Metal binding Flavanoids

1. Pooja

2.  Amyloids are typically hard, waxy deposits of peptide of 36–43 amino
acids that is processed from the amyloid precursor protein (APP)
 They stick to themselves and then propagate to form fibrils, but only some of the
fibrils turn out to be toxic
 Aggregated Aβ found in plaques in the hippocampus and neocortical regions of
the human brain are considered a hallmark of the neuropathology of the
neuro degenerativ Alzheimer’s disease (AD)
 Aggregation is dependent on the metal ions Copper ,Iron and Zinc
 The redox-active Cu and Fe complexes of Aβ can
cause damage to the neurons potentially via ROS
( reactive oxygen species)

3. Oxidation activity of these metal complexes can be controlled by natural antioxidants
like flavonoids
Flavonoids: Flavonoids are polyphenolic compounds that are ubiquitous in nature
and which are characterized by showing a variety of pharmacological
activities
Antioxidant Antihelmintic Antiinflamatory Antiviral
According to stucture they are categorized into different subgroups
Flavonols
Flavanols
Flavanones
•Metal binding of two family of flavonoids and their distinct inhibition mechanisms
toward the oxidation activity of Cu2+−β-amyloid investigated here

4. Oxidative Activity of CuAβ Toward Flavanols
 Flavanols acts as suicide antioxidative substrates ie inhibits oxidation of CuAβ
by being oxidised by itself to protect sensitive biomolecules
 They contain a catechol moiety and are thus expected to be effectively oxidized
by CuAβ to yield o-quinone CuAβ follow a binuclear metal-centered chemistry
through a (CuAβ)2 dimer.
catechin (Ct; II) of the flavanol
family

5. CuAβ also exhibits peroxidation activity in the presence of H2O2. The rates of Ct and
Et oxidation by CuAβ are significantly enhanced in the presence of H2O2
(A) Oxidation of Ct (square) and Et (circle) by 4.95 μMCuAβ with (solid symbols) and without (open symbols)
30 mM H2O2 and Hanes plot representation of the oxidation of Ct (B) and Et (C) by 4.95 μM CuAβ in the
presence of (●) 2.5 mM, (○) 5.0 mM, (▼) 10.0 mM, (∇) 20.0 mM, and (■) 30.0 mM H2O2 in 100.0mM
HEPES at pH 7.0 and 25 °C.

6. Inhibition of the Oxidative Activity of CuAβ
by Flavonols
 Flavonols show competitive inhibition pattern due to their binding to the redox-active
metal center of CuAβ.
Flavonol binding to metal ions and Cu βamyloid is
investigated using Querceitin(Qr) as an example.
 Qr has three possible metal-binding sites: β-ketophenolate, α-ketoenolate, and
catecholate
 The metal-binding site in flavonols has to be a site other than the catechol moiety as
catechol binding would result in its oxidation.
 The mechanism of inhibition was further explored with the pyrone kojic acid (KA; 5-
hydroxy-2-hydroxymethy1-γ-pyrone, that contains an α-ketoenolate moiety as in Qr
 The inhibition constants of the α ketoenolate-containing compounds are not
drastically different from each other

7. Variation in rate oxidation of CuAβ with varying concentration of dopamine and catecol
moiety was investigated for four different concentration of flavonols and compared with
activity of KA
Similar oxidation activity of KA
and flavonols suggests that α-
ketoenolate moiety is probably the
site for Qr binding to CuAβ
inhibitory site is the α- ketoenolate
moiety

8. Ca2+Influence
The rate of catechol oxidation by CuAβ
inhibited by a fixed concentration of Qr
increases with increasing concentration
of Ca2+
Ca2+ ions may compete for binding to
these flavonols and can potentially
reduce the inhibition capability of these
flavonoids

9. Quercetin Binding to Metal Ions and Cu-β-Amyloid
Qr shows a characteristic absorption at 383 nm in
DMSO (trace a,) that shifts to 450 nm upon addition of
metal ions
The flavonoid 5-hydroxyflavone (5-Hf) has only a β-
keto-phenolate metal-binding moiety, while Ct possesses
only the catechol moiety for possible interaction with
metal ions.
The binding of Co2+ with 5-Hf(trace g) or with Ct,( trace
h) does not show the characteristic absorption at 450
nm indicating the α-ketoenolate moiety is the most
likely metal-binding site on Qr
Electronic spectra of different metal flavonoid
complexes (a, Qr; b, Yb3+−Qr; Co2+−Qr; d,
Cu2+−Qr; e, Ca2+− Qr; f,(Cu2+−Aβ1−20)−Qr; g,
Co2+−5Hf; h, Co2+−Ct)
Thechange in
absorption was
fitted to 1:1metal-to-
ligandbinding to
obtain orresponding
affinity constant
forCu2+(●), Co2(O),
and Yb3+ (▼

10. Concluding remarks
 Flavonoids have been shown to exhibit therapeutic benefits toward age-related
neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease.
 The results presented in this report regarding the metal-binding capability and the inhibitory
effect (rather than simply serving as antioxidants and being oxidized) of the flavonols toward the
oxidative chemistry of CuAβ support their further use as molecular templates for drug design
and finding strategies for potential prevention/treatment of oxidative stress in AD and other
disorders
 The metal-binding capability of the flavonols Qr and Mr may play a dual role in preventing
further damages resulted from oxidative stress by acting as an inhibitor toward the oxidation
reaction and as a regulator for biological buffering of metal ions

11. References