Award Date

8-1-2014

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Committee Member

Bryan L. Spangelo

Second Committee Member

Pradip K. Bhowmik

Third Committee Member

Ronald K. Gary

Fourth Committee Member

Vernon Hodge

Fifth Committee Member

Steen Madsen

Number of Pages

219

Abstract

Three series of platinum(II) and platinum(IV) complexes containing 4,4′-disubstituted-2,2′-bipyridine ligands have been synthesized and characterized by 1H NMR, 13C NMR spectroscopy, elemental analysis, mass spectroscopy, and differential scanning calorimetry measurements. The MTS cell proliferation assay was used to examine the in vitro anti-proliferative activities of these complexes in various human breast, lung, and prostate cancer cells. The cell's response to the complexes varies between different cell lines; however, the low EC50 values determined from the MTS data indicate that several of the complexes are much more potent than cisplatin.

Flow cytometric analysis of selected compounds revealed induction of apoptosis and some necrosis. One of the complexes,Pt(II)-4C, was further studied by examining its interaction with DNA and its effect on mitogen-activated protein kinase (MAPK) signaling. Data from UV-Vis analysis with calf thymus DNA, gel electrophoresis with plasmid pBR322 DNA, and inductively coupled plasma-atomic emission spectrometry (ICP-AES) indicate thatPt(II)-4Cis able to bind to DNA, cause unwinding of the circular plasmid DNA, as well as covalently modify cellular DNA. Results from western blotting, flow cytometric immunofluorescence, and immunofluorescence microscopy indicate activation of JNK, ERK, and p38. Cells treated withPt(II)-4Cin the presence of JNK and p38 inhibitors had increased cell viability compared to cells treated withPt(II)-4Calone indicating that JNK and p38 are involved inPt(II)-4Cinduced cell death.

These results demonstrate the potential utilization of these novel complexes for the treatment of cancer.

Keywords

2,2′-bipyridine; Analogues; Bipyridinium compounds; Cancer – Treatment; Cisplatin; Mitogen-activated protein kinases; Platinum; Platinum compounds

Disciplines

Biochemistry | Oncology | Organic Chemistry

Language

English


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