| Co-Investigator(Kenkyū-buntansha) |
MORITA Hiroshi Hokkaido University, Pharmacy, Associate Professor, 薬学部, 助教授 (70220069)
HITOTSUYANAGI Yukio Tokyo Uni.of Pharm. & Life Sci., Pharm., Associate Prof., 薬学部, 助教授 (80218726)
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| Research Abstract |
Antitumor cyclic hexapeptide RA-VII obtained from the roots of Rubia cordifolia and R.akane is a candidate for anticancer drugs from showing the potent antitumor activity, while it has unique action mechanism which inhibits protein synthesis, and the development as an anticancer drug is desired. In the clinical trial of RA-VII, some improvements such as small differences between effective and toxic dose areas and the water solubility as an injection were pointed out. In order to improve these points, various derivatives of RA-VII were prepared and they were estimated by various bio-assay. Namely, the N-alkyl derivatives of the Ala-2 residue, the chemical modifications of the amide carbonyl groups due to the Tyr-3 residue and O-alkyl derivatives of the Tyr-3 or -6 residues were prepared and supplied to in vitro and in vivo assays for antitumor activities. On the other hand, RA analogues prepared by condensing between isodityrosine moieties consisting of 14-membered ring and tetra-peptides suggested the information on the topology of the active expression sites and between the conformations and cytotoxic activities. Namely, a trans N-methyl amide type of two conformers due to the amide bond between the Ala-2 residue and the Tyr-3 residue was revealed to be an active principle. Also, the topology on the Tyr-3 residue and the conformations on 14- and 18-membered rings are important factors in the expression of cytotoxicity. In order to confirm these scope, we prepared further few RA-analogues, [Gly-1]RA-VII, [Gly-2]RA-VII, [Gly-4]RA-VII, [β-Ala-1]RA-VII, [β-Ala-2]RA-VII and [β-Ala-4]RA-VII and their cytotoxic activities were examined.
Searching studies for bio-active cyclic peptides from plant sources except for Rubia plants were also carried out and many novel cyclic peptides were found out from Vaccaria segetalis (Caryophyllaceae), Linum usitatissimum (Linaceae), Stellaria and Leonurus plants.
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