Modified bleomycin disaccharides exhibiting improved tumor cell targeting

Manikandadas M. Madathil, Chandrabali Bhattacharya, Zhiqiang Yu, Rakesh Paul, Michael J. Rishel, Sidney Hecht

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Abstract

The bleomycins (BLMs) are a family of antitumor antibiotics used clinically for anticancer chemotherapy. Their antitumor selectivity derives at least in part from their ability to target tumor cells, a property that resides in the carbohydrate moiety of the antitumor agent. In earlier studies, we have demonstrated that the tumor cell selectivity resides in the mannose carbamoyl moiety of the BLM saccharide and that both the BLM disaccharide and monosaccharide containing the carbamoyl moiety were capable of the delivery/uptake of a conjugated cyanine dye into cultured cancer cell lines. Presently, the nature of the participation of the carbamoyl moiety has been explored further to provide compounds of utility for defining the nature of the mechanism of tumor cell recognition and uptake by BLM saccharides and in the hope that more efficient compounds could be identified. A library of seven disaccharide-Cy5∗ dye conjugates was prepared that are structural analogues of the BLM disaccharide. These differed from the natural BLM disaccharide in the position, orientation, and substitution of the carbamoyl group. Studies of these compounds in four matched sets of tumor and normal cell lines revealed a few that were both tumor cell selective and internalized 2-4-fold more efficiently than the natural BLM disaccharide.

Original languageEnglish (US)
Pages (from-to)6800-6810
Number of pages11
JournalBiochemistry
Volume53
Issue number43
DOIs
StatePublished - Nov 4 2014

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ASJC Scopus subject areas

  • Biochemistry

Cite this

Madathil, M. M., Bhattacharya, C., Yu, Z., Paul, R., Rishel, M. J., & Hecht, S. (2014). Modified bleomycin disaccharides exhibiting improved tumor cell targeting. Biochemistry, 53(43), 6800-6810. https://doi.org/10.1021/bi501102z