The electronic and steric effects of the ligand framework on reactivity of a series of Pt(II) complexes were investigated. Substitution reactions of the Pt(II) with chloride leaving group were studied in the presence of 10 mM LiCl to prevent spontaneous parallel reaction due to hydrolysis or solvolysis. DFT calculations were performed with the Gaussian 09 program suite to account for the observed reactivity of the complexes.
In the second series presented in Chapter Four, the ligand 2,2'-dipyridylamine chelate was modified by incorporating an alkyl group of variable chain length spacing tertiary nitrogen of the bidentate chelate giving analogues of cisplatin Pt(II) complexes. The trend in rate constant shows that the introduction of the alkyl chain on the tertiary nitrogen connecting the two pyridine units introduces the steric effect that blocks the approach of the nucleophile to the Pt(II) center. The decrease in reactivity of the Pt(II) complexes with the increase in length of the alkyl chain is also supported by the dipole moments and the calculated electrophilicity indices.
The effect of methyl σ-electron donating groups present on the pyrazine linker and the reactivity trend of these dinuclears with the azine bridge. The results showed that the chloro ligand in the Pt(N^S^N) complexes is more labile than the Pt(N^N^N) complexes due to the high trans-labilizing effect of the S-donor atom.
Cancer
Chemistry of Platinum
Platinum Based Anticancer Drugs
- Cisplatin
- Cisplatin Analogous
- Non-classical Pt(II) Drugs
- MonofunctionalPt(II) Complexes
- Trans Geometry Platinum Compounds
- Multinuclear Platinum Complexes
Inside the cell, oxaliplatin rapidly undergoes non-enzymatic transformation into reactive compounds after displacement of the oxalate group. Overall, toxicity of these new hybrid agents suggests that additional structural modifications of the tridentate ligand are still needed. In order to improve the potency and cellular uptake of monofunctional Pt(II) complexes, the tridentate stable ligand of the complexes must be varied so that various N/S-heterocyclic ligands can be included.
Modifications by the introduction of lipophilic ligands facilitate the absorption of the drug molecules across the cell membrane and influence the activity of the drug. Such modifications of the tridentate/bidentate carrier ligands of monofunctional Pt(II) complexes form part of this research as presented in Chapters Three, Four and Six of this thesis. Previously, it was generally accepted as a standard that a cis configuration of the leaving groups is necessary for antitumor activity of platinum compounds.40 However, it is.
Replacement of the chloro ligands with malonates (2), to improve water solubility, resulted in a series of 2,2/c,c complexes with good activity in cisplatin-resistant cancer cell lines.43e. For aliphatic chains, the ideal linker length appears to be eight atoms (two amine groups and six methylene).
Aims of the Study
Data from the studies of the binding of DNA with multinuclear platinum complexes in different cancer cell lines show some important structure-activity rules.47 The main factors consistent in the design of multinuclear platinum drugs include; chain length and flexibility, hydrogen bonding capacity and charge of the linker chain and the geometry of the leaving ligand with respect to the linker. In studies where the dpzm ligand was used as the linker, their complexes were found to be less active than their aliphatic equivalents 1,1/t,t (n=6, 12) and BBR3464.43(a) The decrease in activity of the mentioned complexes was therefore attributed to the rigidity of the switch. Geometric isomerization also plays a role, for example complexes with the chlorine ligand trans to the bridging ligand are generally more active, especially in cisplatin-resistant cell lines.50 This type of dinuclear Pt(II) complexes form part of the research objectives and are discussed further . in chapter five.
The results of the substitution reactions with biologically relevant ligands could help to get more information about the possible modes of interaction of Pt(II) complexes with in vivo targets and their representative application in the study of their antitumor properties. Moreover, the reactivity of the complexes will be useful to predict the extent of drug with similar structure that reaches the target sites, as well as the degree of side reactions, its circulation life and more importantly the antitumor activity of the drug at the target sites. In the development of multinuclear Pt(II) complexes, the nature and size of the linker play a role in determining the biological activity of the resulting complexes.
Thiourea nucleophiles were chosen as the entry nucleophile due to their biological importance and their high nucleophilicity prevents possible back reaction.52 The non-labile chelating ligand framework of the complexes was carefully electronically/sterically adjusted to enable a systematic study of the reactivity of the complexes towards the corresponding nucleophile. The electronic and steric effects of the tertiary nitrogen alkyl group with variable chain length of the bidentate chelate are investigated.
Experimentally, it is found that the rate of a reaction depends mainly on the concentration of the reactants. The forward reaction is second order while that of the reverse reaction is first order. The degree of interaction of the sample with radiation (transmission or absorption) is determined by measuring both the intensity of the incident radiation, I0 (without the sample) and the transmitted intensity, I (with the sample).
Alarge value of S means that the complex is very sensitive to changes in the nature of the nucleophilic reagent. It is clear from the optimized structures that the planarity of the complexes increases with the increase in π-conjugation. Substitution of labile chloride from each of the Pt(II) complexes (Figure 3.1) with neutral sulfur-containing nucleophiles, ie.
It is also clear that the alkyl chain also brings with it the steric effect that blocks the nucleophile's access to the Pt(II) center. The boat-like structure of the six-membered chelate ring also contributes to the steric effect. This is expected to influence the electronic properties of the Pt(II) center and thus the substitution reactions.
Acidities of coordinated diaqua ligands on Pt(II) complexes were determined by spectrophotometric titration. The second-order rate constants k1 and k2 of the reactions (where k1 = rate constant for the first stage and k2 = rate constant for the second stage) were obtained from. A set of 1H NMR spectra (showing only aromatic resonances) for the reaction between Ptdppa-Cl and excess TU (six equivalents) is shown in Figure 4.8.
The numbering scheme used for the pyridyl protons is shown in the structure of the Ptdppa-Cl2 complex in Scheme 4.3.
