FLAVONOID FLAVONOID FERVERFERVER

And the Charm of Chalcones

Wine and the French paradox

The French are 2.5 times less likely than Americans to die of coronary heart disease. Regular consumption of red wine is linked to

reduced clumping of platelets; improved cardiovascular risk profile; increased levels of HDL’s

Structural Features of Naturally Occurring Bioflavonoids

O

O

OH

O

O

O

O

Flavanone Flavone

Flavanols

O

Chalcones

Mechanisms of Bioactivity

• Flavonoids are capable of scavenging free radicals and possibly quench singlet oxygen

• Many naturally occurring flavonoids are capable of chelating metals and thereby preventing them from reducing H2O2 in hydroxyl radical formation.

• Flavonoids have a synergistic effect on vitamin C and appear to stabilize ascorbic acid in human tissues

Plant Biosynthesis of Flavonoids

HO

C

O

SCoA

HO

C

O OH

OHHOchalconesynthase

3 malonyl CoA

p-coumaroyl-CoA 4,2',4',6'-tetrahydroxychalcone

chalconeisomerase O

O

HO

OH

OH

Naringenin

O

O

HO

OH

OH

HO

O

O

HO

OH

OH

HOO

O

HO

OH

OH

HO

OH

flavonesynthase

flavonesynthase

flavonoidhydroxylase

flavonoidhydroxylase

Quercitin

Kaempferol

Crystal Structure of Quercetin

Reaction of Quercetin with Reaction of Quercetin with Hydroxyl RadicalsHydroxyl Radicals

.2 HO+ 2 H2O

O

O

OH

HO

OH

O

O

O

O

OH

HO

OH

OH

OH

Fe2+ + H2O2 Fe3+ + HO. + OH-

Cu2+ + HO. + OH-Cu+ + H2O2

Cu+ + Dehydroascorbic acid Ascorbic acid Cu2+

Fenton reaction

Citrus limonCitrus limon

O

O

O

HO

OH

OH

OH

rutinose

Rutin

Dried peels of bitter orange treeDried peels of bitter orange tree

Naringinen-7-rhamnoglucoside

O

O

O

OH

OH

OHDisaccharide

BuchuBuchu

O

O

HO

OH

OH

OCH3

Diosmetin

Marigold Marigold flowerflower

O

O

OH

CH3O

OH

OH

OH

Rhamnetin

Milk ThistleMilk Thistle

O

O

HO

OH

O

O

OH

OCH3

CH2OH

OH

SilybinSilybin

Preparation of 2’-HydroxychalconesPreparation of 2’-Hydroxychalcones

X = H, N(CH3)2

OH O

X

C

O

CH3

OH C

O

HX

5 eq NaOH

ethanol

Preparation of Chalcones by Claisen-Schmidt Condensation

ethanol

NaOH

- H2OC

O

CH CH XC

O

CH2 CH

OH

X

C

O

HX

C

O

CH2C

O

CH3

Stereoselectivity of Condensation

HHO

C

O

HH H H

C

O

OHH

C

C6H5H

O

H

CH

C6H5

O

C6H5

- H2O

trans alkene

Cyclization of 2’-Cyclization of 2’-Hydroxychalcones to Hydroxychalcones to

FlavanolsFlavanols

CCH CH

O

OH O

O

OH

NaOHethanol

H2O2

2'-Hydroxychalcone Flavanol

Delocalization of electrons in Chalcone

O

Charge Distribution in Charge Distribution in 2’-Hydroxy-4-dimethylaminochalcone2’-Hydroxy-4-dimethylaminochalcone

KTaut

O OH

N(CH3)2

O OH

N(CH3)2

O OH

N(CH3)2

X MW mp ( C) IR ( CO) max ( x 10-4)

H 208.26 55 - 7 1665 312(0.89), 230 (2.67)

Cl 242.7 112 - 4 1667 325 (2.15), 313 (2.83),229 (1.45), 204 (1.86)

Br 287.2 127 - 8 1668 324 (2.02), 303 (2.49),229 (1.12), 204 (1.63)

CN 233.26 154 - 6 1671 303 (1.59), 274 (1.87),204 (1.43)

NO2 253.25 164 - 5 1672 316, 263 (2.88)

OCH3 238.28 79 - 81 1663 341 (1.18 ), 245 (2.40)

N(CH3)2 251.32 114 - 6 1656 422 (0.57), 266 (2.29),205 (1.63)

O

X

4-Dimethylaminochalcone, 4-Dimethylaminochalcone, 10-5M in methanol

190 241.667 293.333 345 396.667 448.333 5000

0.575

1.15

1.725

2.3

wavelength in nm

abso

rban

ce2.3

0.0

A1k

500190 k

200 250 300 350 400 450 5000

0.45

0.9

1.35

1.8

wavelength in nm

abso

rban

ce

1.8

0

A1k

500200 k

10-4 M DMAC in acidified methanol

4-Dimethylaminochalcone

Absorbances of some Chalcones Absorbances of some Chalcones in the UV and IRin the UV and IR

1633

1665

1648

1639

C=O(cm-1)X max (nm)

H

H

H

354

323

312

CH CH C

O

X

413N(CH3)2

Y

H

OH(para)

OH(ortho)

OH(para)

Y

OH(ortho)N(CH3)2 434 1619

Features of Strong Hydrogen BondingFeatures of Strong Hydrogen Bonding

• The pKa of the hydrogen donor is similar to the conjugate acid of the hydrogen acceptor;

• The energy barrier to proton transfer diminishes as the distance between the heteroatoms involved in hydrogen-bonding is reduced to value less than the sum of the van der Waals radii: < 255 pm for O-H-O and < 265 pm for O-H-N);

• H NMR chemical shifts for participating proton is far downfield (typically in the range of 16 to 20 ppm).

Crystallographic Data forCrystallographic Data for2’-Hydroxy-4-dimethylaminochalcone2’-Hydroxy-4-dimethylaminochalcone

Nuclei Interato mic Distance ( )

O1 , O2 2.43 (< 2.55)

O1 H 1.20

H O2 1.31

C = O2 1.27 (1.22)

C O1(H) 1.31 (1.36)