Phosphorescent Cellular Probes and Uptake Indicators Derived from Cyclometalated Iridium(III) Bipyridine Complexes Appended with a Glucose or Galactose Entity

A series of phosphorescent cyclometalated iridium­(III) polypyridine complexes appended with a β-d-glucose moiety [Ir­(N∧C)2(bpy-TEG-ONCH3-β-d-glc)]­(PF6) [bpy-TEG-ONCH3-β-d-glc = 4-(10-N-methyl-N-(β-d-glucopyranosyl)-amino-oxy-2,5,8-trioxa-dec-1-yl)-4′-methyl-2,2′-bipyridine; HN∧C = 2-((1,1′-biphenyl)-4-yl)­benzothiazole) (Hbt) (1a), 2-phenylpyridine (Hppy) (2a), 2-phenylquinoline (Hpq) (3a), 7,8-benzoquinoline (Hbzq) (4a)] has been synthesized and characterized. The d-galactose counterparts [Ir­(N∧C)2(bpy-TEG-ONCH3-β-d-gal)]­(PF6) [bpy-TEG-ONCH3-β-d-gal = 4-(10-N-methyl-N-(β-d-galactopyranosyl)-amino-oxy-2,5,8-trioxa-dec-1-yl)-4′-methyl-2,2′-bipyridine; HN∧C = Hbt (1b), Hppy (2b), Hpq (3b), Hbzq (4b)] and a sugar-free bt complex [Ir­(bt)2(bpy-TEG-OMe)]­(PF6) [bpy-TEG-OMe = 4-(2,5,8,11-tetraoxa-dodec-1-yl)-4′-methyl-2,2′-bipyridine] (1c) have also been prepared. Upon photoexcitation, all the complexes displayed intense and long-lived triplet metal-to-ligand charge-transfer (3MLCT) [dπ­(Ir) → π*­(N∧N)] or triplet intraligand (3IL) (π → π*) (N∧C and N∧N) emission. The lipophilicity, the cellular uptake efficiency, and cytotoxicity of the complexes toward human cervix epithelioid carcinoma cells (HeLa) have been examined. Temperature dependence and chemical inhibition experiments indicated that the transport of bt–glucose complex 1a across the cell membrane occurred through an energy-requiring process such as endocytosis, in additional to a pathway that was mediated by glucose transporters (GLUTs). Importantly, the cellular uptake efficiency of this complex was found to be strongly dependent on hormonal stimulation and inhibition, rendering it a new phosphorescent metabolic indicator. Additionally, laser-scanning confocal microscopy revealed that the complex was localized in the mitochondria and highly resistant to photobleaching compared to a fluorescent organic glucose derivative 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)­amino)-2-deoxy-d-glucose (2-NBDG).