RA-VII | 137606-77-0

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物
• 英文名称: RA-VII
• 英文别名: N⁹-desmethyl RA-VII；(N-demethyl-Tyr-3)RA-VII；(1S,4R,7S,10S,13S,16S)-24-methoxy-10-[(4-methoxyphenyl)methyl]-4,7,13,15,29-pentamethyl-22-oxa-3,6,9,12,15,29-hexazatetracyclo[14.12.2.218,21.123,27]tritriaconta-18,20,23,25,27(31),32-hexaene-2,5,8,11,14,30-hexone
• CAS: 137606-77-0
• 化学式: C₄₀H₄₈N₆O₉
• 分子量: 756.856
• InChiKey: OUPSIOVRPPULCC-LZQLRFBTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  55
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  185
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-甲氧基-L-苯丙氨酸 在 盐酸 、 lithium hydroxide 、 二苯基膦叠氮化物 、 碳酸氢钠 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 99.0h， 生成 RA-VII
  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

文献信息

• Conformational analysis of (N-demethyl-tyr(OCH3)-3)Ra-VII, conformationally restricted model approach.
  作者：Hideji ITOKAWA、Keiko SAITOU、Hiroshi MORITA、Koichi TAKEYA

  DOI：10.1248/cpb.39.2161

  日期：——

  A molecular design was carried out in a way that locked the type II β-turn conformation of RA-VII, which was isolated from Rubia cordifolia and R.akane, by removing the N-methyl group of the Tyr-3 residue. Conformational analysis of [N-Demethyl-Tyr(OCH3)-3]RA-VII, derived from RA-VII by hepatic microsomal biotransformation, was conducted by 2D-NMR techniques, temperature effect on NH protons, and NOE experiments. It showed a restricted conformational state with a typical type II β-turn structure between Ala-2 and Tyr-3 in solution.

  通过去除 Tyr-3 残基的 N-甲基，以锁定 RA-VII 的 II 型 β 转构象的方式进行了分子设计。通过二维核磁共振技术、温度对 NH 质子的影响以及 NOE 实验，对通过肝脏微粒体生物转化从 RA-VII 中得到的 [N-Demethyl-Tyr(OCH3)-3]RA-VII 进行了构象分析。它在溶液中显示出一种限制性构象状态，Ala-2 和 Tyr-3 之间具有典型的 II 型 β 转结构。
• N-Desmethyl Derivatives of Deoxybouvardin and RA-VII: Synthesis and Evaluation
  作者：Dale L. Boger、Jiacheng Zhou

  DOI：10.1021/ja00133a010

  日期：1995.7

  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.