structure conformation which possesses an inherently disfavored cis C-30-N-29 tertiary amide central to the 14-membered cycloisodityrosine subunit. Moreover, this cis amide is the predominant conformation (85-95%) observed with N-29-desmethyl RA-VII (14) indicating that even a secondary C-30-N-29 amide adopts this inherently disfavored cis amide stereochemistry. The minor conformation of 8 observed in solution (12-17%) is shown to be derived from a minor cis C-8-N-9 tertiary amide which was not observed with its conversion to a secondary amide. Both N-9-desmethyl RA-VII (15) and N-9,N-29-desmethyl RA-VII (18) adopt exclusively a single solution conformation that corresponds to the major solution conformations of 8 and 14. This conformation contains a characteristic cis C-30-N-29 amide central to a type VI beta-turn and the cycloisodityrosine subunit, a trans C-8-N-9 amide central to a typical type II beta-turn capped with a tight Ala(4)-NH-O=C-Ala(1) hydrogen bond, and a trans C-14-N-15 N-methyl amide. In sharp contrast, removal of the N-15 methyl group within 16, 17, 19, and 20 results in the adoption of solution conformations possessing the inherently favored trans C-30-N-29 amide central to the cycloisodityrosine (14)-membered subunit. Thus, the N-15-methyl group within 8 is responsible for the agents adoption of the disfavored cis C-30-N-29 amide central to the cycloisodityrosine subunit. Importantly, preceding studies have defined the cycloisodityrosine subunit of 8 as the pharmacophore and, in a reversal of the initially assigned roles, revealed that it is the tetrapeptide housed in the 18-membered ring that induces and maintains the rigid, normally inaccessible cis C-30-N-29 amide conformation within the 14-membered cycloisodityrosine subunit. The studies detailed herein reveal that it is the N-15-methyl group that induces this conformational preference for the disfavored cis C-30-N-29 amide and that its removal results in a major conformational change with adoption of the trans C-30-N-29 amide and a loss of biological activity.Thus, the N-15-methyl group is essential for maintenance of the conformational and biological properties of 8; the N-9-methyl group is not essential, and its removal leads to exclusive population of a single biologically active conformation; and the N-29-methyl group once thought essential td the adoption of the C-30-N-29 cis amide is not essential, and its removal does not alter the conformational or biological properties of 8.

  DOI：

  10.1021/ja00133a010