Synthesis of [L-Ala-1]RA-VII, [D-Ala-2]RA-VII, and [D-Ala-4]RA-VII by Epimerization of RA-VII, an Antitumor Bicyclic Hexapeptide fr
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- 作者：Yukio Hitotsuyanagi ; Shin-ichi Sasaki ; Yuji Matsumoto ; Kentaro Yamaguchi ; Hideji Itokawa ; and Koichi Takeya
- 刊名：Journal of the American Chemical Society
- 出版年：2003
- 出版时间：June 18, 2003
- 年：2003
- 卷：125
- 期：24
- 页码：7284 - 7290
- 全文大小：238K
- 年卷期：v.125,no.24(June 18, 2003)
- ISSN：1520-5126
文摘
Three epimers of a natural cyclic hexapeptide RA-VII were prepared via formation of oxazolesfrom thioamides or thioimidates of RA-VII followed by hydrolysis. They are the epimers at L-Ala-1, D-Ala-2,and D-Ala-4, respectively. The one having L-Ala-1 adopted trans-cis-trans-trans-trans-trans (t-c-t-t-t-t) amideconfigurations in the crystal, a type-VI 
-turn for residues 1-4 stabilized by one intramolecular hydrogenbond between Ala-4 NH and L-Ala-1 C = O, and in CDCl3 existed as a mixture of six conformers, of whichthe major conformer was very similar to that in the crystal, but quite different from that of RA-VII in solution.The second epimer, having D-Ala-2 had in the crystalline state t-t-t-t-c-t amide configurations, a 
-turn atTyr-3 stabilized by two intramolecular hydrogen bonds between D-Ala-2 NH and Ala-4 C = O and betweenAla-4 NH and D-Ala-2 C = O, and existed in CDCl3 as a single conformer, the structure of which was verysimilar to its crystal structure, and to the crystal structure of peptide 25 except for the backbone and theside chains at residues 1 and 2. The third epimer, having D-Ala-4 had t-c-t-t-c-t amide configurations in thecrystal, a type-VI -turn for residues 1-4 as observed in the first epimer, and in CDCl3 existed in threeconformers, of which the major one was similar to that in the crystal but different from that of RA-VII insolution. The three epimers showed very weak cytotoxicity on P-388 leukemia cells, which may be becauseof their conformational differences from the active conformation of RA-VII.
-turn for residues 1-4 stabilized by one intramolecular hydrogenbond between Ala-4 NH and L-Ala-1 C = O, and in CDCl3 existed as a mixture of six conformers, of whichthe major conformer was very similar to that in the crystal, but quite different from that of RA-VII in solution.The second epimer, having D-Ala-2 had in the crystalline state t-t-t-t-c-t amide configurations, a -turn atTyr-3 stabilized by two intramolecular hydrogen bonds between D-Ala-2 NH and Ala-4 C = O and betweenAla-4 NH and D-Ala-2 C = O, and existed in CDCl3 as a single conformer, the structure of which was verysimilar to its crystal structure, and to the crystal structure of peptide 25 except for the backbone and theside chains at residues 1 and 2. The third epimer, having D-Ala-4 had t-c-t-t-c-t amide configurations in thecrystal, a type-VI -turn for residues 1-4 as observed in the first epimer, and in CDCl3 existed in threeconformers, of which the major one was similar to that in the crystal but different from that of RA-VII insolution. The three epimers showed very weak cytotoxicity on P-388 leukemia cells, which may be becauseof their conformational differences from the active conformation of RA-VII.