Synthesis of [Gly-1]RA-VII, [Gly-2]RA-VII, and [Gly-4]RA-VII. Glycine-containing analogues of RA-VII, an antitumor bicyclic hexapeptide from Rubia plants.
Three analogues of RA-VII (1), an antitumor bicyclic hexapeptide from Rubia plants, were synthesized. Three analogues, [Gly-1]RA-VII (4), [Gly-2]RA-VII (5), and [Gly-4]RA-VII (6), in which one of the three alanine residues in 1 was replaced by a glycine residue, were prepared by linking of the cycloisodityrosine unit, obtained by degradation of 1, to three different glycine-containing tetrapeptides followed by macrocyclization. Of these three analogues, analogue 4 showed the highest cytotoxic activity. The NMR study revealed that in solution the conformer structures and their ratios of analogue 4 were very similar to those of natural peptide 1, suggesting that the methyl groups at Ala-2 and Ala-4 should be essential for producing the bioactive conformation, whereas that at D-Ala-1 is not essential.
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
Yukio
Y
Hitotsuyanagi
Tomoyo
T
Hasuda
Takayuki
T
Aihara
Hiroshi
H
Ishikawa
Kentaro
K
Yamaguchi
Hideji
H
Itokawa
Koichi
K
Takeya
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D005998:Glycine / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D011487:Protein Conformation; D045470:Rubia / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D001643:Bridged Bicyclo Compounds; D010456:Peptides, Cyclic; C043548:RA VII; D005998:Glycine