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

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. The absolute stereochemistry of compounds 4 and 5 were established by their total syntheses, and the absolute stereochemistry of compound 6 by chemical correlation with deoxybouvardin (3). Comparison of the 3D structures of highly active RA-VII (1) with less-active compounds 4 and 5 suggests that the orientation of the Tyr-5 and/or Tyr-6 phenyl rings plays a significant role in their biological activity. The isolation of peptides 4-6, along with compound 3, and the comparison of their structures seem to indicate that peptide 6 may be the common precursor to bicyclic peptides 3-5 in the plant.

Structural and bioactive studies of terpenes and cyclopeptides from the Genus Rubia

“…Just in last year, Y. Hitotsuyanagi etc . got a series of special cyclopeptides from the Genus Rubia [62,63]. …”

“…RYs I-III (100–102), RA-700 (104), and RC-18 (105) possessed only medium activities against P388 [56]–[58,60,61]. The newly identified compounds 106–108, and RA-V, VII were evaluated for their cytotoxic activities against HL-60 and HCT-116 while only the latter had potent cytotoxicities [62]. Moreover, compound 109 exhibited cytotoxic effects on HL-60 cells, but which was much weaker than those of RA-XXIV and RA-VII [63].…”

RA‐dimer B, a New Dimeric RA‐series Cyclopeptide Incorporating Two Different Types of Cycloisodityrosine Units, from Rubia cordifolia L.

“…[15,16] O-Seco-deoxybouvardin (16)h as been isolated from this plant as ap ossible biosynthetic precursor of deoxybouvardin (4)a nd allo-RA-V (5). [9,17] RA-dimer B( 3)m ay be biosynthesized by oxidative couplingo f16 with 4 to produce dimeric inter-mediate 17 and the subsequento xidative formation of the diphenyle ther ring of the allo-RA-V unit of 3 (Scheme 3). Alternatively, the biosynthesis of peptide 3 may occur by the direct oxidative coupling of deoxybouvardin (4)w ith allo-RA-V (5).…”

“…[6,7] Peptide 1 hasa lso been shown to induce conformationalc hanges in F-actin, therebys tabilizing actin filaments and inducing G2 arrest. [8] In the present study,w ee xamined in detail the peptidec omponents in the roots of R. cordifolia and isolated an ew dimericp eptide, RA-dimer B( 3), comprising one molecule of deoxybouvardin (4) [1][2][3] and one molecule of allo-RA-V (5) [9] linked by an ether linkage. In this paper,w ed e-scribe the isolation and structured etermination of RA-dimer B (3).…”

Synthesis of the Rubiyunnanin B Core Aglycon

“…Deoxybouvardin ( 4 ) exhibits IC 50 concentrations between 0.001 and 0.014 µg/mL against various cancer cell lines; however, the glycosylated variant, RA‐XII, exhibits IC 50 values substantially higher between 1.8 and 10 µg/mL . Conversely, rubiyunnanin B possesses a glycosylated tyrosine with measured IC 50 values between 3.6 and 31 µg/mL, whereas the aglycon does not possess antitumor activity (IC 50 > 100 µg/mL) , …”