Elsevier

Tetrahedron

Volume 64, Issue 18, 28 April 2008, Pages 4117-4125
Tetrahedron

Structures of cytotoxic bicyclic hexapeptides, RA-XIX, -XX, -XXI, and -XXII, from Rubia cordifolia L.

https://doi.org/10.1016/j.tet.2008.01.094Get rights and content

Abstract

Novel bicyclic hexapeptides, RA-XIX, -XX, -XXI, and -XXII, were isolated from the roots of Rubia cordifolia L. The structures of RA-XIX and RA-XX were established by semisynthesis from a cycloisodityrosine, derived from previously reported RA-VII, and those of RA-XXI and RA-XXII by chemical correlation with RA-XX and previously reported RA-VIII, respectively. The IC50 values of these new peptides against P-388 leukemia cells were 0.013–0.63 μg/mL.

Introduction

RA-VII (1)1, 2 and bouvardin (NSC 259968, 2)3 are tumor cell growth inhibitors isolated from the plants, Rubia cordifolia L. (Rubiaceae) and Bouvardia ternifolia (Cav.) Schltdl. (Rubiaceae), respectively. Their structures are characterized by the presence of a 14-membered strained ring, an unusual cycloisodityrosine unit, formed by an ether linkage between the two aromatic rings of Tyr-5 and Tyr-6. Their antitumor action is considered to be due to inhibition of protein synthesis through interaction with eukaryotic ribosomes.4, 5 Recently, RA-VII (1) was shown to cause conformational changes in F-actin and stabilization of actin filaments to induce G2 arrest.6 In our further studies on the cyclopeptide constituents in the roots of R. cordifolia, four new RA-series peptides, RA-XIX (3), -XX (4), -XXI (5), and -XXII (6), were isolated. This paper describes their isolation, structure determination, and cytotoxicity against P-388 cells.

Section snippets

Results and discussion

A methanol extract obtained from dried roots of R. cordifolia (50 kg) was partitioned between chloroform and water. The chloroform-soluble portion was subjected to a series of column chromatography using silica gel, alumina, and then aminopropyl-bonded silica gel eluting with a series of chloroform/methanol mixtures to give a fraction rich in RAs. The residue of this fraction, obtained after removal of the solvent, was crystallized from methanol to give crystals of crude RAs, which, after

General

Melting points were determined on a Yanaco MP-3 apparatus and are recorded uncorrected. Optical rotations were measured on a JASCO P-1030 digital polarimeter, IR spectra on a JASCO FT/IR 620 spectrophotometer, and UV spectra on a JASCO V-530 spectrophotometer. NMR spectra were measured on a Bruker DRX-500 spectrometer at 300 K. The 1H chemical shifts in CDCl3 or CD3OD were referenced to the residual CHCl3 (7.26 ppm) or CD2HOD (3.31 ppm), and the 13C chemical shifts were referenced to the solvent

References and notes (14)

  • H. Itokawa et al.
  • M. Zalacaín et al.

    FEBS Lett.

    (1982)
  • B.V. Sirdeshpande et al.

    Bioorg. Chem.

    (1995)
  • H. Fujiwara et al.

    Cancer Lett.

    (2004)
  • H. Morita et al.

    Tetrahedron

    (1991)
  • H. Itokawa et al.

    Tetrahedron

    (1991)
  • H. Itokawa et al.

    Chem. Pharm. Bull.

    (1983)
There are more references available in the full text version of this article.

Cited by (17)

View all citing articles on Scopus
View full text