A crystallographic and mechanistic investigation of rhenium (I) tricarbonyl complexes as model radiopharmaceuticals
| dc.contributor.advisor | Roodt, Andreas | |
| dc.contributor.advisor | Visser, Hendrik G | |
| dc.contributor.author | Brink, Alice | |
| dc.date.accessioned | 2017-06-02T06:00:54Z | |
| dc.date.available | 2017-06-02T06:00:54Z | |
| dc.date.issued | 2011-11 | |
| dc.description.abstract | 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 other coordinated solvents) is the high stability of the classic low spin d6 [M(CO)3]+ core in water and the potential of exchanging the labile solvent ligands. The SalH bidentate ligands were bonded 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. The complexes were also characterized via NMR and IR spectroscopy. The solid state behaviour of these fac-[Re(Sal)(CO)3(S)] complexes were investigated by X-ray crystallography, and included 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 substituents crystallize in similar orientations despite various steric sizes, while the bond angles and lengths were not significantly affected by the different nitrogen-coordinated substituents. The study of the solid state coordination of the complexes was further supplemented with a theoretical 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 structure and the crystal data reveal small differences, illustrating that predictions can be made in terms of the coordination of the bidentate ligands to the rhenium metal centre utilising DFT techniques. 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 entering ligands 3-chloropyridine, pyridine, 4-picoline and 4-dimethylaminopyridine in methanol as solvent. The rates were quite fast and varied from seconds to minutes under the conditions studied. Only one reaction was observed under dry conditions. The Sal-Re ligand systems allowed the unique opportunity to confirm non-associative behaviour since for selected ligands, pyridine and DMAP, limiting kinetic profiles were obtained; clear evidence of either I or D intimate mechanisms. An interchange dissociative (Id) mechanism was proposed for the 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. No significant cell activity was found but limited cell growth inhibition was observed. | en_ZA |
| dc.description.abstract | Afrikaans: Renium(I) en tegnesium(I) trikarbonielkomplekse het betekenisvolle potensiaal as model kerngeneesmiddels wat gebruik sou kon word as terapeutiese- en beeldingsagente. 99mTegnesium word spesifiek In meer as 80% van alle radiofarmaseutiese middels as diagnostiese middel gebruik. Die bioverspreiding van "n potensiële radiofarmaseutiese middel kan in beginsel gemanipuleer word deur die koërdinasie van "n biologies-aktiewe verbinding aan die radionuklied. 'n Primêre doel van hierdie studie was om beter insig in die chemiese, koërdinatiewe en kinetiese gedrag van fac-[M(CO)3t (M = Tc, Re) komplekse te verkry. Met hierdie as uitgangspunt, is daar eerstens "n reeks salisielidien vry ligande, SaIH, met behulp van die Schiff-basis reaksie gesintetiseer. Hierdie organiese ligandstukture is gesintetiseer om potensieel as multifunksionele groepe tussen die trikarboniel radionuklied en die biologies aktiewe molekuul op te tree. Die ligande bevat verskeie amienverbindings wat aan die imien stikstofatoom op die salisielidien 'ruggraat' gekoordineer is. Die iminosubstituente bestaan uit aromatiese, alifatiese en biologies aktiewe onderdele met verskillende steriese, elektroniese en biologiese eienskappe en het die volgende ingesluit: m-toluïdien, 3- metielbutielamien, anilien, histamien, triptamien, tiramien ens. Die ligande is gekarakteriseer deur middel van KMR en IR spektroskopie. Enkelkristal X-straaldiffraksiestudies is uitgevoer en het gefokus op die verskeie oriëntasies van die substituente ten opsigte van die salisielidienruggraat. Die verbindings wat met behulp van enkelkristal X-straalkristallografie ondersoek is, sluit die volgende ligande in: 2-(m-tolieliminometiel)fenol, 5-metiel-2-(mtolieliminometiel )fenol, 4-fluoro- 2-(m-tolieliminometiel )fenol, 2-(4- nitrofenieliminometiel)- fenol, 2- [(4-hydroksifen yl)iminometiel] -5-metielfenol , 2- [(2-imidasol-4- iel)etieliminometiel] -5-metielfenol, 2- [(2-indol- 3-iel-etiel )iminometiel] -5-metielfenol , 2-(9-etielkarbasol- 3-ieliminometiel)- 5-metielfenol, 2- [2-(4-hydroksifen yl)etieliminometiel] -5-metielfenol, 5- metiel- 2-( 1,2,4-triasol- 3-ieliminometiel)fenol. "n Verdere belangrike doelstelling van hierdie ondersoek was die sintese en evaluasie van die vastetoestand eienskappe van die SalH ligande wanneer dit aan die renium(I) metaalkern gekoordineer is. 