Systematic kinetic and thermodynamic analyses of the substitution reactions of different Pt(II) complexes with a series of bio-relevant nucleophiles have been investigated as a function of concentration and temperature, using standard stopped-flow and UV–Vis Spectrophotometric methods. For this purpose, five different systems involving squareplanar Pt(II) complexes, viz. (i) mononuclear Pt(II) complexes with tridentate nitrogendonor ligands of varying degree of π-conjugation, and (ii) polynuclear Pt(II) complexes with azine, pyridyl units separated by S, S-S and CH2CH2 spacer groups, and α,ω- alkanediamine bridging ligands were synthesised and characterised by various spectroscopic methods. All substitution reactions of the Pt(II) chlorido complexes of the type [Pt(terpy)Cl]+ were studied in the presence of 10 mM LiCl to prevent spontaneous parallel reaction due to hydrolysis or solvolysis. The substitution reactions of the coordinated water molecules in the dinuclear Pt(II) complexes by thiourea nucleophiles of varying steric hindrance were studied under acidic conditions. The concentration of the nucleophile solution was prepared in 0.1 M NaClO4, at pH 2.0 and always at least 10- fold excess to provide pseudo first-order conditions. The pKa values of the coordinated aqua ligands of the dinuclear Pt(II) complexes were determined by Spectrophotometric acid-base titrations. DFT calculations were also performed in an effort to account for the observed reactivity of homologous analogues in each series of complexes, in terms of NBO charges and energies of frontier molecular orbitals. Substitution reactions of the Mononuclear Pt(II) complexes with tridentate ligands showed reactivity of the complexes is controlled by the π–acceptor characteristics of the chelate ligands. The fused rigid pyridyl system allows electronic interaction between the platinum centre and the pyridyl ligands, because of the extended conjugated π-system. This effect is controlled by how the fused ring system around the terpy moiety is structured. The isoquinoline moiety was found to reduce the effective π-backbonding and the lability of CH3PhisoqPtCl complex compared to 1,10-phenanthroline and terpyridine systems, indicating that isoquinoline ligand is a net σ-donor. The results obtained for the substitution reactions of the diaqua Pt(II) complexes with the thiourea and ionic (Br-, I- SCN-) nucleophiles demonstrate that reactivity increases with decreasing pKa values as well as decreasing distance between the Pt(II)centres. An increase in steric crowding at the Pt(II) centre imposed by the methyl groups on the azine linker decelerates the lability of the aqua ligands. The 1H and 195Pt NMR spectroscopic results confirmed degradation of the aromatic-based bridging ligand from the metal centre. The final cleavage of the complex linkers was only achieved after addition of excessive amounts of thiourea and other strong nucleophiles. The negative activation entropies and second-order kinetics for all the substitution reactions support the Associative mode of substitution mechanism. / Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2012.

Thesis (Ph. D.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 269-285).

Thesis (M. Phil.)--University of Hong Kong, 1994. / Includes bibliographical references (leaves 173-181).

Thesis (Ph. D.)--Virginia Commonwealth University, 2007. / Prepared for: Dept. of Chemistry. Bibliography: leaves 217-221. Also available online via the Internet.

