73
3 Formation of DNA Lesions, its Prevention and Repair
It was found that when an OH
•
attacks UCA, the RAF mechanism takes place
and the lowest Gibbs barrier energy for this reaction corresponds to the C5 site
(Fig. 3.7d). Barrier energies for the corresponding reactions at the C6 and C7 sites
were found to be similar. The second OH
•
attack at all these three sites led to adduct
formation barrierlessly. Binding energy analysis of the thus formed adducts revealed
that the most stable adduct was formed by the addition of an OH
•
at the C6 site of the
C7-OH
•
adduct. The third OH
•
abstracts the hydrogen atom of OH group bonded to
the C6 or C7 site leading to two different mechanims which are initiated barrierlessly. Attack of the fourth OH
•
leads to the formation of imidazole-4-carboxaldehyde,
glyoxylic acid and two water molecules as the primary products [142]. Formation
of imidazole-4-carboxaldehyde and glyoxylic acid as the primary products has been
observed experimentally [143, 144]. It was found that a positive barrier energy was
involved only in the addition reaction of the first OH
•
to urocanic acid, while the
reactions of the other three OH
•
were barrierless each [142]. Thus UCA has been
shown to be an effective anti-oxidant. It is believed that UCA can serve as a better
OH
•
scavenger than the traditional anti-oxidants like vitamins C and E.
Recently, it has been shown that compounds with phenolic rings in general can
act as good OH
•
scavengers. For example, resveratrol and salicylates have been
shown to have protective roles in this respect [145–147]. Curcumin, an extract of
turmeric, has been shown to act as a potential OH
•
scavenger (Fig. 3.7j). It is known
to have protective roles in cancer and the Alzheimer’s disease [148]. On the basis of
density functional theoretical studies, it has been shown that curcumin exhibits its
anti-oxidant property by donating an electron to OH
•
, by undergoing hydrogen abstraction or by addition reactions with OH radical [149]. Ferulic acid which can be
derived from curcumin [150] also scavenges OH
•
in a similar manner as curcumin.
It is present in leaves and seeds of brown rice, whole wheat, apple, orange etc. In
addition to the above, phenolic compounds can also scavenge OH radicals following
addition of OH
•
to their double bonds in aromatic rings. Natural polyene and polyphenol classes of substances, such as flavonoids, present mostly in fruits and vegetables can also protect biological systems against OH
•
mediated oxidative damage.
A detailed theoretical study of the anti-oxidant activity of curcumin has been
performed [149]. All geometry optimization calculations were carried out at the
BHandHLYP/6-31G(d, p) level of density functional theory in the gas phase. It was
followed by single-point energy calculations in the gas phase at the B3LYP/aug-ccpVDZ and BHandHLYP/aug-cc-pVDZ levels of theory. Solvent effect in aqueous
media was treated at the level of single point energy calculations at all the levels
of theory mentioned above and employing the PCM along with the gas phase optimized geometries at the BHandHLYP/6-31G(d, p) level. Geometry optimization in
aqueous media was also performed for certain reaction steps, and the Gibbs barrier
energies thus obtained were quite similar to those obtained by single-point energy
calculations. The SET mechanism was found to be more likely in polar media than
in the gas phase. For hydrogen abstraction and OH
•
addition, all the possible sites
were considered (Fig. 3.7j). It was observed that the most favorable site for hydrogen abstraction is the OH group attached to C2 while OH
•
addition was found
to be the most favored at the C10 site of the heptadiene chain (Figs. 3.7j, 3.8). In
3 Formation of DNA Lesions, its Prevention and Repair
It was found that when an OH
•
attacks UCA, the RAF mechanism takes place
and the lowest Gibbs barrier energy for this reaction corresponds to the C5 site
(Fig. 3.7d). Barrier energies for the corresponding reactions at the C6 and C7 sites
were found to be similar. The second OH
•
attack at all these three sites led to adduct
formation barrierlessly. Binding energy analysis of the thus formed adducts revealed
that the most stable adduct was formed by the addition of an OH
•
at the C6 site of the
C7-OH
•
adduct. The third OH
•
abstracts the hydrogen atom of OH group bonded to
the C6 or C7 site leading to two different mechanims which are initiated barrierlessly. Attack of the fourth OH
•
leads to the formation of imidazole-4-carboxaldehyde,
glyoxylic acid and two water molecules as the primary products [142]. Formation
of imidazole-4-carboxaldehyde and glyoxylic acid as the primary products has been
observed experimentally [143, 144]. It was found that a positive barrier energy was
involved only in the addition reaction of the first OH
•
to urocanic acid, while the
reactions of the other three OH
•
were barrierless each [142]. Thus UCA has been
shown to be an effective anti-oxidant. It is believed that UCA can serve as a better
OH
•
scavenger than the traditional anti-oxidants like vitamins C and E.
Recently, it has been shown that compounds with phenolic rings in general can
act as good OH
•
scavengers. For example, resveratrol and salicylates have been
shown to have protective roles in this respect [145–147]. Curcumin, an extract of
turmeric, has been shown to act as a potential OH
•
scavenger (Fig. 3.7j). It is known
to have protective roles in cancer and the Alzheimer’s disease [148]. On the basis of
density functional theoretical studies, it has been shown that curcumin exhibits its
anti-oxidant property by donating an electron to OH
•
, by undergoing hydrogen abstraction or by addition reactions with OH radical [149]. Ferulic acid which can be
derived from curcumin [150] also scavenges OH
•
in a similar manner as curcumin.
It is present in leaves and seeds of brown rice, whole wheat, apple, orange etc. In
addition to the above, phenolic compounds can also scavenge OH radicals following
addition of OH
•
to their double bonds in aromatic rings. Natural polyene and polyphenol classes of substances, such as flavonoids, present mostly in fruits and vegetables can also protect biological systems against OH
•
mediated oxidative damage.
A detailed theoretical study of the anti-oxidant activity of curcumin has been
performed [149]. All geometry optimization calculations were carried out at the
BHandHLYP/6-31G(d, p) level of density functional theory in the gas phase. It was
followed by single-point energy calculations in the gas phase at the B3LYP/aug-ccpVDZ and BHandHLYP/aug-cc-pVDZ levels of theory. Solvent effect in aqueous
media was treated at the level of single point energy calculations at all the levels
of theory mentioned above and employing the PCM along with the gas phase optimized geometries at the BHandHLYP/6-31G(d, p) level. Geometry optimization in
aqueous media was also performed for certain reaction steps, and the Gibbs barrier
energies thus obtained were quite similar to those obtained by single-point energy
calculations. The SET mechanism was found to be more likely in polar media than
in the gas phase. For hydrogen abstraction and OH
•
addition, all the possible sites
were considered (Fig. 3.7j). It was observed that the most favorable site for hydrogen abstraction is the OH group attached to C2 while OH
•
addition was found
to be the most favored at the C10 site of the heptadiene chain (Figs. 3.7j, 3.8). In