Synthesis and Antiproliferative Activity of Fluorinated N-Acetylmannosamine Analogs

Introducing fluorine into monosaccharides, or their incomplete acylation that leaves the anomeric group unprotected, can impart antitumor properties to the resulting glycomimetics. This property could be exploited in the development of new antiproliferative agents. Herein, we report the synthesis and antiproliferative activity of a complete series of deoxyfluorinated analogs of acylated N-acetylmannosamine (ManNAc) hemiacetals, which combine both aforementioned structural features. In addition, retentive deoxyfluorination at C4 of a 1,6-anhydro-β-d-mannopyranose derivative provided access to 3,4-difluoro and 3,4,6-trifluoro talosazides (TalN₃). Attempted conversion of the fluorinated talosazides to fluorinated N-acetyltalosamine (TalNAc) analogs was prevented by unwanted reactions, partly arising from an elimination-addition mechanism. The in vitro antitumor activity of the fluoroanalogs against MDA-MB-231 breast cancer cells was investigated using an MTT proliferation assay, a colony forming assay, a wound healing assay, and cell cycle analysis. The trifluorinated ManNAc analog showed the most pronounced antiproliferative activity. In addition, Western blot analysis indicated the induction of programmed cell death in MDA-MB-231 cells.