N-Donor Ligands as Potential Linkers For Bioconjugation

Abstract

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.