Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 5, Pages 2678-2690Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c01875
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- ARC [DP140101574]
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A glucose-based vector conjugated to a tris(methylpyridyl)amine ligand is described for generating targeted chaperone and caging complexes for active anticancer agents. The ligand inhibits hexokinase in cells, showing potential for phosphorylation and targeting cancer cells. The Co(III) complex incorporating this ligand demonstrates glucose-dependent cellular accumulation and potential for targeted delivery of highly toxic anticancer agents.
A glucose-based vector for targeting cancer cells conjugated to a tris(methylpyridyl)amine (tpa) ligand to generate targeted chaperone and caging complexes for active anticancer agents is described. The ligand, tpa(CONHPEGglucose)1, inhibits hexokinase, suggesting that it will be phosphorylated in the cell. A Co(III) complex incorporating this ligand and coumarin-343 hydroximate (C343ha), [Co(C343ha){tpa(CONHPEGglucose)(1)}]Cl, is shown to exhibit glucose-dependent cellular accumulation in DLD-1 colon cancer cells. Cellular accumulation of [ Co( C343ha){tpa(CONHPEGglucose)(1)}](+) is slower than for the glucose null and glucosamine analogues, and the glucose complex also exhibits a lower ability to inhibit antiproliferative activity. Distributions of cobalt (X-ray fluorescence) and C343ha (visible light fluorescence) in DLD-1 cancer cell spheroids are consistent with uptake of [Co(C343ha){tpa(CONHPEGglucose)(1)}](+) by rapidly dividing cells, followed by release and efflux of C343ha and trapping of the Co{tpa(CONHPEGglucose)(1)} moiety. The Co{tpa(CONHPEGglucose)(1)} moiety is shown to have potential for the caged and targeted delivery of highly toxic anticancer agents.
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