No abstract

Copper bis(4-ethyl-3-thiosemicarbazonato) acenaphthenequinone (1) and copper bis(4-methyl-3-thiosemicarbazonato) acenaphthenequinone (2) are synthesized and characterized in solution, in the solid state, and radiolabeled. Serum-protein binding radioassays show good stability in solution and about 25 % binding to protein over 1 h, which is comparable with the hypoxia selective tracer [(64)Cu(ATSM)]. Cyclic voltammetry shows fast and reversible reduction at redox potentials similar to the values known for hypoxia-selective copper compounds. However, despite this, complex 1 does not show any hypoxic-selective uptake in HeLa cells over 1-h standard assays. Possible reasons for this are studied by using the intrinsic fluorescence of the Cu(II) complexes to determine the cellular distributions and uptake mechanism by confocal microscopy. The complexes are found to bind to the external cell membrane and disperse evenly in the cytoplasm only after a very slow cell internalization (>1 h). No significant changes in distribution are observed by fluorescence imaging under hypoxic conditions. The rate of localization in the cytoplasm contrasts with their Zn(II) analogues, which are known to have fast cell uptake (up to 20 min) and a clear localization in lysosomes and mitochondria. The cytotoxicity mechanism of 1 over 24 h against a number of adherent cell lines is seen to be by membrane disruption and is of a comparable magnitude to that of [Cu(ATSM)], as demonstrated by methyl tetrazolium (MTT) and lactate dehydrogenase (LDH) assays.

Seven discrete sugar-pendant diamines were complexed to the {M(CO)(3)}(+) ((99m)Tc/Re) core: 1,3-diamino-2-propyl beta-D-glucopyranoside (L(1)), 1,3-diamino-2-propyl beta-D-xylopyranoside (L(2)), 1,3-diamino-2-propyl alpha-D-mannopyranoside (L(3)), 1,3-diamino-2-propyl alpha-D-galactopyranoside (L(4)), 1,3-diamino-2-propyl beta-D-galactopyranoside (L(5)), 1,3-diamino-2-propyl beta-(alpha-D-glucopyranosyl-(1,4)-D-glucopyranoside) (L(6)), and bis(aminomethyl)bis[(beta-D-glucopyranosyloxy)methyl]methane (L(7)). The Re complexes [Re(L(1)-L(7))(Br)(CO)(3)] were characterized by (1)H and (13)C 1D/2D NMR spectroscopy which confirmed the pendant nature of the carbohydrate moieties in solution. Additional characterization was provided by IR spectroscopy, elemental analysis, and mass spectrometry. Two analogues, [Re(L(2))(CO)(3)Br] and [Re(L(3))(CO)(3)Br], were characterized in the solid state by X-ray crystallography and represent the first reported structures of Re organometallic carbohydrate compounds. Conductivity measurements in H(2)O established that the complexes exist as [Re(L(1)-L(7))(H(2)O)(CO)(3)]Br in aqueous conditions. Radiolabelling of L(1)-L(7) with [(99m)Tc(H(2)O)(3)(CO)(3)](+) afforded in high yield compounds of identical character to the Re analogues. The radiolabelled compounds were determined to exhibit high in vitro stability towards ligand exchange in the presence of an excess of either cysteine or histidine over a 24 h period.

An approach to a new class of potential radiopharmaceuticals is demonstrated by the labeling of a glucosamine derivative with the tricarbonyls of 99mTc and 186Re. The proligand HL2 (N-(2'-hydroxybenzyl)-2-amino-2-deoxy-D-glucose) was produced by hydrogenation of the corresponding Schiff base and reacted with [NEt4]2[Re(CO)3Br3] to form the neutral complex [(L2)Re(CO)3] in 40% yield. 1H and 13C NMR spectra indicate that the [Re(CO)3] core is bound in a tridentate fashion via the amino N, phenolato O, and C-3 hydroxyl O atoms of the ligand. At the tracer-level, labeling of HL2 with [99mTc(CO)3(H2O)3]+ and [186Re(CO)3(H2O)3]+ was achieved in aqueous conditions in 95 +/- 2% and 94 +/- 3% average radiochemical yields, respectively.