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(PS5-07) Cisplatin adducts sensitize DNA to attack by hydrated electrons leading to cisplatin detachment
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and base damage. Behnaz Behmand ; Pierre Cloutier, MSc ; Richard Wagner, Pr ; Léon Sanche, Pr ; Darel
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Hunting, Pr ; Jean-louis Marignier, Pr ; and Mehran Mostafavi, Pr
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2
Université de Sherbrooke, Sherbrooke, Canada and Université de Paris-Sud, Orsay, France
Cisplatin [PtCl2 (NH3)2] is a chemotherapeutic agent that chemically binds to DNA purines bases,
especially guanine (G) at position N7 [1]. Recent experiments have shown enhancement of single and
double strand breaks by low energy electrons in dry supercoiled plasmid containing low levels of cisplatin
adducts [2]. In the present work, we studied hydrated electron interactions with short oligonucleotides
(5'-TTTTTGTGTTT-3' and 5'-TTTTTTTGTTT-3') containing cisplatin adducts on the guanine(s). Cisplatin-
oligonucleotides, with either a cisplatin monoadduct or a diadduct between the guanines were labelled
with 32P and exposed to hydrated electrons in solution generated by gamma ray induced radiolysis.
Damage was evaluated with gel electrophoresis [3] and high-performance liquid chromatography. These
results show that the hydrated electrons induce the detachment of cisplatin adducts from the
oligonucleotides. We propose that cisplatin leads to the capture of a hydrated electron by the
oligonucleotide giving rise to a transient anion, which dissociates, breaking of one or two guanine-cisplatin
bonds that is dissociative electron transfer. Furthermore, much higher levels of base damages are
detected when cisplatin adducts are present. This damage was largely localized at cisplatin attachment
sites (guanines) but also on thymines. Finaly, the rate constant for the hydrated electron interactions with
cisplatin-oligonucleotide was measured using pulse radiolysis. The large rate contant (2, 23x10^10 Lmol^-
1s^-1) demonstrates that the presence of a cisplatin adduct leads to a strong interaction with hydrated
electrons. Our results have revealed the probable mechanism by which cisplatin adducts sensitize DNA to
the indirect effects of ionising radiation. [1]Reedijk, J. Platinum Anticancer Coordination Compounds:
Study of DNA Binding Inspires New Drug Design. Eur. Inorg. Chem. 2009, 1303-1312 [2] Zheng, Y.; Hunting,
D. J.; Ayotte, P.; Sanche, L. Role of Secondary Low-Energy Electrons in the Concomitant Chemoradiation
Therapy of Cancer. Phys. Rev. Lett. 2008, 100, 198101/1−198101/4. [3] Behmand, B.; Cloutier, P.;
Girouard, S.; Wagner, J. R.; Sanche, L.; Hunting, D. Hydrated Electrons React with High Specificity with
Cisplatin Bound to Single-Stranded DNA. J. Phys. Chem. B. 2013, 117, 15994-15999.
(PS5-08) Double oxidation of A-T and G-C base pairs: a density functional theory study. Anil Kumar and
Michael D. Sevilla, Department of Chemistry, Rochester, MI
It is well known that one-electron oxidation of A-T or G-C base pair removes an electron from the
doubly occupied HOMO (highest occupied molecular orbital) localized on adenine (A) or guanine (G) in
DNA as they have lower ionization potentials than thymine (T) and cytosine (C). For the resulting one-
electron oxidized A-T or G-C base pairs (A•+-T and G•+-C) the SOMO is localized on A or G and is lower in
energy than the doubly occupied HOMO localized on the pyrimidines (T or C). The SOMO lying lower in
energy than the HOMO apparently violates the Aufbau principle which does not always apply to radical
states. This directs second ionization to the pyrimidine bases resulting in triplet state diradical dications,
(A•+-T•+) and (G•+-C•+). On inter-base proton transfer the SOMO and HOMO levels switch and the
second oxidation is redirected to deprotonated G and A (G (-H) + and A (-H) +). For G-C the doubly oxidized
singlet G (-H) +-C (H+) is more stable than its triplet (G•+-C•+); however, for A-T the triplet state (A•+-T•+)
lies lower in energy than the singlet (A (-H) +-T (H+). The present study demonstrates that DNA directs
multiple ionizations to guanine after proton transfer. Supported by NIH R01 CA045424.
