104(P-24) チオノペプチドを経由する抗腫瘍性環状ペプチドRA-VIIの化学修飾(ポスター発表の部)

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Substitution of a particular L-amino acid by a D-amino acid in a biologically active peptide is a common method to provide analogues resistant to enzymatic degradation. Such analogues are also useful for the tools to identify the active sites of the parent peptide and their topology responsible for expressing the activity in combination with conformational analysis. Although the D-amino acid analogues of linear peptides composed of standard amino acids are prepared in a straightforward manner, it is a difficult task to prepare such analogues in the case of cyclic peptides since their construction inevitably requires elusive macrocyclization reactions. Also, in many cases biologically important cyclic peptides of natural origin include less accessible unusual amino acids. We have developed a new method from natural cyclic peptides to provide their epimers via thionopeptide intermediates, which was delineated by using RA-VII (1), an antitumor bicyclic hexapeptide originated from Rubia plants. Monothioamides 2 and 3 were prepared from peptide 1. Thioamide 2 was then converted into thioiminoethers 11a and 11b. Treatment of 11a or 11b with AgBF_4 afforded oxazole 8 as a major product, whereas oxazole 9 and acetimide 10 were produced when they were treated with Hg(OAc)_2. In the same manner, oxazoles 8, 9 and 13 were obtained from 3 via thioiminoethers 12a or 12b. Hydrolysis of oxazoles 8, 9 and 13 proceeded under mild conditions to afford [D-Ala-4]RA-VII (14), [D-Ala-2]RA-VII (15) and [L-Ala-1]RA-VII (16), respectively. Their structures were established by X-ray crystallography. The ROESY experiments suggested that the major solution form of each analogue was very similar to the corresponding crystal structure, and none of them resembled that of RA-VII (1). Analogues 14-16 were more than 100 times less cytotoxic than peptide 1 when tested on P-388 murine leukemia cells. Their reduced activity will be accounted for by the changes in the stereostructures.
天然有機化合物討論会の論文
2000-10-01

104(P-24) チオノペプチドを経由する抗腫瘍性環状ペプチドRA-VIIの化学修飾(ポスター発表の部)

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