Bouvardins

Cyclic hexapeptides can be considered as the classical and the most prominent representatives among cyclic peptides. Natural products are numerous and widespread (see Scheme 11), e.g. segetalin A,[278] bouvardin/279280 RA-IIlJ281-283 or pneumocandin B0,[284 286] and this type of ring structure has frequently been used to stabilize conformational preferences of bioactive portions of larger peptides or even proteins. 

Scheme 11 Structures of the Naturally Occurring Cyclic Hexapeptides Segetalin A, 2781 Bouvardin, 279-2801 Pneumocandin b, 284-2861 and of a Synthetic Cyclic Somatostatin Analogue 2871...

Macrolactamization has limitations. All macrolactamization methods studied to date are ineffective at forming 14-membered cycloisodityrosines of the type found in deoxy-bouvardin (2) and RA-VII (3).[1° In addition, macrolactamization was not successful at preparing 16-membered rings that are structurally similar to cycloisodityrosines, such as the type found in the vancomycin family of glycopeptide antibiotics.[11 12 ... 

N-Alkylation is an important modification of the peptide bond. In particular, N-methylation is widespread and commonly occurs in natural peptides from plants, marine sources, and various microorganisms. Several of these compounds have important biological activity, such as antibiotic (e.g., enniatins, 1 monamycins, 2 echinomycin 3 ), antitumor (e.g., bouvardin, 4 dolastatin 56 ) and immunosuppressor activity (e.g., cyclosporin 7 ). For reviews see refs 8-10. ... 

Borneol acetate 10.4t, 10.5t Bornyl acetate 10.4t, 10.5t Boswellic acid 13.4Ht Bougainmlka RIP-I 9.1A Bouvardin 9.2a Bowringia lectin 12.2A Bradykinin 5.7B Bran 14.2o Brassica DEF PI 13.5J... 

Bouvardin (165) as the first compound of this type of cyclic hexapeptide to be isolated from Bouvardia ternifolia belonging to Rubiaceae, was isolated by Cole et al [85]. 

Moreover recently, mechanistic studies using purified elongation factors and ribosomes identified RA-VII as a peptidyl transferase inhibitor. Thus similar to the related natural products bouvardin (165) and RA-XII (158), RA-VII (153) appears to function by binding to eukaryotic ribosomes [88]. 

RA-V is the same compound as deoxybouvardin (151). Bouvardin (165) has been investigated for development as an antitumor drug at the U.S. NCI. Adryamycin has CH2OH instead of CH3 as in daunomycin. With such minor chemical differences, adryamycin was revealed to have a much stronger activity and less toxicity than daunomycin. Therefore, it is expected that RA-VII will show different activity from that of bouvardin. RA-VII (RA-700) was under investigation for phase I clinical trials at the NCI in Japan. 

Bouvardin (165), originally isolated in 1977 from Bouvardia ternifolia (Rubiaceae), was the first member of the RA family and its solid state... 

Later, the crystal structures of RA-VI (152) (Fig. 25) [95] and isomerized RA-VII (174) (Fig. 26) [96], neither showing antitumor activity, were reported. The backbone conformation of these molecules differ from that of the 18-membered ring of RA-VII and bouvardin. 

The presence of two conformers in chloroform solution was suggested by HPLC analysis [97]. However, separation on a preparative scale was not achieved because of fast exchange at room temperature. Conformational analysis of the two states in chloroform solution was performed using NMR and computational methods. R. B. Bates et al. indicated that the predominant stereoisomer and conformer in solution for deoxybouvardin and bouvardin is the same as that found in the solid state by X-ray diffraction [98]. A minor stereoisomer (ca. 15%) separated by a 20.6 kcal/mol barrier was detected and is believed to contain a rotation about the Tyr and/or Tyr amide bond, however its precise conformation could not be deduced. 

Fig. 24. Perspective view of the X-ray structure of RA-V p-bromobenzoate. The backbone conformation possesses almost the same characteristics as bouvardin (Fig. 23).

A cyclic hexapeptide, bouvardin (28), isolated from Bouvardia temifolia, shows high cytotoxic properties through inhibiting the division of hamster ovary cells. 

Figure 14. Bouvardin with a cyclic hexapeptide backbone without any intraannular hydrogen bonds (Jolad et a/., 1977).

Stems, leaves, and flowers of Bouvardia ternifolia (Rubiaceae) from Mexico were shown to contain cytotoxic and antitumor compounds. Fractionation revealed two cyclic hexapeptides, bouvardin (26) and deoxybouvardin (27) (Fig. 37.8) (Suffness and Cordell, 1985). The antitumor effects of these compounds were attributed to the ability of these compounds to inhibit protein synthesis because of an effect on the 80-S ribosome. Similar compounds have been found to be the antitumor principles of Rubia akane and R. cordi-folia (Suffness and Cordell, 1985). 

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