For the free ligands, the most important structural differences were observed for the position of the pyridyl imine. From the observed changes in absorbance, possible modes of binding to DNA were suggested for the metal complexes.
Acknowledgements III
- Metal-based pharmaceutical drugs 11
- General Information 24
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]1,3-
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]1,2-
- Synthesis of N,N'-bis[(pyridin-2-yl)ethylene]1,3-
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]1,2-
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]-
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]-
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]-
- Characterisation data for the cyclised hexahydro-
- Characterisation of the metal complexes 38 2.5 Discussion of the methods and characterisation 42
- X-ray Crystallography 46
- X-ray structures of the Schiff base ligands 68 3.4.4 X-ray data for the platinum(II) and palladium(II)
- X-ray structures of the metal complexes 80
- Density Functional Theory 101
- DFT and Schiff Base Ligands 112 .1 Choosing the Functionals and Basis Sets 115
- DNA Binding Studies 160
B1 - Crystallographic data tables for PtL1 248 B2 - Crystallographic data tables for PdL1 252 B3 - Crystallographic data tables for Ptl2 256 B4 - Crystallographic data tables for PdL2 260 B5 - Crystallographic data tables for PtL4 264 B6 - Crystallographic data tables for PdL4 269 B7 - Crystallographic data tables for Pdl4m 275 B8 - Crystallographic data tables for PdL4b 280.
APPENDIX E (CD)
Introduction
- Introduction
- The Quandary
- A Solution
- Schiff Bases
- Background
- This Work
An azomethine is a Schiff base with a hydrogen atom on the carbon atom of the imine bond. Studies have also been made on many of the ligands in this particular range, as well as similarly structured Schiff base ligands that have been metallized.
2KPF 6
Metal-based pharmaceutical drugs
- Background
- Drug actions against cancer
- DNA Intercalation
They cause a change in the tertiary structure of the DNA helix207, mainly through non-covalent interactions. A gap must be created by a degree of unwinding of the DNA strands depending on the intercalator.
The metals
- Platinum(II)
- Palladium(II)
Platinum(II) complexes showed considerable biological activity, as determined in cytotoxicity assays.215 The binding properties of Pt(II) and Pd(II) complexes to DNA were studied in vitro216 and showed cytotoxicity comparable to cisplatin.217 Many of the well-known anticancer platinum complexes developed because cisplatin has amine ligands. Palladium(II), on the other hand, will be a four-coordinate square structure, which should have similar properties to some platinum complexes.
Drug Discoveries
- Cisplatin
- Platinum-based Drugs
- Examples of Other Cancer Drugs 238,239
It has been used in combination with cisplatin to treat non-small cell lung cancer. Mitomycin® (originally approved by the FDA on April 19, 1995) has the active ingredient of the same name.
Feasibility and Objectives
Experimental
- General Information
- Instrumentation
- Schiff base free ligands
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]diamine
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]1,2- diaminophenylene (L6) 162
- Synthesis of N,N'-bis[(pyridin-2-yl)ethylene]diamine
- Synthesis of N,N'-bis[(pyridin-2-yl)methylene]1,2- diaminophenylene (L6m)
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]diamine
- Synthesis of N,N'-bis[phenyl(pyridin-2-yl)methylene]
- Characterisation data for the cyclised hexahydro- pyrimidine- and imidazole-containing bidentate ligands
The solution was filtered to remove a fluffy pale orange solid that formed.* The filtrate evaporated to give a yellow powder which was found to contain. The cooled solution was passed through a column of alumina with DCM as the eluting solvent to remove any traces of starting material. The solvent was removed and the resulting tan oil was collected.
Platinum Group Metal complexes
- Metallation with PGMs
- Template Metallation
- Characterisation of the metal complexes
AgSbF6, AgBF4 or AgPF6 (1.2 mmol)) was added dropwise to the solution as a suspension in acetonitrile (5 mL). The diamine (0.46 mmol) was dissolved in 4 mL of acetonitrile and added dropwise to the metal solution.
Discussion of the methods and characterisation
It appears that the methyl ligands generally behaved differently in solution causing problems for the assignment of the NMR data. There is a clear change in the shift of the 1H NMR peaks for the metalated derivatives from the spectra of the free ligands.
X-ray Crystallography
- Introduction
- Objectives
- Methodology
- Results and Discussion
- General
- X-ray data for the free ligands
- N'-bis[(pyridin-2-yl)methylene]ethane-1,2-diamine (L1)
- N'-bis[(pyridin-2-yl)methylene]cyclohexane-1,2-diamine (L5)
- X-ray structures of the Schiff base ligands
- X-ray data for the platinum(II) and palladium(II) complexes
- N'-bis[(pyridin-2-yl)methylene]propane-1,3-diamine platinum(II) hexafluorophosphate(V) (PtL2)
- N'-bis[(pyridin-2-yl)methylene]propane-1,3-diamine palladium(II) hexafluorophosphate(V) (PdL2)
- X-ray structures of the metal complexes
The only distortion for L2 from the mostly flat plane of the N4 ligand (formed by two imine (Ni) and two pyridine (Np) nitrogen atoms) is for the bridging propyl group. Each of the metals is bound to one imine nitrogen (Ni) and one pyridine nitrogen (Np) by different ligands that coordinate at the other two (or four, in the case of octahedral platinum) available positions on the metal. The nickel (NiL2263,264) L2 complexes are almost perfectly planar, while the copper (CuL2265) complex of the same ligand is much more distorted.
Thus, the deformation from the plane and the non-plane of the bridging group are complimentary to each other. This bite angle has been shown to increase with the size of the chelate ring. This distortion was caused by the large distortion in the 2,2'-dimethyl-substituted biphenyl backbone of the bridging group.
