Doctor of Philosophy (PhD)
The potential application of metals in medicine is enormous. This study explores the fundamental chemistry directed at the eventual use of novel Re, Pt, and B12-conjugates with potential application for targeted delivery of metal-containing therapeutic and diagnostic agents. This study explores two different approaches that could be used in bioconjugation. The first approach employs the use of the cyclic C2-symmetrical amine, 1-(4-pyridyl)piperazine, to form new amidine complexes, fac-[Re(CO)3(Me2bipy)(HNC(CH3)(pyppz))]BF4. Such amidine complexes have an exposed, highly basic pyridyl nitrogen that readily coordinates to the cobalt atom in a simple B12 model, (py)Co(DH)2Cl (DH = monoanion of dimethylglyoxime), producing dinuclear fac-[Re(CO)3(Me2bipy)(u-(HNC(CH3)(pyppz)))Co(DH)2Cl]BF4 complexes. The present goal was to provide guidance for the development of 99mTc and 186/188Re radiopharmaceuticals for targeted tumor imaging and therapy. 1H NMR spectroscopic analysis of all compounds and single-crystal X-ray crystallographic data for selected complexes established that the amidine had only the E configuration in both the solid and solution states, and that the pyridyl group is bound to Co in the respective dinuclear complexes. We anticipate that our method of employing a coordinate bond for conjugating the fac-[ReI(CO)3] core to a vitamin B12 model could be extended to natural B12 derivatives. Such an approach is a very attractive method for the development of 99mTc and 186/188Re radiopharmaceuticals for targeted tumor imaging and therapy since B12 compounds are known to accumulate in cancer cells. I extended this chemistry to include new pyppzSO2R ligands (R = Me Me2Nnap = 5-(dimethylamino)naphthyl)), and 3,5-Me2C6H3 = 3,5-dimethylphenyl) bearing sulfonamide sulfonamide links. The novel pyppzSO2R ligands are very good donors that bind very strongly to the respective Re or Co metal centers; a feature that is necessary for our bioconjugation approach. Treatment of fac-[ReI(CO)3(Me2bipy)(CH3CN)]BF4 and (Cl or CH3)Co(DH)2(py) (DH = monoanion of dimethylglyoxime) with these sulfonamide ligands afforded the respective fac-[ReI(CO)3(Me2bipy)(pyppzSO2R)]BF4, (CH3)Co(DH)2(pyppzSO2R), and (Cl)Co(DH)2(pyppzSO2R) complexes. These ligands and compounds are characterized by NMR spectroscopy and X-ray crystallography. In the second approach we synthesized new trans-[PtII(4-Xpy)2Cl2] and [PtII(4-Xpy)4]Cl2 complexes bearing 4-substituted pyridines (4-Xpy) with limited volatility and water solubility; properties typical of 4-Xpy with X being a moiety targeting drug delivery. The high solubility of [PtII(4-Xpy)4]Cl2 salts in CDCl3 as well as the very downfield shift of [PtII(4-Xpy)4]Cl2 H2/6 signals indicated that the ion pairs are stabilized by CH•••Cl contacts. Furthermore, crystal structures of the [PtII(4-Xpy)4]Cl2 salts confirmed that the chloride ions occupy a pseudo axial position with non bonding (py)C-H•••Cl distances well within the range of a typical CH•••Cl H-bonding contacts. Our synthetic and spectroscopic results can be readily extended to other non-volatile ligands.
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Lewis, Nerissa Abigail, "N-Donor Ligands as Potential Linkers For Bioconjugation" (2017). LSU Doctoral Dissertations. 4438.