Identification of the structural requirements of RA-series peptides for expressing antitumor activity useful for designing novel antitumor drugs.

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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.