There is no obvious trend in metal distortion for complexes of these ligands. However, there is a noticeable change in the out-of-plane distortion of the metal from the 2-carbon-bridged to the 3-carbon-bridged ligand. The metal is in the N4 plane for the ethyl bridge and then moves out of plane for the longer propyl bridge.
The ethyl bridge groups show a slight out-of-plane distortion, which increases for the central carbon of the propyl bridges. This also applies to distortion of the pyridine rings from the N4 plane, except for the complexes of L1.
- Crystal Packing
These short C–H···F contacts are presented in Table 3.5 and correspond to relatively strong hydrogen bonds between the hydrogen atoms of the cationic metal chelates and. One important reason for this, despite the aromatic nature of the pyridyl groups and the fact that they are well known to π-stack,303 is that the cationic chelates in the present salts are divalent. The observed short contacts can be explained for the L1 complexes by the size of the bridging group.
Due to the bridging group being rather small, the cation is mostly flat and thus there is hardly any out-of-plane tilting of the pyridyl groups. The conformation of the propyl bridge connecting the two pyridyl groups is not the regular staggered arrangement for an aliphatic chain. For PdL2, the distortion from the N4 plane is slightly larger (visible in the packing in Figure 3.31).
These molecules crystallize in alternating layers of the two types of cations (salted and twisted) with the anions forming a barrier between them. The complementary π–π stacking of the pyridine rings of neighboring cations is also slightly offset, as observed for PdL4. Thus, it appears that the change in bulk of the group on the imine carbon and the subsequent distortion of planarity causes major changes in the way these cations stack in the crystal lattice.
Density Functional Theory
- Introduction
- Functionals
- Local Density Methods
- Gradient Methods
- Hybrid Functionals
- Performing a calculation
- DFT and Schiff Base Ligands
- Choosing the Functionals and Basis Sets
- Computational Methods
- Objectives
- Results and Discussion
- Introductory remarks
- Geometry Optimisations
- Molecular Orbitals
Most of the literature is focused on Salen-type ligands (ONNO donor ligands synthesized from aromatic diamines and o-hydroxyaldehydes). Crystal packing can result in either flattening of the structure (planarity) or a distortion that pushes the structure out of its planar position (nonplanarity). Similarly, the theoretically and experimentally determined conformations for each of the metal complexes of these ligands are nearly identical.
In each conformation, the deviation can be seen by the slight tilt (out of the N4 plane) of the pyridine rings. The least-squares fits of the N4 level for the platinum complexes of L1, L2 and L4 are shown in Figure 4.5. The most striking differences (if any) from the overlay of the X-ray structures and the DFT-calculated structures are for the bridges of the chelating ligand structure.
This can be explained by the very different structures for the theoretical and experimental orientations of the pyridine rings. There is also a slight discrepancy in the bite angle for metal complexes with a chelate ring of the same size. The four frontier molecular orbitals (FMOs) for each of the metal complexes were also determined from the calculations.
This is also the case for the equivalent MOs of the platinum and palladium complexes of L2m and L2b. The energies of the metal complexes of the phenyl-substituted ligands increase even more (Figure 4.13).
Complex Energy
An increase in the metal-ligand interaction energy is noted when the electron-donating methyl group is present on the imine carbon and a decrease when it is exchanged for a conjugating phenyl ring.287 This is expected because the energy levels of the occupied orbitals will change markedly. change due to electrostatic effects caused by these groups.
DNA Binding Studies
- Introduction
- Objectives
- Experimental
- Materials and Chemicals
- Physical Measurements
- Results and Discussion
After the discovery of the chemical nuclease activity of transition metal complexes in the 1980s, interest in the interaction and mechanism of these complexes with DNA increased significantly. For an aromatic complex it has been found that perfect co-planarity of the rings present is unnecessary. The quality of a potential drug's toxicity (its cytotoxicity) does not depend entirely on its interaction with DNA.
These enzymes are involved in the fundamental steps of cellular growth (DNA replication), DNA recognition and the S and M phases of the cell cycle. The efficiency of the intercalation event can be fundamentally influenced by the electronic and steric properties of non-interacting ligands. Here we report the experimental findings of the biological testing and the results of an investigation into the interaction of six metal complexes with CT-DNA.
Adsorption titrations of complexes were performed in phosphate buffer at pH 7 using a fixed complex concentration to which aliquots of DNA stock solution were added. This was an unfortunate result; however, it does not exclude the interaction of the complexes with DNA. Thus we have studied the interactions of the complexes with calf thymus (CT) DNA, using a.
For brevity, examples of the data obtained for the metal complexes during the CT-DNA titrations will be discussed. Although no obvious bathochromic or hypsochromic effects were noted for the bands seen in Figure 5.2, there is the characteristic hypochromism for each of the five bands. The appearance of isosbestic points for the duration of the titration of the metal complexes with DNA can help to prove the existence of only the free and intercalated complex.
It was also found that the nonlinear equation fit the data for the palladium complexes slightly better than the data for the platinum complexes. The binding constants (Kb) for the platinum(II) and palladium(II) complexes in this section in the CT-DNA direction are of the order of 105 dm3 mol-1, estimated using UV/vis absorption spectroscopy. The results for binding constants, binding sites, and % hypochromicity for each of the metal complexes tested are shown in Table 5.3.
If the mode of action of the complexes in this work were to be considered cross-linking, then several factors must be considered. Addition of CT-DNA to EB, at pH ∼7, causes immediate spectral changes characterized by strong hypochromism and a significant red shift of the absorption maximum. These values compare well with those in this work; however, there is considerable variation in the shape of the plots.