'n Voordeel van diefac-[M1(C0)3(S)3t komplekse (M = Tc of Re; S = H20 of ander koordinerende oplosmiddel) is die hoë stabiliteit van die klassieke laespin d6 [M(CO)3]+kerne in water en die potensiële uitruiling van die labiele oplosmiddelligande. Die SalH bidentate ligande is aan die fac-[M(CO)3]+ volgens die [2+1) benadering gekoppel en laat dus "n derde posisie oop wat deur "n oplosmiddelof "n neutrale monodentate ligand beset kan word. Die komplekse is ook deur middel van KMR en IR spektroskopie gekarakteriseer. Die vastetoestand gedrag van fac-[Re(Sal)(CO)3(S)) komplekse is deur middel van X-straal kristallografie bestudeer, en het die volgende ingesluit: fac-[Re(Sal-pTol)(C0)3(HOCH3)], fac-[Re(Sal-Ph)(C0)3(HOCH3)), fac-[Re(Sal-pTol)(C0)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)(C0)3(NCsHs)), fac-[Re(5Me-Sal-mTol)- (CO)3(HOCH3)), fac-[Re( 5Me-Sal- 3Me2Bu )(CO)3(HOCH3)). Die koërdinasiegeometrie rondom die Re(l) is in die vorm van 'n verwronge oktaheder en die iminosubstituente kristalliseer in soortgelyke oriëntasies ten spyte van verskille in steriese groottes. Die bindingshoeke en -afstande word nie sigbaar deur die verskillende stikstof-gekoordineerde substituente beïnvloed nie. Die studie van die vastetoestand koërdinasiechemie van die komplekse is verder aangevul met "n teoretiese DFT (digtheidsfunksieteorie) studie vir spesifiek die 2-(mtol ieliminometiel )fenol, 5-metiel- 2-(m-tolielimi nometiel )fenol, 2-(9-etielkarbasol- 3-ieliminometiel)- 5-metielfenol, fac-[Re(Sal-mTol)(CO)3(S)), fac-[Re(Sal-Ph)(CO)3(S)), fac- [Re(5Me-Sal-Carba)(C0)3(S)) verbindings. 'n Vergelyking tussen die geoptimiseerde strukture en die vanaf die kristaldata toon slegs geringe verskille. Dit bevestig gevolglik dat hierdie teoretiese studies gebruik kan word om voorspellings te maak ten opsigte van koërdinasie van soortgelyke bidentate ligande aan die renium metaalkern. "n Kinetiese studie van die substitusie van die gekoordineerde oplosmiddel ligand van 'n reeks fac-[Re(Sal)(CO)3(S)) komplekse is ook onderneem. Die volgende komplekse is geëvalueer: fac-[Re(Sal-mTol)(CO)3(HOCH3)), fac-[Re(Sal-pTol)(C0)3(HOCH3)), fac- [Re(Sal-Ph)(CO)3(HOCH3)), fac-[Re(Sal-3MeBu)(CO)3(HOCH3)), fac-[Re(Sal-CyHex)- (C0)3(HOCH3)), met 3-chloropiridien, piridien, 4-pikolien en 4-dimetielaminopiridien as inkomende ligande in metanol as oplosmiddel. Die tempo's was redelik vinnig en het van sekondes tot minute gewissel en slegs een reaksie is onder droë toestande waargeneem. Die Sal-Re ligandsisteme het die unieke geleentheid gebied om die nie-assosiatiewe gedrag met piridien en 4-dimetielaminopiridien as inkomende ligande te bestudeer, en het beperkende kinetiese gedrag geopenbaar, wat goeie getuienis ten gunste van 'n I of selfs 'n D intieme meganisme is. "n Uitruilings dissosiatiewe (Id) meganisme is gevolglik voorgestel vir hierdie substitusiereaksies, met positiewe aktiveringsentropie- en entalpie waardes. In vitro kankeraktiwiteit van geselekteerde vry ligande en fac-[Re(Sal)(CO)3(S)] komplekse is ondersoek in "n 3-sellynpaneel bestaande uit TKIO (renale), UACC62 (melanomiese) en MCF7 (bors) kankerselle met "n Sulforodamien B (SRB) toets. Geen noemenswaardige selakiwiteit is gevind nie, maar beperkte selgroei-inhibering is tog waargeneem. | af |
| dc.description.sponsorship | National Research Foundation (NRF) | en_ZA |
| dc.description.sponsorship | University of the Free State, UFS Biomolecular Cluster | en_ZA |
| dc.description.sponsorship | SASOL | en_ZA |
| dc.identifier.uri | http://hdl.handle.net/11660/6323 | |
| dc.language.iso | en | en_ZA |
| dc.publisher | University of the Free State | en_ZA |
| dc.rights.holder | University of the Free State | en_ZA |
| dc.subject | Radiopharmaceutical | en_ZA |
| dc.subject | Radionuclide | en_ZA |
| dc.subject | Cancer activity | en_ZA |
| dc.subject | Rhenuim | en_ZA |
| dc.subject | Rhenium | en_ZA |
| dc.subject | Technetium | en_ZA |
| dc.subject | Tricarbonyl complexes | en_ZA |
| dc.subject | Salicylidene | en_ZA |
| dc.subject | Bidentate ligands | en_ZA |
| dc.subject | Crystallography | en_ZA |
| dc.subject | Kinetic study | en_ZA |
| dc.subject | Radioisotopes | en_ZA |
| dc.subject | Thesis (Ph.D. (Chemistry))--University of the Free State, 2011 | en_ZA |
| dc.title | A crystallographic and mechanistic investigation of rhenium (I) tricarbonyl complexes as model radiopharmaceuticals | en_ZA |
| dc.type | Thesis | en_ZA |