Studies on Rubia akane(RA) derivatives. Part 10. Backbone transformation of RA-VII, an antitumour cyclic hexapeptide, through thionation. X-Ray crystal structure of [Tyr-3-Ψ(CH2NH)-Ala-4]RA-VII

RA-VII 1 was thionated with Davy reagent methyl 6 or Davy reagent p-tolyl 7 to afford novel thionopeptides, [Tyr-6-Ψ(CS-NH)-D-Ala-1]RA-VII 8, [D-Ala-1-Ψ(CS-NH)-Ala-2; Tyr-3-Ψ(CS-NH)-Ala-4]RA-VII 9 and [Ala-2-Ψ(CS-NH)-Tyr-3; Tyr-3-Ψ(CS-NH)-Ala-4]RA-VII 10 in addition to known analogues [Tyr-3-Ψ(CS-NH)-Ala-4]RA-VII 4 and [Tyr-3-Ψ(CS-NH)-Ala-4; Tyr-6-Ψ(CS-NH)-D-Ala-1]RA-VII 5. Thionopeptide 4 was reduced with nickel borohydride to give reduced peptide 11. An X-ray analysis and an NMR study revealed that compound 11 adopts a different conformation within the 18-membered-ring moiety from the predominant solution conformation of peptide 1 and of thionopeptides 4, 5, 8–10, which would explain the loss in activity of compound 11.

[1]  H. Itokawa,et al.  Antitumor substances from higher plants , 2010 .

[2]  H. Matter,et al.  Unusual thionation of a cyclic hexapeptide. Conformational changes and dynamics. , 2009, International journal of peptide and protein research.

[3]  J. Bali,et al.  Synthesis of pseudo-peptide analogues of the C-terminal tetrapeptide of gastrin and evaluation of their biological activity on acid secretion. , 2009, International journal of peptide and protein research.

[4]  K. Clausen,et al.  The geometry of the thiopeptide unit. , 2009, International journal of peptide and protein research.

[5]  R. Hanzlik,et al.  Peptidyl thioamides as substrates and inhibitors of papain, and as probes of the kinetic significance of the oxyanion hole. , 1994, Biochimica et biophysica acta.

[6]  H. Itokawa,et al.  Studies on RA derivatives. V. Synthesis and antitumor activity of Ala2-modified RA-VII derivatives. , 1993, Chemical & pharmaceutical bulletin.

[7]  D. Boger,et al.  Total synthesis of cycloisodityrosine, RA-VII, deoxybouvardin, and N29-desmethyl-RA-VII: Identification of the pharmacophore and reversal of the subunit functional roles , 1993 .

[8]  F. Opperdoes,et al.  Selective Inhibition of Trypanosomal Triosephosphate Isomerase by a Thiopeptide , 1992 .

[9]  T. Moody,et al.  Metabolic stability and tumor inhibition of bombesin/GRP receptor antagonists , 1992, Peptides.

[10]  D. Boger,et al.  Synthesis of N29-desmethyl RA-VII. Identification of the pharmacophore of RA-I-VII and deoxybouvardin and reassignment of the subunit functional roles , 1992 .

[11]  P. Kitabgi,et al.  Reduced peptide bond pseudopeptide analogues of neurotensin: binding and biological activities, and in vitro metabolic stability. , 1991, European journal of pharmacology.

[12]  R. Jensen,et al.  Probing peptide backbone function in bombesin. A reduced peptide bond analogue with potent and specific receptor antagonist activity. , 1988, The Journal of biological chemistry.

[13]  H. Heimgartner,et al.  2,4‐Bis(4‐methylpheylthio)‐1,3,2λ5,4λ5‐dithiadiphosphetan‐2,4‐dithion: Ein neues Reagens zur Schwefelung von N,N‐disubstituierten Amiden , 1987 .

[14]  C. Williams,et al.  The behaviour of leucine aminopeptidase towards thionopeptides. , 1987, The Biochemical journal.