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1
and base damage. Behnaz Behmand ; Pierre Cloutier, MSc ; Richard Wagner, Pr ; Léon Sanche, Pr ; Darel
1
2
2
Hunting, Pr ; Jean-louis Marignier, Pr ; and Mehran Mostafavi, Pr
1
2
Université de Sherbrooke, Sherbrooke, Canada and Université de Paris-Sud, Orsay, France
Cisplatin [PtCl2 (NH3)2] is a chemotherapeutic agent that chemically binds to DNA purines bases,
especially guanine (G) at position N7 [1]. Recent experiments have shown enhancement of single and
double strand breaks by low energy electrons in dry supercoiled plasmid containing low levels of cisplatin
adducts [2]. In the present work, we studied hydrated electron interactions with short oligonucleotides
(5'-TTTTTGTGTTT-3' and 5'-TTTTTTTGTTT-3') containing cisplatin adducts on the guanine(s). Cisplatin-
oligonucleotides, with either a cisplatin monoadduct or a diadduct between the guanines were labelled
with 32P and exposed to hydrated electrons in solution generated by gamma ray induced radiolysis.
Damage was evaluated with gel electrophoresis [3] and high-performance liquid chromatography. These
results show that the hydrated electrons induce the detachment of cisplatin adducts from the
oligonucleotides. We propose that cisplatin leads to the capture of a hydrated electron by the
oligonucleotide giving rise to a transient anion, which dissociates, breaking of one or two guanine-cisplatin
bonds that is dissociative electron transfer. Furthermore, much higher levels of base damages are
detected when cisplatin adducts are present. This damage was largely localized at cisplatin attachment
sites (guanines) but also on thymines. Finaly, the rate constant for the hydrated electron interactions with
cisplatin-oligonucleotide was measured using pulse radiolysis. The large rate contant (2, 23x10^10 Lmol^-
1s^-1) demonstrates that the presence of a cisplatin adduct leads to a strong interaction with hydrated
electrons. Our results have revealed the probable mechanism by which cisplatin adducts sensitize DNA to
the indirect effects of ionising radiation. [1]Reedijk, J. Platinum Anticancer Coordination Compounds:
Study of DNA Binding Inspires New Drug Design. Eur. Inorg. Chem. 2009, 1303-1312 [2] Zheng, Y.; Hunting,
D. J.; Ayotte, P.; Sanche, L. Role of Secondary Low-Energy Electrons in the Concomitant Chemoradiation
Therapy of Cancer. Phys. Rev. Lett. 2008, 100, 198101/1−198101/4. [3] Behmand, B.; Cloutier, P.;
Girouard, S.; Wagner, J. R.; Sanche, L.; Hunting, D. Hydrated Electrons React with High Specificity with
Cisplatin Bound to Single-Stranded DNA. J. Phys. Chem. B. 2013, 117, 15994-15999.
(PS5-08) Double oxidation of A-T and G-C base pairs: a density functional theory study. Anil Kumar and
Michael D. Sevilla, Department of Chemistry, Rochester, MI
It is well known that one-electron oxidation of A-T or G-C base pair removes an electron from the
doubly occupied HOMO (highest occupied molecular orbital) localized on adenine (A) or guanine (G) in
DNA as they have lower ionization potentials than thymine (T) and cytosine (C). For the resulting one-
electron oxidized A-T or G-C base pairs (A•+-T and G•+-C) the SOMO is localized on A or G and is lower in
energy than the doubly occupied HOMO localized on the pyrimidines (T or C). The SOMO lying lower in
energy than the HOMO apparently violates the Aufbau principle which does not always apply to radical
states. This directs second ionization to the pyrimidine bases resulting in triplet state diradical dications,
(A•+-T•+) and (G•+-C•+). On inter-base proton transfer the SOMO and HOMO levels switch and the
second oxidation is redirected to deprotonated G and A (G (-H) + and A (-H) +). For G-C the doubly oxidized
singlet G (-H) +-C (H+) is more stable than its triplet (G•+-C•+); however, for A-T the triplet state (A•+-T•+)
lies lower in energy than the singlet (A (-H) +-T (H+). The present study demonstrates that DNA directs
multiple ionizations to guanine after proton transfer. Supported by NIH R01 CA045424.
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