Abstract
A series of 3-carbamoyl- and 2,3-dicarbamoyl-mannose derivatives were synthesized, conjugated to a fluorescent dye (Cy5GE, AF 647 or NBD) and their cellular uptake in A549 and THP-1 cell lines was studied by FACS. In contrast to earlier studies on carbamoyl mannosides, the observed uptake was not related to carbamoyl group on the mannose residue but rather to the cyanine dye attached, a trend previously observed for Cy5-fructose conjugates. The NBD-conjugates however, showed a temperature and concentration dependent uptake in case of mannose conjugates. These results suggest a profound impact of the dye which should be taken into consideration when studying the uptake of small molecules by dye conjugation.
Highlights
The selective uptake of diagnostics and cytostatics in cancerous tissue is one of the main challenges in cancer diagnosis and therapy, respectively
A number of cancers can be targeted by utilizing their aberrant carbohydrate uptake and metabolism e.g. overexpressing of glucose transporter GLUT-1 [1] and the enzymes involved in the anaerobe glycolysis related to the Warburg effect [2,3,4]
To prepare carbamoylated mannose derivatives 9–10 in a divergent manner from known thioglycoside 1 we developed the synthetic route shown in Scheme 1
Summary
The selective uptake of diagnostics and cytostatics in cancerous tissue is one of the main challenges in cancer diagnosis and therapy, respectively. It was discovered that the carbohydrate portion of bleomycin, a natural product used to treat various cancers, enables its selective uptake in cancerous cells [6]. Subsequent studies showed that the disaccharide portion itself was sufficient to enable selective uptake using disaccharides conjugated to fluorescent dyes to assay cellular uptake [8]. The position and substitution (Fig. 1, highlighted in blue) of the carbamoyl functionality in the bleomycin disaccharides was explored [11]. From these studies it became clear that N-methyl carbamoyl group at the 2- or 3-position of mannose showed even greater uptake than the parent 3-carbamoyl mannose. Cellular uptake was assayed by fluorescence activated cell sorting (FACS)
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