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Title: Mechanism of action of platinum anticancer drugs : from kinetic to structural studies
Author: Chen, Yu
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Cisplatin, cis-[Pt(NH3)2Cl2], has been a successful and most widely used anticancer drug since its first discovery 30 years ago. Up to now the mechanism of action of this drug is still not well understood. In this thesis, pH dependent platinum-sulfur interactions, the solution structure of cisplatin DNA GpG intrastrand adduct and the chemistry of a new anticancer active drug have been investigated. Using [1H, 15N] 2D NMR spectroscopy and HPLC, together with 15N-labelled amine ligands highly pH dependent interconversion between S- and N-bound methionine adducts of {Pt(dien)}2+ (dien = diethylenetriamine) via dien ring-opened intermediates has been observed. This isolated ring-opened intermediate exists as four diastereomers and was surprisingly long-lived. This study suggests a possible role for thioether-sulfur in the transfer and activation of platinum drugs. The solution structure of a DNA 14mer duplex containing a cisplatin 1,2-GpG intrastrand crosslink has been determined by combined NMR and estimated molecular dynamics. Plantation at GpG site causes significant bending and unwinding of the DNA duplex. Sequence dependent structural characteristics are discussed. The 2-picoline (2-methylpyridine) complex, cis[PtCl2(NH3)(2-Pic)] (1), is a recently reported anticancer active complex with high activity against cisplatin resistant cell-lines and has now entered clinical trials. The crystal structure of 1 shows steric hindrance induced by the 2-CH3 group towards an axial approach to Pt. 15N labelling of 1 and 2D [1H, 15N] NMR spectroscopy allowed both the hydrolysis rates and pKa values of the complex to be determined. The steric effect of 2-picoline ligand reduces the reactivity of the complex during substitution reactions and the position cis to 2-picoline is more affected. Reactions between 1 and guanosine 5'-monophosphate (5'-GMP) were followed by 2D NMR and kinetic rates were calculated. The reactivity of 1 with thiol ligand of glutathione (GSH) was greatly reduced compared with its 3-picoline analogue which is less sterically hindered. Both mono- and bis-GMP adducts were observed in the competitive reactions of 1 with GSH and GMP. Slow rotation about the Pt-N picoline bond and fast rotation about Pt-N7 GMP bonds on the NMR time scale were observed for the bis(GMP) adducts. These features of 1 may play an important role in its altered spectrum of biological activity compared to cisplatin. Complex 1 forms four stereoisomers in the reactions with d(GpG) and a 14mer DNA single strand due to the different orientations of 2-picoline (either towards 5'-G or 3'-G) and slow rotation of Pt-N(2-Pic) bond. These contrast with reactions of 1 with a 14mer DNA duplex, in which only one major stereoisomer is observed. 2D NMR experiments and molecular modelling suggest that favourable steric interactions, H-bonding and van der Waals contact provide the structural basis for this unusually high stereoselectivity. These results give new insights into the effect of ligand design on the nature of platinated DNA lesions.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available