107(P38) 抗腫瘍性環状ヘキサペプチドRA-VIIの骨格変換(ポスター発表の部)

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RA-VII (1) is a bicyclic hexapeptide isolated from Rubia akane and R. cordifolia (Rubiaceae) and closely related to bouvardin (NSC 259968, 2) from Bouvardia ternifolia.. These peptides possess potent antitumor activity against various tumor models. Although the l4-membered cycloisodityrosine moiety is identified as the pharmacophore unit for this class of antitumor agents, the role of the 18-membered ring moiety composed of the tetrapeptide, D-Ala-1-Ala-2-Tyr-3-Ala-4, for the activity still remains to be clarified. To obtain information about structure/conformation-activity relationships of the 18-membered ring moiety and to obtain analogs which might express more promising biological properties, we studied backbone modification of peptide 1. The amide nitrogen of Ala-2 residue was effectively alkylated under phase-transfer catalysis conditions. By using this method, various N-alkylated analogs including potentially water-soluble ones were synthesized. Some of those analogs showed more promising antitumor activity than the parent peptide 1 in terms of T/C values. When peptide 1 was treated with Lawesson's reagent (6), thionopeptides 7 and 8 were obtained in yields of 80 and 3%, respectively. Alternatively, treatment of 1 with Davy reagent methyl (17) or Davy reagent p-tolyl (18) produced thionopeptides 19-21 in addition to 7 and 8. These thionopeptides retained potent activity, and an NMR study revealed that their solution conformation is almost identical to that of peptide 1. Compound 7 was further transformed into desoxopeptde 22, epi-analog 25, dehydroanalog 27 and seco-analog 28. Compound 27 showed only weak activity, and compounds 22, 25 and 28 showed no activity. These results suggested that the 18-membered ring structure, especially the orientaion of the p-methoxybenzyl side chain of the Tyr-3 residue, is important for full expression of the activity.
天然有機化合物討論会の論文
1996-09-02

107(P38) 抗腫瘍性環状ヘキサペプチドRA-VIIの骨格変換(ポスター発表の部)

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