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Dissertation Information for Kevin Michael Williams

NAME:
- Kevin Michael Williams

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (2000)

ADVISORS:
- Luigi G. Marzilli

COMMITTEE MEMBERS:
- Karl S. Hagen
- Craig L. Hill

MPACT Status: Fully Complete

Title: Effects of carrier ligands on platinum anticancer drug chemistry

Abstract: "For [PtX2( Me 2 DAP )] complexes ( Me 2 DAP = N,N ' -dimethyl-2,4-diaminopentane, X = Cl, I), the flexible six-membered chelate ring can assume chair and skew conformations. Steric interligand interactions resulted in a preference for axial N-Me groups. Likewise, in Me 2 DAP Pt G 2 complexes [ G = guanine derivative], the N-Me groups favored axial positions, resulting in rapid rotation around the Pt-N7 bond.

For cis -PtA 2 (GpG) complexes (A 2 = amine ligand), four conformer classes are possible: HH1, HH2, ¥ÄHT1, and ¥ËHT2 (bases head-to-head or head-to-tail and the propagation direction of the phosphodiester backbone similar (1) or opposite (2) that of B-DNA). Additionally, each residue can be syn or anti and the canting left (L) or right (R) handed, giving 32 possible variants. Bip Pt(GpG) complexes [ Bip = 2,2 ' -bipiperidine] form variants similar to those of the corresponding Bip Pt(d(GpG)) complexes except that no anti, anti HH2 R variant is observed for ( R,S,S,R )- Bip Pt(GpG) [N,C,C,N stereochemistries of R,S,S,R , respectively]. At pH 10, both G N1H's are deprotonated, and the anti, syn ¥ÄHT1 L variant becomes more favorable for ( S,R,R,S )- Bip complexes. The syn, syn ¥ËHT2 R variant slowly emerges at pH 10 for ( R,S,S,R )- Bip complexes and disappears immediately when the pH was dropped to ¡­3. 1 H NMR and CD spectra of cis -Pt(NH 3 ) 2 (GpG) at physiological pH are similar to those of ( R,S,S,R )- Bip Pt(GpG), suggesting anti, anti HH1 R is favored for cis -Pt(NH 3 ) 2 (GpG). At -40¡ÆC in 1:1 D 2 O:CD 3 OD, a second form observed for cis -Pt(NH 3 ) 2 (d(GpG)) by 1 H NMR spectroscopy was concluded to be anti, anti HH2 R. Based on comparison of spectral data to that of Bip Pt(d(GpG)), cis -Pt(NH 3 ) 2 (d(GpG)) was concluded to be a mixture of variants in rapid exchange at room temperature in D 2 O.

Steric interligand interactions influence the variant distribution of Me 2 DAP Pt(GpG) complexes. At pH ¡­9.5, isomerization at the nitrogen centers occurs for the Me 2 DAP ; the isomer distribution is influenced by the GpG ligand."

MPACT Scores for Kevin Michael Williams

A = 0
C = 1
A+C = 1
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2014-03-10 23:14:27

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