Development and assessment of metal containing drugs as model radiopharmaceuticals for cancer treatment

[摘要] English: This research focuses on the development of new teatradentate carboxamide ligands and their coordination to gallium(III) and gold(III). The solid state characteristics and reactivity studies in solution of these model compounds would give more insight into the behaviour of radiopharmaceuticals for cancer treatment.The crystallographic characterization of two carboxamide ligands, di-Mebpb and bpb and two metal complexes, [Ga(bpb)(H2O)2]NO3·CH3OH and [Au(bpb)]Cl, is fully discussed and compared to literature in Chapter 5. The ligand, di-Mebpb crystallizes in a non-centrosymmetric, monoclinic Cc space group, with four molecules per unit cell. The ligand, bpb crystallizes in a centrosymmetric monoclinic P21/c space group, with four molecules in the unit cell. The dihedral angles between the central phenyl ring and the two picoline rings for the di-Mebpb ligand, is calculated as 57.06(5) ° and 22.05(8) °, respectively and the dihedral angle between the central phenyl ring and the two picoline rings of the bpb ligand are calculated as 57.82(4) ° and 17.96(7) °, respectively. [Ga(bpb)(H2O)2]NO3·CH3OH crystallizes in a centrosymmetric, orthorhombic Pbca space group, with four molecules per unit cell while the [Au(bpb)]Cl, complex crystallizes in a centrosymmetric, triclinic Pī space group, with two molecules per unit cell. The octahedron around the gallium(III) ion is somewhat distorted as indicated by the large bite angle of N1-Ga-N4 (115.03(1) °) and the small bite angle of O4-Ga-O3 (161.62(1) °). The gold(III) complex crystallizes in a distorted square planar formation with the gold(III) deviating 0.0518(3) Å from the plane formed by the four coordinating nitrogen atoms (N1-N2-N3-N4) and the bond angles of N-Au-N range from 81.8(2) ° to 111.9(2). °.A kinetic investigation was conducted to follow the rate at which methanol is substituted from a trans-[Ga(bpb)(CH3OH)2]+ complex with 4-methylpyridine as entering ligand. The proposed substitution mechanism is postulated to involve two distinguishable reaction steps. The equilibrium constant, K1, for the first methanol substitution was obtained as ~1 M-1 from the overall equilibrium constant, Koverall, which was determined as 44(2) M-1. The equilibrium constants, K2 and K3, were determined as 5.8(1) M-1 and 6(1) M-1, respectively at 25.0 °C.The rate constant for the second substitution step, k3, was determined as 8.5(1) x 10-4 (s-1) which is much slower than what was expected at 25.0 °C. A large negative ΔS�?value of -122(10) (J K-1.mol-1) was determined for the forward reaction (k3), which suggests an associative mechanism for the MeOH substitution with 4-mepy as entering ligand, but high pressure kinetic studies are required to investigate this fully.Cell studies were performed on two newly synthesized compounds, di-Mebpb and [Ga(bpb)(H2O)2]NO3·CH3OH. These compounds were tested on oesophageal cancer cell lines which showed promising results towards inhibition, however it was not reactive enough to be considered as active substance for inhibition, with respective IC50 values of 3.796 μM and 2.285 μM for di-Mebpb and [Ga(bpb)(H2O)2]NO3·CH3OH.

[发布机构] University of the Free State