The aim of this thesis was to investigate the properties of novel platinum compounds with possible potential as anticancer agents, and to determine how their behaviour could lead to a better understanding of the chemistry involved. The final criteria were improvement of their anticancer behaviour. Since many questions are still unanswered as to the role of sulfur in anticancer action, studies were undertaken to synthesize novel platinum(II) complexes having non-leaving groups consisting of a combination of an aromatic nitrogen and thioetherial sulfur capable of forming a five membered ring upon coordination. The structural unit was 1-methyl-2-methylthioalkyl/aryl. Numerous complexes formed by these ligands each having chloro, bromo, iodo and oxalato leaving groups were then fully characterized. The results obtained by the various synthetic methods were compared and explained in terms of the chemistry involved. The role of the sulfur donor was indicated in both the halo- and oxalato-complexes and proved to be strongly influenced by the nature of the leaving groups. Their differences are reflected in their anticancer behaviour. The study was extended to mononitroplatinum(IV) complexes, in view of the kinetically stable platinum(IV) compounds and advantages related to this. A specific mononitroplatinum(IV) complex which proved to have good anticancer and STAT 3 properties could according to the literature not be synthesized successfully in a good yield and a high degree of purity. The results of extensive studies showed that the main problem centred around the simultaneous reactions in equilibrium during the synthesis. A number of these species formed as a result of side reactions could be identified and their close separation factors indicated chromatographically. The mechanism of these reactions and the unstable intermediate species involved could be rationalized and compared to analogues in the literature. All the complexes studied were characterized by spectral and thermal methods both in solution as well as the solid state. Their anticancer behaviour towards three anticancer cell lines (Hela, MCF 7, Ht 29) were determined and acted as a guide towards possible structural modifications for their improved capability. Three crystal structures of platinum(II) complexes were determined. The extent of the ionization of the platinum(II) complexes as well the redox potentials (Pt(II) / Pt(IV)) of the platinum(IV) complexes were particularly important factors pertaining to their anticancer action.

Chemical hardness (eta), calculated by density functional theory (DFT), was firstly used as one of the chemical reactivity descriptors to set up the one descriptor 2D-QSAR model of platinum drugs. In this simple but promising model, the antitumour activities (log GI50) evaluated by National Cancer Institute (NCI) of structure-based groups containing normal sp 3 nitrogen and R,R-diamminecyclohexane (R,R-DACH) as the ligand showed good correlation. It was also demonstrated that silane and stereoisomers of DACH groups showed special patterns. This study also made use of the COMPARE program from NCI to evaluate the activity profile and the analysis of the data revealed these distinct patterns are influenced by the mechanism of the drugs. / Computer-aided drug design (CADD) techniques have been applied to establish quantitative structure-activity relationships (QSAR) and quantitative structure- property relationships (QSPR) models. Although these techniques are widely used in organic drugs, new metal-based drugs were hindered from development for lack of metal parameters, such as potent new platinum drugs as a major group of drugs used in cancer treatment. The purpose of the present study, therefore, is to generate novel platinum parameters based on previous work and then set up the simple QSAR/QSPR model with predictive abilities. / Finally, two 3D-QSAR and 3D-QSPR models obtained using Sybyl software. One was for demethylcantharidin (DMC) analogues as phosphatase 2A (PP2A) inhibitors. The other was describing the hydrophobicity of platinum drugs. In this research, the platinum atom was introduced to Sybyl and thus made it possible for the first time to use comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods to investigate platinum drugs. All 3D models indicated good predictive ability and thus provided an effective method to design new potent platinum drugs. / To clarify the pattern of stereoisomers of the DACH group, new platinum parameters was introduced to the AMBER software successfully. Moreover, stereoisomers of the DACH group which formed 1,2-GG intrastrand cross-links with DNA were studied by molecular dynamics (MD) simulations using AMBER. The calculated binding energies between R,R-DACH-Pt, S,S-DACH-Pt and cis-DACHPt moieties and DNA revealed a strong correlation with antitumour activities. The result provided more clues to understand the biological interactions of chiral platinum drugs. DNA structure analysis indicated that DNA tolerated the distortion resulted in the different Pt-DNA adducts and various local and global structure distortions were found. Natural bond orbital (NBO) analysis of hydrogen bonding on Pt-DNA adducts at a AGGC site revealed that R,R-DACH-Pt moiety alleviated the repulsion by unwinding the DNA, whereas the S,S-DACH-Pt adduct avoided the interaction by distorting the H bonds of binding site basepairs. Hence, the structural differences of chiral platinum drug led to its distinct activity. / Yang, Lifeng. / "June 2008." / Advisers: Steve C. F. Au Yeung; Yee-Ping Ho. / Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1541. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (p. 159-172). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (p. 137-147).

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Chemistry / Doctoral / Doctor of Philosophy