2007 Fiscal Year Final Research Report Summary
Identification of the structural requirements of RA-series peptides for expressing antitumor activity useful for designing novel antitumor drugs.
| Project/Area Number |
16590015
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Chemical pharmacy
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
HITOTSUYANAGI Yukio Tokyo University of Pharmacy and Life Science, School of Pharmacy, Associate Professor (80218726)
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| Project Period (FY) |
2004 – 2007
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| Keywords | RA-VII / peptide / cycloisodityrosne / cytotoxicity / analogue / conformer / akane / Rubia |
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| Research Abstract |
Eight new cytotoxic bicyclic hexapeptides, RA-XVII-RA-XXIV, were isolated from the roots of Rubia cordifolia L., and their structures were determined by the analysis of spectroscopic data, chemical methods, and X-ray crystallography. Practical synthetic methods of N-mehyl- and N,N'-dimethyl-cycloisodityrosines, key intermediates for the syntheses of the natural RA-series peptides and their analogues, from commercially available 3-iodo-L-tyrosine were developed. To investigate the structural requirements for adopting the active conformation, analogues of RA-VII with an extended alkyl side chain at D-Ala-1, analogues in which one of the three alanine residues in RA-VII was replaced by a glycine residue, analogues in which Ala-2 of RA-VII was replaced by an aromatic amino acid, a conformationally restricted analogue modified at Tyr-3, a des-N-methylated analogue at Tyr-5, analogues having a substituent on the aromatic ring of Tyr-6, and a per-N-methylated analogue of RA-VII were synthesized. Conformational analysis and cytotoxicity assay of those analogues indicated that (1) the methyl groups at Ala-2 and Ala-4 and the N-methyl group at Tyr-5 should be essential for producing the bioactive conformation, whereas that at D-Ala-1 is not essential ; (2) introduction of an aromatic ring at the side chain of Ala-2 resulted in reduction of the activity ; (3) introduction of a substituent on the aromatic ring of Tyr-6 decreases the activity ; (4) introduction of /V-methy groups at three alanine residues produced an analogue with unique conformational properties and much reduced activity.
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