86229-97-2Relevant academic research and scientific papers
Synthesis of [L-Ala-1]RA-VII, [D-Ala-2]RA-VII, and [D-Ala-4]RA-VII by epimerization of RA-VII, an antitumor bicyclic hexapeptide from rubia plants, through oxazoles
Hitotsuyanagi, Yukio,Sasaki, Shin-ichi,Matsumoto, Yuji,Yamaguchi, Kentaro,Itokawa, Hideji,Takeya, Koichi
, p. 7284 - 7290 (2007/10/03)
Three epimers of a natural cyclic hexapeptide RA-VII were prepared via formation of oxazoles from thioamides or thioimidates of RA-VII followed by hydrolysis. They are the epimers at L-Ala-1, D-Ala-2, and D-Ala-4, respectively. The one having L-Ala-1 adop
A new approach to the epimeric analogue of cyclic peptides: Epimerisation via oxazoles of RA-VII, an anti-tumour bicyclic hexapeptide from Rubia plants
Hitotsuyanagi, Yukio,Matsumoto, Yuji,Sasaki, Shin-ichi,Yamaguchi, Kentaro,Itokawa, Hideji,Takeya, Koichi
, p. 1535 - 1537 (2007/10/03)
[D-Ala-4]RA-VII (9) and [D-Ala-2]RA-VII (10) were prepared from RA-VII (1), an anti-tumour bicyclic hexapeptide from Rubia plants, by conversion of its thioamide 3 into oxazoles 4 and 5 and subsequent acid-catalysed hydrolysis.
Total synthesis of an antitumor agent RA-VII via an efficient preparation of cycloisodityrosine
Bigot, Antony,Tran Huu Dau, Marie Elise,Zhu, Jieping
, p. 6283 - 6296 (2007/10/03)
Details of efficient syntheses of (9S, 12S)-cycloisodityrosine (6) and a concise total synthesis of RAVII (1) were described. An intramolecular S(N)Ar-based cycloetherification reaction was employed as the key ring- closure step for construction of the illusive 14-membered m,p-cyclophane. Treatment of methyl N-[N-(tert-butyloxycarbonyl)-L-(3-hydroxy-4- methoxyphenylalanyl]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)-10) with potassium carbonate in DMSO at room temperature provided a mixture of two atropdiastereomers 20a and 20b in 75% yield that were transformed into cycloisodityrosine 6 in good overall yield. Furthermore, a size-selective ring-forming process was established for methyl N-[N-(tert-butyloxycarbonyl)- L-(3,4-dihydroxyphenylalanyl)]-L-4-fluoro-3-nitrophenylalaninate ((9S,12S)- 11). Thus, cyclization of 11 (K2CO3, DMSO, rt), followed by in situ methylation, gave exclusively the 14-membered m,p-cyclphane 20a and 20b without competitive formation of the alternative 15-membered p,p-cyclophane. The selective ring-forming process allowed us to develop one of the shortest and the most efficient synthesis of cycloisodityrosine to date. Computational studies have shown that it was the elimination, but not the addition, step that determined the ring-size selectivity observed in the cyclization of substrate 11. Coupling of 6 with L-N-Boc-Ala (51) proceeded efficiently to provide the corresponding tripeptide 52 that, after removal of the N-Boc function, was allowed to react with another tripeptide 53 to afford the hexapeptide 50 in good overall yield. Saponification followed by liberation of amino function from 50 gave the seco-acid, whose cyclization (DPPA, DMF, NaHCO3) afforded the natural product RA-VII (1).
Studies on Rubia akane (RA) derivatives. Part 8. Design, syntheses and antitumour activity of cyclic hexapeptide RA analogues possessing an alkyl substituent on the Tyr-3 aromatic ring
Hitotsuyanagi, Yukio,Lee, Suguru,Ito, Izumi,Kondo, Kazuyuki,Takeya, Koichi,Yamagishi, Takehiro,Nagate, Takatoshi,Itokawa, Hideji
, p. 213 - 217 (2007/10/03)
The effective conversion of RA-VII 1 into the naturally less-accessible RA-II 4 has been devised through boron tribromide bis-O-demethylation and successive selective partial O-methylation using diazo(trimethylsilyl)methane. The O-triflate 11 prepared from RA-II 4 was subjected to cross-coupling reaction with alkylstannanes to produce analogues 12, 13 and 15, while compounds 13 and 15 were later converted into analogues 14 and 16, respectively. Analogues 12-16 showed antitumour activity against P-388 leukaemia both in vitro and in vivo.
Regioselective synthesis of 14-membered biaryl ethers: Total synthesis of RA-VII and deoxybouvardin
Inoue,Inaba,Umezawa,Yuasa,Itokawa,Ogura,Komatsu,Hara,Hoshino
, p. 1325 - 1335 (2007/10/02)
In order to obtain a key compound (22a'') for synthesis of RA-VII (1) and deoxybouvardin (2), construction of the 14-membered ring system was performed by means of thallium trinitrate-mediated oxidation of the tetrahalogeno amides 5-7. The dibromo dichlor
Total synthesis of cycloisodityrosine, RA-VII, deoxybouvardin, and N29-desmethyl-RA-VII: Identification of the pharmacophore and reversal of the subunit functional roles
Boger, Dale L.,Yohannes, Daniel,Zbou, Jiacheng,Patane, Michael A.
, p. 3420 - 3430 (2007/10/02)
Full details of a concise total synthesis of RA-VII (1) and deoxybouvardin (2) are described based on the implementation of an effective intramolecular Ullmann reaction as the key macrocyclization reaction in the preparation of the elusive 14-membered cycloisodityrosine subunit (33) of the bicyclic hexapeptides. Subsequent coupling of 34 to tetrapeptide 17 and macrocyclization with C2-N3 amide bond formation provided 1 and 2. In efforts that address the key structural and conformational features of the agents that contribute to their antitumor activity, N29-desmethyl-RA-VII was prepared and its chemical, conformational, and preliminary biological properties are detailed. The comparable conformational features of N29-desmethyl-RA-VII and RA-VII including a characteristic cis C30-N29 amide bond suggest that the tetrapeptide housed within the 18-membered ring induces the 14-membered cycloisodityrosine to adopt a conformation possessing an inherently disfavored cis secondary or tertiary amide. Moreover, in contrast to prior suppositions in which the rigid 14-membered ring of N-methylcycloisodityrosine has been suggested to serve the functional role of inducing a rigid, normally inaccessible conformation within the biologically relevant D-Ala-Ala-N-Me-Tyr-(OMe)-Ala tetrapeptide, experimental studies demonstrating that the intrinsic activity of the agents resides within the cycloisodityrosine subunit are presented. Thus, the results of the experimental studies require a reversal of the functional roles of the subunits of the agents in which it is the tetrapeptide housed within the 18-membered ring that potentiates the inherent biological properties and alters the conformation of cycloisodityrosine.
