Defense Date

2010

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Nicholas Farrell

Abstract

Polynuclear platinum compounds represent a new class of potential platinum anticancer therapeutics. Derived from the most widely used platinum anticancer drug, cisplatin, these novel compounds are distinct in their interactions with bio-molecules. The effectiveness of platinum anticancer agents is influenced by three pharmacological factors: (i) their resistance to deactivating sulfur nucleophiles, (ii) the ability to gain cellular entry and efficient cellular uptake, and (iii) the ability to form stable and specific complexes with DNA. BBR 3464, the first multinuclear platinum compound to reach phase II clinical trials, has created a new approach to cancer drug design. Large, highly charged platinum compounds have been shown to form favorable covalent and noncovalent interactions with bio-molecular structures. Compounds such as BBR 3464, form an immediate pre-association with anionic structures on biomolecules before covalent attachment. To better characterize these interactions, a new set of compounds was designed that exclusively interacts via electrostatic associations and hydrogen bonding. The investigation of noncovalent complexes between DNA, proteins, and peptides with a variety of synthetic and biological relevant structures has become increasingly more common with the coupling of electrospray ionization and mass spectrometry (ESI-MS). Mass spectrometry has been useful to the drug design community by allowing the rapid and accurate characterization of drug binding sites. In the first project we have explored the use of collision induced dissociation (CID) to map the potential binding sites of noncovalent polynuclear platinum compounds of varying size and charge with an antisense oligonucleotide of the Bcl-2 sequence. In the second project, the gas-phase dissociation and stabilizing effects of these polynuclear platinum compounds on duplex DNA were determined. Correlations between the size and charge of associating platinum compounds were determined by comparing the change in gas phase stability under CID conditions. Additionally, the association of these new types of noncovalently binding polynuclear platinum compounds was investigated with model cell surface structures such as anionic heparan sulfate and phospholipids.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2010

Included in

Chemistry Commons

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