The mode of action of the antitumor drug bouvardin, an inhibitor of protein synthesis in eukaryotic cells

Abstract

Bouvardin is an antitumor drug that inhibits protein synthesis in intact eukaryotic cells and cell-free systems. Our present studies have shown that bouvardin acts at the level of the 80 S ribosome in a site somehow involved with the interaction of EF1 and EF2. Indeed bouvardin inhibits EF1-dependent binding of aminoacyl-tRNA and EF2-dependent translocation of peptidyl-tRNA but does not affect the nonenzymic translocation since this reaction does not require EF2. The site of the 80 S ribosome involved in the interaction with bouvardin appears to be independent from the cycloheximide and the cryptopleurine binding sites since yeast mutants resistant to cycloheximide or cryptopleurine are sensitive to bouvardin.

Isolation, Structure Determination, and Synthesis of Allo‐RA‐V and Neo‐RA‐V, RA‐Series Bicyclic Peptides from Rubia cordifolia L.

“…[5,6] In addition, peptide 1 also causes conformational changes in F-actin, which stabilizes the actin filaments and induces G2 arrest. [7] Herein, we report the isolation and structural elucidation of two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), along with the known RA-series peptides from the roots of Rubia cordifolia L. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the stereochemistry of compound 6 was established by chemical Abstract: Two bicyclic hexapeptides, allo-RA-V (4) and neo-RA-V (5), and one cyclic hexapeptide, O-seco-RA-V (6), were isolated from the roots of Rubia cordifolia L. Their gross structures were elucidated on the basis of spectroscopic analysis and X-ray crystallography of compound 5.…”

Fast atom bombardment mass spectrometry of bouvardin and selected analogs

“…Some common fragments include all of those ions indicated for compounds 1,2 and 3 in Scheme 2 which lead to the base peak. The base peak, however, is not m/z164 but rather m / z 150, which is tentatively assigned (CH,-NH=CHCH,C,H,-OH)+ arising from the two N-methylated tyrosines present in 4 instead of one pair of preferred fragments as seen with compounds 1-3. The most notable difference in the spectrum of 4 is the absence of fragments corresponding to the phenolic ring-retaining fragments in Scheme 1 for 1-3.…”

“…Another comparison illustrating the fragmentinducing function of the coupled tyrosine residues is provided by the FAB mass spectrum of a synthetic hexapeptide analog of bouvardin 4 (Fig. 3), which does not contain the phenolic-bridged 14-membered ring.…”

“…The most recent biochemical study on the mode of action of 1 shows this hexapeptide acts at the level of the 80s ribosome and, although the exact site is yet unknown, the interaction of bouvardin with the ribosome occurs at a previously undefined ribosomal binding site. 4 Structurally bouvardin is comprised of three alanines and three modified N-methyltyrosines, constituting an 18-membered ring. Fused to the 18-membered ring is an unusual 14-membered ring formed by the oxidative coupling of the phenolic rings of two adjacent tyrosines6 The 14-membered ring in bouvardin is also unique in that it contains a cis peptide bond, a feature which is not present in other cyclic hexapeptides.…”

New Cytotoxic Bicyclic Hexapeptides, RA-XXIII and RA-XXIV, from Rubia cordifolia L.

“…3) Their antitumor action is considered to be due to inhibition of protein synthesis through interaction with eukaryotic ribosomes, 4,5) and peptide 1 is known to cause conformational changes in F-actin and stabilization of actin filaments to induce G2 arrest. 6) In the present study, two new RA-series peptides, RA-XXIII (2) and RA-XXIV (3), were further isolated from the roots of R. cordifolia.…”