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Dissertation Information for Jamil S. Saad

NAME:
- Jamil S. Saad

DEGREE:
- Ph.D.

DISCIPLINE:
- Chemistry

SCHOOL:
- Emory University (USA) (2002)

ADVISORS:
- Luigi G. Marzilli

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

MPACT Status: Fully Complete

Title: Duplex and retro models of the cisplatin-DNA cross-link

Abstract: Cisplatin ( cis -Pt(NH 3 ) 2 Cl 2 ) is the most powerful inorganic anticancer drug. Cisplatin attack on DNA preferentially forms the key G*G* lesion (G* = N7-platinated dG). Adducts with single-stranded (ss) and duplex DNA models and complexes formed with unlinked guanine derivatives cis -PtA 2 G 2 (A 2 = two amines or a diamine, G = guanine derivative) have been employed frequently to study the cisplatin-DNA lesion. In these models, head-to-head (HH) and head-to-tail (HT) conformers are possible. The studies presented here cover a wide area of Pt-DNA adducts including unlinked complexes, single-stranded adducts, and a duplex. We studied a cisplatin-duplex with only G·C bps in the XG*G*Y site by NMR methods for the first time. We concluded that all XG*G* and XA*G* (X = C or T) duplexes undoubtedly have structures similar to our model. The cross-link (G*G*) and the adjacent (XG*) base pair (bp) steps in the XG*G* region of reacted DNA have large distortions from B-form DNA. Stabilizing factors of HT and HH conformers were extensively studied for Me 2 DAB Pt G 2 and Bip Pt G 2 adducts ( Me 2 DAB = N,N \' -dimethyl-2,3-diaminobutane, Bip = 2,2 \' -bipiperidine) by NMR spectroscopy and CD methods. Conformer distribution 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 \"second-sphere communication\" for stabilization of the dominant HT forms. We present novel data on Bip Pt adducts with ss oligonucleotides (oligo) longer than d(GpG). Data establish that the HH1 conformer clearly dominated when the oligo had a 5 \' -residue (including a phosphate group) on the 5 \' -G*. Finally, we extended our retro-modeling approach and studied unlinked and linked adducts of Me 4 DAB Pt ( Me 4 DAB = N,N,N \' , N \' -tetramethyl-2,3-diaminobutane). Only HT conformers were observed for Me 4 DAB Pt G 2 adducts; however, HH and HT conformers were observed and characterized for Me 4 DAB Pt ss adducts.

MPACT Scores for Jamil S. Saad

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2008-03-23 20:44:47

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