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Origem Química: Policetídeos; Ácido Chiquímico
Distribuição Taxonômica: ampla (ex. ácido caféico é um dos compostos fenólicos mais comuns em plantas)
Fontes comuns: Uva-Ursi, Salgueiro, Tomilho, Rosmarino, Lúpulo, cebolas, etc.
Propriedades Terapêuticas: antisépticos & antimicrobianos; antiinflamatórios & analgésicos; antispasmódicos; antipréticos; diuréticos; irritantes tópicos.
O
CH2OH
OH
OH
OH
OH
CO2
hn
fotossíntese
Glucose (6 carbonos)
O
CH2OH
O
OH
OH
OH
O
CH2OH
O
OH
OH
O
CH2OH
O
OH
OH
amido n glicólise
CH
CH2OP
OH
CHO
C OP
CH2
COOH
C
CH2OP
O
CH2OH
fosfoenol
piruvato (PEP) (3 carbonos)
CH3
C
O
SCoA
acetil-
Coenzima A (2 carbonos)
Ciclo
Ácido
cítrico
energia (ATP)
+ CO2 + H2O
CH3
C
O
CH2
C
O
CH2
policetídeos
acetogeninas
lipídeos
Ácidos graxos
Ácido
mevalônico
terpenos
esteróides
carotenóides
O O
OH CH3
CH OH
CH OH
CH2OP
CHO
eritrose-
4-fosfato
COOH
OH OH
OH
ácido chiquimico
NH2
COOH
ácido
antranilico
fenilalanina
tirosina
alcalóides
triptofano
oxal-
acetato
lisina
ornitina
Ácido aspártico ácido
nicotinico
Fenóis simples
Fenilpropanóides
Biossíntese de
ácidos graxos CH3C
O
SCoA
C
O
CH2 C
O
SCoA-O
malonil CoA
acetil CoA
malonil ACP
C
O
CH2 C
O
SACP-O
cetobutiril ACP3
3 hidroxibutiril ACP
NADPH + H+
NADP+
CH CH2 C
O
SACPCH3
trans-2-butenoil-SACP
butiril-SACP
CH2 C
O
SACPCH3CH2
3 cetoacil ACP
C
O
CH2 C
O
SACPR
CO2
CO2
NADP+
NADPH + H+
H2O
outro ciclo
CH2 C
O
SACPC
O
CH3
CH2 C
O
SACPCH
OH
CH3
OH O
OH
Ácido anacárdico
(Pistachia vera - Anacardiaceae)
OH O
HO OH
produto de algas (Zonaria - Dictyotales)
OH OH OH OH
NH2
OH
O
6-metiltetraciclína
ácido 6-metilsalicílico
OH
O
OH
O O O
OH OH O
OH-
2,4,6-heptanotriona
Collie (1907): Síntese biomimética que gerou a hipótese da biossintese
policetídica de moléculas aromáticas.
O O O
O O O
Birch (1950): Confirmou a hipótese através da incorporação de
acetato marcado.
CH314CO2H
P. patulum
OH
O
OH*
* *
*
ácido 6-metilsalicílico
OH
O
OO
OO
OH
OOOCH3 C
O
SR-O C
O
CH2 C
O
SR
acetil-SR (1) malonil-SR (3)
Claisen
Claisen
floroacetofenona
OH
HO OH
OO
OO
OCoAS
aldol
ácido orselínico
OHHO
O
OHSCoA
O
OO
O
Humulus lupulus L.
(Cannabaceae)
humulona, lupulona (derivados do
floroglucinol)
Usados na preparação da cerveja
OH
OHHO
floroglucinol
O OH
HOOH
O
humulone
O OH
HO O
lupulone
Hipericina: ação antibiótica, inibidora da dopamina ß-hidroxilase (aumentando níveis de dopamina).