[15]  S W Dietrich,et al.  Mean geometry of the thiopeptide unit and conformational features of dithiopeptides and polythiopeptides. , 1987, Biochemical and biophysical research communications.

[16]  A. Bax,et al.  1H and13C Assignments from Sensitivity-Enhanced Detection of Heteronuclear Multiple-Bond Connectivity by 2D Multiple Quantum NMR , 1986 .

[17]  M. Billeter,et al.  Calibration of the angular dependence of the amide proton-Cα proton coupling constants, 3JHNα, in a globular protein: Use of 3JHNα for identification of helical secondary structure , 1984 .

[18]  C. Warren,et al.  Structure determination of a tetrasaccharide: transient nuclear Overhauser effects in the rotating frame , 1984 .

[19]  H. Itokawa,et al.  Isolation and antitumor activity of cyclic hexapeptides isolated from Rubiae radix. , 1984, Chemical & pharmaceutical bulletin.

[20]  H. Itokawa,et al.  Studies on the antitumor cyclic hexapeptides obtained from Rubiae radix. , 1983, Chemical & pharmaceutical bulletin.

[21]  A. Jimenez,et al.  The mode of action of the antitumor drug bouvardin, an inhibitor of protein synthesis in eukaryotic cells , 1982, FEBS letters.

[22]  M. Szelke,et al.  Potent new inhibitors of human renin , 1982, Nature.

[23]  N. Nashed,et al.  Carboxypeptidase A catalyzed hydrolysis of thiopeptide and thioester analogs of specific substrates. An effect on kcat for peptide, but not ester, substrates , 1982 .

[24]  P. Balaram,et al.  Aggregation of apolar peptides in organic solvents. Concentration dependence of 1H‐nmr parameters for peptide NH groups in 310 helical decapeptide fragment of suzukacillin , 1982 .

[25]  P. Bartlett,et al.  A thioamide substrate of carboxypeptidase A. , 1982, Biochemistry.

[26]  L. Mueller.  Sensitivity enhanced detection of weak nuclei using heteronuclear multiple quantum coherence , 1979 .

[27]  G. Kriek,et al.  Bouvardin and deoxybouvardin, antitumor cyclic hexapeptides from Bouvardia ternifolia (Rubiaceae). , 1977, Journal of the American Chemical Society.

[28]  J. Ibers,et al.  Dispersion corrections and crystal structure refinements , 1964 .

[29]  Martin Karplus,et al.  Vicinal Proton Coupling in Nuclear Magnetic Resonance , 1963 .

[30]  H. Itokawa,et al.  Studies on Rubia akane(RA) derivatives. Part 7. Thioamide analogues of RAs: antitumour cyclic hexapeptides , 1994 .

[31]  N. Tomioka,et al.  Conformational analysis of antitumor cyclic hexapeptides, RA series , 1991 .

[32]  F. S. Guziec,et al.  An improved method for the preparation of desoxopeffides—reductions of endothiopeptides☆ , 1990 .

[33]  D. Sherman,et al.  Compatibility of thioamides with reverse turn features: synthesis and conformational analysis of two model cyclic pseudopeptides containing thioamides as backbone modifications , 1990 .

[34]  G. Lajoie,et al.  Productive conformation in the bound state and hydrolytic behavior of thiopeptide analogues of angiotensin-converting enzyme substrates , 1986 .

[35]  S. Lawesson,et al.  Studies on organophosphorus compounds XLVII preparation of thiated synthons of amides, lactams and imides by use of some new p,s-containing reagents , 1984 .

[36]  S. Lawesson,et al.  Studies on amino acids and peptides-V: Syntheses of endothionated melanostatin analogs , 1983 .

[37]  D. I. Stuart,et al.  An empirical method for correcting diffractometer data for absorption effects , 1983 .

[38]  H. Davy.  A direct conversion of carboxylic acids into dithioesters , 1982 .