bc6b00332_si_001.pdf (11.47 MB)
Targeting Iron in Colon Cancer via Glycoconjugation of Thiosemicarbazone Prochelators
journal contribution
posted on 2016-07-29, 19:19 authored by Eman A. Akam, Elisa TomatThe implication of iron in the pathophysiology
of colorectal cancer
is documented at both the biochemical and epidemiological levels.
Iron chelators are therefore useful molecular tools for the study
and potential treatment of this type of cancer characterized by high
incidence and mortality rates. We report a novel prochelation strategy
that utilizes a disulfide redox switch to connect a thiosemicarbazone
iron-binding unit with carbohydrate moieties targeting the increased
expression of glucose transporters in colorectal cancer cells. We
synthesized three glycoconjugates (GA2TC4, G6TC4, and M6TC4) with
different connectivity and/or carbohydrate moieties, as well as an
aglycone analog (ATC4). The sugar conjugates present increased solubility
in neutral aqueous solutions, and the ester-linked conjugates M6TC4
and G6TC4 compete as effectively as d-glucose for transporter-mediated
cellular uptake. The glycoconjugates show improved selectivity compared
to the aglycone analog and are 6–11 times more toxic in Caco-2
colorectal adenocarcinoma cells than in normal CCD18-co colon fibroblasts.