Atividade fotossensibilizadora, acumulando em células cancerosas, sendo testada em terapia fotodinâmica
SCoA
O
O O O O
O O O
O
OOH
HO
OH
Emodina
OOH
HO
OH
OOH
HO
OH
Hipericina
Probable age
106 yr BP
Primary metabolites Secondary metabolites
Algae 1500 phenylalanine/tyrosine
Bryophyta 380 cinnamic acids flavones
flavonols
anthocyanidins
Lycopodiatae 350
Equisetatae 300 procyanidins
Filicatae 300 cinnamyl alcohols lignins
Gymnospermae 280 propenyl/allylphenols lignans
Angiospermae 135 neolignans
Evolution of phenylpropanoid pathway in plants
General phenylpropanoid metabolism
OMTOMT
sinapil alcohol
coniferyl alcohol
p-coumaric alcohol
4CL/CCR/CAD
F5HC3H
LIGNANS
LIGNINS
OH
OH
OH
OH
OMe
OH
OH
OMeMeO
sinapateferulatep-coumarate
O O-
OH
OMeMeO
O O-
OH
OMe
O O-
OH
FLAVONOIDS ANDOTHER DERIVATIVES
DIMERIZATION
POLYMERIZATION
Bryophytes
and ferns
Filicatae and Gymnospermae
OH
HO OH
COOH
shikimic acidOH
HOOC CH2COCOOH
prephenic acid
tyrosine
phenylalanine
COOH
cinnamic acid
COOH
NH2
NH2
COOH
HO
COOH
HOp-coumaric acid
O
COOH
OH
OH
dehydroshikimic acid
sugar
COOH
HO
OH
OH
gallic acid
JOHAN FREDERIK EYKMAN (1851-1915)
“Sur les principles constituents
de I’llicium religiosum (Seib)
Recueil Travaux Chimique des Pays-Bas 4, 32-54 (1885)
1881 - Faculty of Medicine of University of Tokyo
Shikimic acid
(“shikimi-no-ki” - Illicium religiosum)
C7H10O5;
mp 184oC;
[a]D – 176o EtOH;
[a]D – 246o water
CO2-
HO
OH
OH
CO2-
HO
OH
OHCO2
-
OH
OH
HO
1 2 3
Pi
Pi
Pi
Pi Pi
+
phosphoenolpyruvate (PEP)
3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP)
3-dehydroquinate 3-dehydroshikimate shikimate shikimate-3-phosphate 5-enolpyruvylshikimate-3-phosphate
chorismate
PEP
PiO= phosphate ester
D-erythrose-4-phosphate
OO
HOH
OH
O COO-
O
COO-
OH
HO
OH
O
COO-
OH
OH
HO
O
COO-
O OH
OH
COO-
HO OH
OH
COO-
O OH
OH
COO-
O
OH
COO-O
COO-
OH
COO-
Aldol
H+
"PEP"
D-erythrose-4-phosphate
X-
CO2-
OEnz
O
HO
OH
PO
O
HDAHP synthase
3-Deoxy-D-arabino-
heptulosonate-7-phosphate
HO
OH
PO
CO2-
OH
O
H
O
OH
CO2-
OH
HO
PO
3-Deoxy-D-arabino-heptulosonate 7-phosphate
(DAHP) synthase
DAHP synthase is induceable upon wounding in potatoes
and tomatoes
[Dyer at al. (1989) Proc. Natl. Acad. Sci. USA 86:7370-73].
Aldol
3-dehydroquinate
OH
CO2-
OHO
HO
3-deoxy-D-arabino-
heptulosonate-7-phosphate
HO
OH
PO
CO2-
OH
O
H
H+
O
OH
CO2-
OH
O
H
3-Dehydroquinate synthase
3-Dehydroquinate dehydratase
(3-dehydroquinase)
3-dehydroquinate
OH
CO2-
OHO
HOHs
Hr
3-dehydroshikimate
OH
CO2-
OHO
Hrsyn-Elim
Shikimate dehydrogenase
(shikimate oxido-reductase)
NADPH
shikimate
OH
CO2-
OHHO
OH
CO2-
OHO
3-dehydroshikimate
NADP+
5-enolpyruvylshikimate
-3-phosphate synthase
"glyphosate - Roundup"
(N-phosphonomethylglycine
inhibitor of EPSP)
CCH2NCH2
O
HO
P OH
O
OH
5-enoylpyruvyl-3
-phosphoshikimate
(5-EPSP synthase)CO2
-
PO
OH
CO2-
OHPO
3-phosphoshikimate
OH
CO2-
OPO
CO2-
O O-
O
PO
O-
O-
H
H
XH
X- O O
-
O
PO
O-
O-
H
H
H
5-enolpyruvylshikimate
-3-phosphate synthase
PEP
O O-
NH
H
X-
O
P
O-
O-
glyphosate
Figure 1- Diversion of chorismic acid into the secondary metabolism by the enzymes anthranilate synthase (AS), chorismate mutase and isochorismate synthse (ICS)
L -phenylalanineL- tyrosine
L-tryptophan
anthranilic acid
isochorismic acid
prephenic acid
chorismic acid
o -succynylbenzoic acid
ASICSCM
indole acetic acidindole alkylaminescarbolinesindole alkaloids
phylloquinoneanthraquinones
lignin precursorsflavonoidscoumarinsanthocyanins
