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Advances in platinum-amine chemotherapeutic agents : their chemistry and applicationc

The research conducted in this study focussed on advancing the knowledge database of diamineplatinum complexes on two frontiers: 1) the development of novel anticancer complexes, and 2) improvements in their synthetic chemistry. Novel square-planar dichloro and oxalato platinum(II) complexes were synthesized as potential anticancer agents in accordance with a comprehensive set of factors identified as being significant in optimizing such action. The nonleaving ligands consisted of asymmetric chelating chiral diamines of the form 1- (1-R-imidazol-2yl)(R')methanamine (R representing methyl, butyl and R' methyl, phenyl). The complexes were characterized by a host of spectral, thermal and crystallographic techniques. In addition, the stabilities of the complexes were monitored in aqueous and saline solutions. Cytotoxicity screening on three cultured cancer cell lines (MCF-7, HeLa and HT29) indicated the compounds, present as their respective racemates, to have rather modest activities relative to cisplatin; with complexes having the smallest substituents, R,R' = methyl, being most active. In recognition of the limitations of traditional silver-based syntheses of oxalatoplatinum(II) complexes, innovative non-silver methods were developed using the well known cancer drug, oxaliplatin, (trans-R,R-1,2- diaminocyclohexane)oxalatoplatinum(II), as a prototype. These involved direct ligand exchange reactions of the dichloro precursor, (trans-R,R-1,2- diaminocyclohexane)dichloroplatinum(II), with tetrabutylammonium oxalate in essentially non-aqueous solvents. A 90:10 mixture of isoamyl alcohol (3-methyl- 1-butanol):water, proved to be a promising solvent, enabling the recovery of pure oxaliplatin (~98 percent) after 9 hours at 88 °C in yields of up to 86 percent. In light of the perceived unique mode of anticancer action available to mononitroplatinum(IV) complexes (i.e. their STAT3-binding potential), octahedral diamineoxalatoplatinum(IV) complexes containing axially-coordinated nitro and halo co-ligands were synthesized and extensively characterized. Electrochemical studies revealed trends in reduction potential which could be correlated to structural / chemical traits of the coordinated diamine and axial ligands. The similarities of the determined cytotoxicities of the platinum(IV) compounds and their respective platinum(II) analogues, implicated reduction as a means of activation of the platinum(IV) complexes.

Identiferoai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:nmmu/vital:10446
Date January 2009
CreatorsJaganath, Yatish
PublisherNelson Mandela Metropolitan University, Faculty of Science
Source SetsSouth African National ETD Portal
LanguageEnglish
Detected LanguageEnglish
TypeThesis, Doctoral, PhD
Formatxviii, 222 leaves, pdf
RightsNelson Mandela Metropolitan University

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