Chemistry Reference
In-Depth Information
R
2
R
1
HN
R
2
N
N
N
S
R
3
R
1
, R
2
, R
3
=H, Me, Et
HL
fIGure 7.10
Triapine-related ligands of type Hl.
was far higher than that of simple
67
Ga cations, and the compound wash-out was significantly faster. The pharmacokinetic
properties suggested that this may be an interesting radio-gallium complex of relevance to both SPECT and PET (with
68
Ga)
imaging of fibrosarcoma tumours and other malignancies [65, 66].
metal complexes of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine) were first synthesised by the
Keppler group [67, 68], and the Fe(III) and Ga(III) complexes were studied by X-ray crystallography. Ga(III) and Fe(III)
complexes [m(l)
2
]
+
were also prepared with related ligands Hl (where Hl = 2-formylpyridinethiosemicarbazone,
2-acetylpyridinethiosemicarbazone, or 2-pyridineformamidethiosemicarbazone, Figure 7.10) and exhibited moderate
fluorescence in aqueous solutions. All ligands and complexes were tested for their
in vitro
anti-proliferative activity in
two human cancer cell lines (41 m and SK-BR-3). Selected compounds were studied for the capacity of inhibiting ribo-
nucleotide reductase measured by incorporation of 3H-cytidine into DNA. Formation of high stability bis-ligand
complexes was found in all cases, and these are predominant at physiological pH with Fe(III)/Fe(II), but only at the acidic
pH range with Ga(III). It appears that the N-terminal dimethylation does not affect the redox potential, but has the highest
impact on the stability of the complexes. Structure-activity relations established that in general, coordination to Ga(III)
increased the cytotoxicity, while the Fe(III) complexes show reduced cytotoxic activity compared to the metal-free thios-
emicarbazones, especially in the absence of a NH
2
group on the pyridine [67, 68].
In parallel work, gallium(III) and iron(III) complexes of alpha-N-heterocyclic thiosemicarbazones
hl
(2-acetylpyridineN,N-
dimethylthiosemicarbazone, 2-acetylpyridineN-pyrrolidinylthiosemicarbazone, acetylpyrazineN,N-dimethylthiosemicarba-
zone, acetylpyrazineN-pyrrolidinylthiosemicarbazone and acetylpyrazine N-piperidinylthiosemicarbazone) with the general
formula [GalCl
2
] and [ml
2
][y] (m = Ga(III), y = PF
6
) have also been developed for biomedical imaging and therapeutic
applications. Their syntheses, characterization, cytotoxicity, and interaction with ribonucleotide reductase were recently
reported. The
in vitro
antitumour potency was studied in two human cancer cell lines (41 m and SK-BR-3). As was the case
with the earlier work, gallium(III) enhances, whereas iron(III) reduces, the cytotoxicity of the ligands [69].
A parallel investigation of the synthesis and structural studies of gallium(III) and indium(III) complexes of 2-acetylpyri-
dine thiosemicarbazones has also been reported by another group. Several new 2-acetylpyridine 4 N-alkyl/phenyl thiosemi-
carbazones and their Ga(III) and In(III) complexes were prepared and fully characterised. A comparison of the crystal
structures demonstrated the preference for [ml
2
]
+
type complexes with gallium and [mlX
3
] species with indium. Stability
studies indicated that complexes of the type [InlCl
2
meOH] are stable for prolonged periods in human serum, suggesting
they have potential for radiolabelling and SPECT imaging [70].
A related
67
Ga complex of 2-acetylpyridine N
4
-
ortho
fluorophenylthiosemicarbazone (PhoF) was developed as a radiotracer
for brain imaging
in vivo
. The labelling of the free ligand with
67
GaCl
3
was performed in methanol with high radiochemical
yield, as demonstrated by radioHPlC (97.5 ± 0.6% of radiochemical purity and high specific activity, 1.0 TBq / mmol). The
biodistribution and SPECT imaging of this new
67
Ga-based SPECT imaging agent were evaluated in Swiss mice and nude mice
bearing glioblastoma multiforme tumours (u87-mG).
In biodistribution studies,
67
Ga- PhoF displayed not only significant tumour uptake, but also rapid blood clearance and
low accumulations in nontarget tissues, resulting in high target-to-nontarget ratios. Scintigraphic images of
67
Ga-PhoF in
nude mice bearing u87-mG tumours showed a significant activity in tumour (~7% of total activity), and tumour-to-normal
tissue ratio was more than 10-fold higher depending on the organ. It is believed that this compound fulfils the characteristics
required for a radiotracer for brain tumour diagnosis [71]. Further structural investigations are needed to establish the precise
structure and physico-chemical characteristics of this gallium species, in particular to establish whether the complex involved
in binding to the brain tumour site is neutral or cationic.
Related Ga(III) octahedral complexes of the general formula [Gal
2
]NO
3
(l = 2-pyridineformamidethiosemicarbazone) were
also prepared. These thiosemicarbazones were cytotoxic against malignant RT2 glioblastoma cells (expressing the p53 protein)
with IC
50
values ranging from 7.3 to 360 mm, and against malignant T98 glioblastoma cells (expressing mutant p53 protein)
with IC
50
values ranging from 3.6 to 143 mm. Coordination to Ga strongly increased the cytotoxicity of the N(4)-alkylated
