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  • Title: Biotin reagents for antibody pretargeting. 7. Investigation of chemically inert biotinidase blocking functionalities for synthetic utility.
    Author: Wilbur DS, Hamlin DK, Chyan MK.
    Journal: Bioconjug Chem; 2006; 17(6):1514-22. PubMed ID: 17105231.
    Abstract:
    An investigation was conducted to evaluate three biotin derivatives designed to block biotinidase cleavage of the biotinamide bond. Difficulties in multistep syntheses of molecules containing tert-butyl protected hydroxymethyl and carboxylate groups positioned alpha to a biotinamide bond led to the investigation of alternative biotinidase-blocking moieties that do not require protection and deprotection. The targeted biotin derivatives contained serine-O-methyl ether, 2-aminobutyric acid, and valine moieties conjugated to the biotin carboxylate functionality. Those derivatives were further modified with a radioiodinated aryl ring to study their biotinidase stability. As a comparison to previously studied biotin derivatives, radioiodinated versions of biotin conjugates that contained (a) no biotinidase stabilizing group, (b) an N-methyl (sarcosine) stabilizing group, (c) an alpha-carboxylate (aspartate) stabilizing group and hydroxymethyl (serine) stabilizing group were also prepared and tested. When tested in human serum, all of the radioiodinated biotinidase-stabilized biotin derivatives had <1% biotinamide cleavage. Thus, under the conditions studied, all of the tested biotinidase blocking moieties appeared to be equal with regards to protection from biotinidase cleavage. Further testing of the biotin derivatives included a HPLC assay to determine their relative dissociation from recombinant streptavidin (rSAv). The dissociation of cyanocobalamin (CN-Cbl) adducts of biotin-serine-O-methyl ether, biotin-aminobutyric acid, and biotin-valine were compared with the CN-Cbl adduct of biotin-sarcosine. The relative rates of dissociation found were biotin-sarcosine-CN-Cbl > biotin-valine-CN-Cbl > biotin-serine-O-methyl ether-CN-Cbl > biotin-aminobutyric acid-CN-Cbl. Due to the high cost of serine-O-ethyl ether (and its N-Boc derivative) and difficulty in syntheses of its biotin derivatives, that adduct is not an attractive candidate for application to compounds used in vivo. The higher lipophilicity and diminished binding of the biotin-valine adduct also makes its use in vivo less attractive. Thus, the biotin-aminobutyric acid adduct appears to be the best candidate for incorporation into biotin derivatives used in vivo, as it simplifies the synthetic procedures, has low cost, and provides effective blocking of biotinidase while retaining high binding affinity.
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