A crystallographic and mechanistic investigation of rhenium (I) tricarbonyl complexes as model radiopharmaceuticals

[摘要] English: Rhenium(I) and technetium(1) tricarbonyl complexes hold significant potential as model radiopharmaceuticals which could be utilized as therapeutic and imaging agents. 99mTechnetium in particular, is one radionuclide which is used in more than 80% of radiopharmaceuticals as a diagnostic agent. The biodistribution of a potential radiopharmaceutical can in principle be manipulated by the coordination of a biologically active molecule to the radionuclide. The principle aim of this study was to gain further insight into the chemistry, coordination and kinetic behaviour of fac-[M(CO)3+ (M = Tc, Re) complexes. With this idea in mind, a range of salicylidene ligands, SaIH, were synthesised according to the Schiff-base reaction. These organic ligands were synthesized as potential bifunctional chelators between the tricarbonyl radionuclide and the biologically active directing molecule. The ligands contain various amine compounds which were coordinated to the imine nitrogen atom on the salicyclidene backbone. The imino substituents consisted of aromatic, aliphatic and biologically active moieties with varying steric, electronic and biological properties and included amines such as m-toluidine, 3-methylbutylamine, aniline, histamine, tryptamine, tyramine etc. The ligands were characterized via NMR and IR spectroscopy. A single crystal X-ray diffraction study of the ligands was reported and revealed the various orientations of the substituents relative to the salicylidene backbone. The reported X-ray crystallographic structure determinations included the following ligands: 2-(m-tolyliminomethyl)phenol, 5- methyl-2-(m-tolyliminomethyl)phenol, 4-fluoro-2-(m-tolyliminomethyl)phenol, 2-(4-nitrophenyliminomethyl) phenol, 2-[(4-hydroxyphenyl)iminomethyl]-5-methylphenol, 2-[(2- imidazol-4-yl)ethyliminomethyl]-5-methylphenol, 2-[(2-indol-3-yl-ethyl)iminomethyl]-5- methylphenol, 2-(9-ethylcarbazol-3-yliminomethyl)-5-methylphenol, 2-[2-(4-hydroxy- phenyl)ethyliminomethyl]-5-methylphenol, 5-methyl-2-(1,2,4-triazol-3-yliminomethyl)-phenol. A further important part of this investigation was concerned with the synthesis and evaluation of the solid state characteristics of the SalH ligands coordinated to the rhenium(I) metal centre. The advantage of the fac-[M'(CO)3(S)3]+complex (M = Tc or Re; S = H20 or othercoordinated solvents) is the high stability of the classic low spin d6 [M(CO)3]+ core in waterand the potential of exchanging the labile solvent ligands. The SalH bidentate ligands werebonded to the fac-[M(CO)3]+ core according to the [2+1] approach, thus leaving an 'open'third position occupied by either a solvent or by a neutral monodentate ligand. Thecomplexes were also characterized via NMR and IR spectroscopy. The solid state behaviourof these fac-[Re(Sal)(CO)3(S)] complexes were investigated by X-ray crystallography, andincluded the complexes: fac-[Re(Sal-mTol)(CO)3(HOCH3)], fac-[Re(Sal-Ph)(C0)3(HOCH3)],fac-[Re(Sal-pTol)(CO)3(HOCH3)],fac-[Re(Sal-CyHex)(C0)3(HOCH3)],fac-[Re(Sal-3MeBu)(CO)3(HOCH3)], fac-[Re(Sal-Ph)(CO)3(NCsHs)], fac-[Re(Sal-3MeBu)(CO)3(NCsHs)], fac-[Re(5Me-Sal-Hist)(CO)3], fac-[Re(5Me-Sal-Trypt)(CO)3(NCsHs)], fac-[Re(5Me-Sal-Carba)(CO)3(NCsHs)], fac-[Re(5Me-Sal-mTol)(C0)3(HOCH3)],fac-[Re(5Me-Sal-3Me2Bu)(CO)3(HOCH3)]. The coordination geometry around the Re(l)metal centre in the crystal structures was a distorted octahedron. The imino substituentscrystallize in similar orientations despite various steric sizes, while the bond angles andlengths were not significantly affected by the different nitrogen-coordinated substituents.The study of the solid state coordination of the complexes was further supplemented with atheoretical DFT (density functional theory) study for specifically the 2-(mtolyliminomethyl)phenol, 5-methyl-2-(m-tolyliminomethyl)phenol, 2-(9-ethylcarbazol-3-yliminomethyl)-5-methylphenol,fac-[Re(Sal-mTol)(CO)3(S)],fac-[Re(Sal-Ph)(COh(S)],fac-[Re(5Me-Sal-Carba)(CO)3(S)] compounds. The comparison between the optimised structureand the crystal data reveal small differences, illustrating that predictions can be made in termsof the coordination of the bidentate ligands to the rhenium metal centre utilising DFTtechniques.A kinetic study of substitution of the coordinated solvent ligand of fac-[Re(Sal)(CO)3(S)]complexes was done. The following complexes were evaluated: fac-[Re(SalmTol)(CO)3(HOCH3)], fac-[Re(Sal-pTol)(CO)3(HOCH3)], fac-[Re(Sal-Ph)(CO)3(HOCH3)],fac-[Re(Sal-3MeBu)(CO)3(HOCH3)], fac-[Re(Sal-CyHex)(CO)3(HOCH3)] for enteringligands 3-chloropyridine, pyridine, 4-picoline and 4-dimethylaminopyridine in methanol assolvent. The rates were quite fast and varied from seconds to minutes under the conditionsstudied. Only one reaction was observed under dry conditions. The Sal-Re ligand systemsallowed the unique opportunity to confirm non-associative behaviour since for selectedligands, pyridine and DMAP, limiting kinetic profiles were obtained; clear evidence of eitherI or D intimate mechanisms. An interchange dissociative (Id) mechanism was proposed forthe substitution reaction with positive activation entropy and enthalpy values.An in vitro cancer screen was conducted on selected non-coordinated ligands and fac-[Re(Sal)(CO)3(S)] complexes in a 3-ce]] line panel consisting of TKlO (renal), UACC62(melanoma) and MCF7 (breast) cancer cells using a Sulforhodamine B (SRB) assay. Nosignificant cell activity was found but limited cell growth inhibition was observed.

[发布机构] University of the Free State