Water-soluble rhenium phosphine complexes incorporating the Ph 2 C(X) motif (X = O − , NH − ): Structural and Cytotoxicity studies.

: Reaction of [ReOCl 3 (PPh 3 ) 2 ] or [ReO 2 I(PPh 3 ) 2 ] with 2,2 / -diphenylglycine (dpgH 2 ) in refluxing ethanol afforded the air stable complex [ReO(dpgH)(dpg)(PPh 3 )] ( 1 ). Treatment of [ReO(OEt)I 2 (PPh 3 ) 2 ] with 1,2,3-triaza-7-phosphaadamantane (PTA) afforded the complex [ReO(OEt)I 2 (PTA) 2 ] ( 2 ). Reaction of [ReOI 2 (PTA) 3 ] with dpgH 2 led to the isolation of the complex [Re(NCPh 2 )I 2 (PTA) 3 ]·0.5EtOH ( 3 ·0.5EtOH). A similar reaction but using . Using benzilic acid (2,2 / -diphenylglycolic acid, benzH) with 2 afforded the complex [ReO(benz) 2 (PTA)][PTAH]·EtOH ( 6 The potential for the formation of complexes using radioisotopes with relatively short half-lives suitable for nuclear medicine applications by developing conditions for of [ Re(NCPh 2 )(dpg)I(PTA) 3 ] ( 7 )[ReO 4 ] - in a 4 h timescale. A procedure the technetium analog of complex [Re(NCPh 2 )I 2 (PTA) 3 ] ( 3 ) from 99m Tc[TcO 4 ] - was then investigated. The molecular structures of 1 – 7 are reported, whilst 3 - 7 have been studied using in vitro cell assays (Hela, HCT116, HT-29 and HEK 293) and were found to have IC 50 values in the range 29 to 1858 µM. characterisation of molybdenum complexes bearing highly functionalised imido substituents.

The HPLC sample was prepared by taking 10 l of sample dissolved in 90 l of methanol.
Use of benzilic acid. two PTA ligands at -90.4 and -94.5 ppm. The stability of 6 was examined in D2O via 31 P NMR spectroscopy, which revealed two singlets at -88.5 and -91.6 ppm, similar to the signals observed for complex 6 in C6D6 albeit with slightly downfield shifts. The complex is completely soluble in benzene and less soluble in water. For example in 5 mL D2O, when 100 mg of 6 was dissolved, after filtration, the remaining undissolved solid weighed 40 mg, i.e. 60 wt% uptake.
Complex 6 was isolated as single crystals from EtOH and examined by X-ray diffraction.
The molecular structure is shown in figure 5 (for an alternative view see figure S7, ESI), with selected bond lengths and angles given in the caption. The rhenium center adopts a distorted octahedral geometry in which the phosphine (Re (1) (14), Re(1)-O (4) 2.1238 (14), Re(1)-O(6) 1.9677 (14), Re(1)-O (7) 1.7009 (15), Re(1)-P(1) 2.3904 (5); O(7)-Re(1)-O(1) 97.28 (6) (16), O(1)-Re(1)-P(1) 84.32 (15), N(10)-Re(1)-P(2) 96.65 (16).  -Cl), suggesting that the mechanism of action is direct binding of a protein or DNA to the metal centre, in a similar manner to that of cisplatin. The IC50 values observed here are slightly higher than that of cisplatin for the cancer cell lines (Table 2). 44,45 The addition of the two benzilic acid or diphenylglycine ligands in 6 and 7 with regards to HeLa cells must allow for access to mechanism of resistance in this cell line. Although the mechanism of action has not been explored, it is clear that the change in structure either amino acid ligands or halogen has an effect on the IC50 value. To check the biostability of compound 3 and 7, a 10 µl of compound (6.25 mM) was diluted in 100 µl of biological media (DEME) and monitored by 31 P NMR spectroscopy over a period of 5 days; the spectral form does not change across the study (Figures S31 -S35). This suggests that the coordination of the watersoluble phosphine ligand (PTA) remains on the metal centre and these are not removed as part of the mechanism of action within the cells. This also suggest that the complexes have a good stability under biological conditions. Synthesis of novel technetium-99m phosphadamantane precursor. An attempt was made to translate these protocols to produce technetium-99m analogues of the rhenium complexes.
Multistep protocols, such as this, are challenging to translate to radiochemistry where the amounts of the metal ion isotope precursor are limited and the concentrations are low (due to accessible amounts of the radioisotope and radiation protection issues), After several attempts to be explored. It is a significant advance to have synthesized these novel compounds with the rhenium analogues in a procedure that can be carried out on an appropriate timescale for transfer to radiopharmaceutical production.