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Dissertation Information for Sharon T. Sullivan

NAME:
- Sharon T. Sullivan

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (2001)

ADVISORS:
- Luigi G. Marzilli

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

MPACT Status: Fully Complete

Title: Retro models of the cisplatin-DNA cross-link

Abstract: "Cisplatin ( cis -Pt(NH 3 ) 2 Cl 2 ) and its analogues are the most important inorganic compounds used in the treatment of cancer. The anticancer activity of cisplatin is widely attributed to the formation of a cross-link adduct involving two adjacent guanines in DNA. Adducts with single-stranded DNA [ cis -PtA 2 (oligonucleotide)] and complexes formed with unlinked guanine derivatives ( cis -PtA 2 G 2 ) have been frequently employed to model the cisplatin-DNA lesion (A 2 = two amines or a diamine). In these two model types, head-to-head (HH) and head-to-tail (HT) conformers are possible. The studies presented here concentrate on unlinked complexes and single-stranded adducts formed with a novel type of PtA 2 system where A 2 = N,N ' -dimethylpiperazine ( Me 2 ppz ).

HT and HH rotamers were found for Me 2 PPz Pt G 2 adducts by NMR spectroscopy. The relative distribution of conformers varied as a function of pH and identity of G . NMR and CD spectroscopic studies established the importance of phosphate group-cis G N1H interactions for stabilization of the dominant HT forms. The detection of the HH form for the Me 2 Ppz Pt G 2 complexes is the first report of this form for a cis -PtA 2 G 2 adduct where A 2 lacks NH groups. The chemical shifts of the H8 signals of the Me 2 PPZ Pt G 2 HH form suggest that the G bases assume an uncanted orientation; this unusual structural feature was supported by molecular modeling calculations.

Three dominant forms were found for the Me 2 ppz Pt(d(GpG)) adduct. Based on 1D and 2D NMR data, CD spectra, and molecular modeling calculations, these forms were assigned as two HH forms, HH1 and HH2, (differing with respect to the propagation direction of the phosphodiester backbone) and a HT conformer. This marks the first time three dominant conformers have been found and characterized for a cis -PtA 2 (d(GpG)) complex. Conformer distributions were influenced by pH and presence of residues flanking the 5 ' -side of the G-Pt-G cross-link lesion.

Unlinked and linked model adducts were also studied with the mono-methyl derivative, N -methylpiperazine ( Meppz )."

MPACT Scores for Sharon T. Sullivan

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2008-04-07 08:31:10

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