Maleimido derivatives of diethylenetriaminepentaacetic acid and triethylenetetraaminehexaacetic acid: their synthesis and potential for specific conjugation with biomolecules.
Immunoconjugates sometimes suffer changes in immunoreactivity and tumor targeting because the chelators used interfere with antigen binding. To try to circumvent such problems, two new homobifunctional chelating agents, 2,6-bis[p-[(beta-maleimidopropionyl) amino]benzyl]diethylenetriamine- N,N,N',N",N"-pentaacetic acid (MPBz-DTPA) and 2,9-bis [p-(beta-maleimidopropionyl)amino]benzyl] triethylenetetraamine-N,N,N',N',N",N"-hexaacetic acid (MPBz-TTHA), were synthesized for chelation of 111In and 90Y metal ions. Each of the new chelators contains two maleimido functional groups substituted at the carbon backbone. In this study, the overall chemical yields for MPBz-DTPA and MPBz-TTHA were approximately 5 and 4%, respectively. The intermediate and final compounds were purified by flash chromatography and fully characterized by 1H-NMR, 13C-NMR, and mass spectroscopy. Chemical modification of the maleimido group on each of these derivatives allowed specific conjugation with a sulfhydryl group at the hinge region of an antibody molecule and conjugation with other peptides. For instance, the two Fab' fragments, through their hinge-region sulfhydryl groups, could covalently attach to a homobifunctional chelator via thioether linkage to generate a Fab'-S-chelator-S-Fab' immunoconjugate. By design, immunoconjugates containing these new chelators will contain only one chelator derivative at a known region of antibody away from the antigen binding site. Consequently, these chelators may minimize changes in the immunoreactivity and improve tumor targeting of immunoconjugates that contain them.
Department of Experimental Radiotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
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D002614:Chelating Agents / Q000138:chemical synthesis*; D002942:Circular Dichroism; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D008301:Maleimides / Q000737:chemistry*; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D002614:Chelating Agents; D008301:Maleimides; C060068:diethylenetriaminetetraacetic acid; D004369:Pentetic Acid; C026059:triethylenetetraminehexaacetic acid; D004492:Edetic Acid