Dye conjugates of template-fixed peptidomimetics

摘要

Dye conjugates of template-fixed β-hairpin peptidomimetics of the general formula (I) wherein Z is a template-fixed chain of 14 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Gly, or Pro or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have CXCR4 antagonizing properties, and are useful for cancer therapy; diagnostic imaging; for detection of tumors and other abnormalities; for photoacoustic tumor imaging, detection and therapy; and for sonofluorescence tumor imaging, detection and therapy. The various dyes forming part of these conjugates are useful over the range of 300-1200 nm, the exact range being dependent upon the particular dye. These dye conjugates of β-hairpin peptidomimetic can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.;

主权项

1. A compound of the general formulawhereinis DPro-LPro or LPro-DPro and Z is a chain of 14 alpha-amino acid residues, the positions of said amino acid residues in the chain being counted starting from the N-terminal amino acid, whereby a N terminus of P1 is attached a C-terminus of said template, and a C-terminus of P14 is attached to a N terminus of said template, whereby these amino acid residues in positions 1 to 14 are:
P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Cit; and P14: Lys(Ds1)or
P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg; P6: Gly; P7: Pro; P8: Dpr(Dsl); P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Cit; and P14: Lys;or
P1: Lys(FHS); P2: Arg; P3: Cit; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Cit; and P14: Gln;or
P1: Tyr; P2: Arg; P3: Lys(FHS); P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Cit; and P14: Gln;or
P1: Tyr; P2: Arg; P3: Thr; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: 2-Nal; P11: Cys; P12: Tyr; P13: Cit; and P14: Lys(FHS);or
P1: Tyr; P2: Arg; P3: Thr; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: 2-Nal; P11: Cys; P12: Tyr; P13: Cit; and P14: Lys(FITC);or
P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Lys(FHS); and P14: Gln;or
P1: Tyr; P2: Lys(FHS); P3: Cit; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Trp; P11: Cys; P12: Tyr; P13: Cit; and P14: Gln;or
P1: Tyr; P2: Arg; P3: Thr; P4: Cys; P5: Arg; P6: Gly; P7: Pro; P8: Arg; P9: Arg; P10: 2-Nal; P11: Cys; P12: Tyr; P13: Cit; and P14: Lys(ALX);or
P1: His; P2: His; P3: Gln; P4: Cys; PS: Ser; P6: Ala; P7: DPro; P8: Phe; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Leu; P2: His; P3: Thr; P4: Cys; P5: Arg; P6: Ala; P7: DPro; P8: Arg; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: His; P2: His; P3: Tyr; P4: Cys; P5: Arg; P6: Ala; P7: DPro; P8: Phe; P9: Arg; P10: Phe; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Ser; P2: His; P3: Tyr; P4: Cys; P5: Arg; P6: Ala; P7: DPro; P8: Phe; P9: Arg; P10: Phe; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Tyr; P2: Arg; P3: Thr; P4: Cys; P5: Arg; P6: Gly; P7: DPro; P8: Arg; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Tyr; P2: Arg; P3: Thr; P4: Cys; PS: Arg; P6: Ala; P7: DPro; P8: Arg; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Tyr; P2: Arg; P3: Tyr; P4: Cys; P5: Arg; P6: Ala; P7: DPro; P8: Phe; P9: Arg; P10: Phe; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);or
P1: Tyr; P2: His; P3: Tyr; P4: Cys; PS: Ser; P6: Ala; P7: DPro; P8: Phe; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; and P14: Lys(FITC);
with said Lys(Dsl) standing for L-Nε-Dansyl-lysine, Dpr(Dsl) standing for L-Nσ-Dansyl-2,3-Diaminopropionic acid; Lys(FHS) standing for L-Nε-Fluorescin-5(6)-carboxamidocaproic-lysin; Lys(FITC) standing for L-Nε-Fluorescin-isomer I-lysine; and Lys(Alx) standing for L-Nε-Alexa Fluor 647-lysine;with the proviso that Cys at P4 and P11 can form a disulfide bridge; andwith the further proviso that the molecule contains at least one Lys(Dsl) and/or Lys(FHS) and/or Lys(FITC), and/or Lys(Alx) and/or Dpr(Dsl) moiety;and pharmaceutically acceptable salts thereof.