isoquinoline alkaloidsbetalaines
CO2H
OH
O CO2H
H2OC
OH
CO2H
OCO2H
NH2CO2H
OH
O CO2H
OH
NH
CCO2H
NH2
CNH2
CO2H
CNH2
CO2H
CO2H
CO2H
O
CO2-
O
OH
O2-C
TPP
HO CO2-
H+
O
O2-C CO2
-TPP
CO2
CO2-
O
OH
CO2-
H
2. ATP/CoASH
CO2-
O
COSCoA
1. -H2O
OH
OH
CO2-
1. -CO2
2. ROPP
O
O
R
Formação de Naftoquinonas a partir do Isocorismato
COOH
OH
COOH
Ácido Corísmico
COOH
COOH
Ácido Isocorísmico
OH
ICS
OH
OH
COOH
COOH
OH
OH
OH
COOH
- Piruvato
Formação de compostos C6-C1 a partir do Isocorismato
Ácido 2,3 di-hidróxibenzóico
Ácido Salicílico
Corismate mutase The only example in the primary/intermediate
metabolism of a 3,3-sigmatropic rearrangement
of the Claisen type
OH
O
CO2-
CO2-
chorismate
-O2C
OH
OCO2
-
prephenate
corismate mutase
Corismate mutase
2 x 106 fold rate enhancement over the uncatalysed process
Only 127 amino acids residues (3 sub-unities)
Corismate mutase inhibitor
CO2-
O
CO2-
HO
chorismate - pseudo-diequatorial
CO2-
OH
O
-O2C
chorismate - pseudo-diaxial
CO2-
OH
O
H
HO2C
Corismate mutase inhibitor
CO2-
O
CO2-
HO
chorismate - pseudo-diequatorial
CO2-
OH
O
-O2C
chorismate - pseudo-diaxial
CO2-
OH
O
H
HO2C
OH
O
CO2-
CO2-
chorismate
-O2C
OH
OCO2
-
prephenate
corismate mutase
-O2C
OH
CO2-+
H3N
CO2-
O
CO2-
NH3+
L-arogenate
CO2-
NH3+
OH
CO2-
O
OH tyrosine
phenylalanine
Pathways to
L-phenylalanine
and L-tyrosine
cinnamateL-phenylalanine
C4HPAL
p-coumarate
O O-
OH
O O-O O-
NH3+
Hydroxylases (monoxygenases, mixed-function oxidases):
(i) Membrane-bound (microsomal) cytochrome P450
dependent oxygenases;
(ii) Soluble phenolase(introduce the second OH
O O-
OH
OMe
O O-
OH
OMeMeO
ferulatesinapate
F5HOMT
OMT
p-coumarate
O O-
OH
O O-
OH
OH
C3H
caffeate
OMT methylation:
requires SAM (S-adenosyl-L-methionine
Occurrence of coumarins
Up to 1990:
1000 coumarins
(especially from Rutaceae and
Umbelliferae species).
Biological activities
of coumarins
O O
cumarina(aromatizante)
O OHO
OH
cumestrol(estrogênico)
O OO
O
OMe
O
aflatoxina B1
(hepatotóxica ecarcinogênica)
OO
OH
O O
OH
dicumarol(antibacteriano,
coagulante)
Biosynthesis of coumarins
ácido 2,4-dihidroxicinâmico
O
OHOH
OH
ácido p-cumárico R=OH
ácido cinâmico R=H
R
O
OH
tirosina R=OH
fenilalanina R=H
O OH
NH2
R
espontânea
ciclização
7-hidroxicumarina
O
OH
O
O
OHO-Gl
OH
ácido 2-glicosil-4-hidroxicinâmico
Flavonóides
O
OOH
HO
OH
OH
luteolin (350 nm)
O
OOH
HO
OH
OH
OH
quercetin (374 nm)
delphinidin (535 nm)(purple)
O
OH
HO
OH
OH
OH
OH
Biosynthesis of flavonoids
OH
O
CoAS
OH
O
O
O
OSCoA
SCoA
O
O-O
3 x
OH
OOH
HO O
H
chalcone
synthase
chalcone
O
OO
O
SCoA
OH
HO OH
O
Claisen
OH
O
CoAS
OH
O
O
O
OSCoA
SCoA
OO-
O
3x
p-hidroxicumaril-SCoA
OH
O
O
O
OSCoA
OH
OOH
HO OHchalcona
sintase
chalcona
Biosynthesis of flavonoids
rotenoid
OOH
HO O
OH
O
isoflavone
OOH
HO O
OH
auroneO
O
HO
OH OH
condensed
tannins
OH
OHO
OH
OH
OH
OHO
OH
OH
epicatequins
catequins
OH
OH
HO O
OH
anthocyanins
+
OH
OH
HO O
OH
flavanonol
OH
OOH
HO O
OH
flavone
OH
OOH
HO O
flavanone
OH
OOH
HO O
chalcone
OH
OOH
HO O
H
Distribution of flavonoids in the leaf fraction of the
Pisum sativum cv. Argentum mutant
Compound Upper
epidermis
Mesophyll-
vascular layer
Lower
epidermis
anthocyanin 70.3 0 29.7
Flavonol
glycoside
68.7 0 31.3
O O-
HO
L-tyrosine
ATP
Pi
O OAMP
HO
+CoA-SH
-AMP
O
HO
SCoA
Hydroxycinnamoyl-CoA
Activation step for cinnamoyl moiety
O
HO
SCoA
Hydroxycinnamoyl-CoA
O
HO
NR
H
O
HO
O R
OHO
HO
O
CO2-
HO
OH
OH
OH
OH
OH
CO2-
HO
OH
CO2-
HO
O
HO
OH
OH
HO
OH
OH
O
O
OH
OH
HO
HOHO
O O
O
HO
OH
N
O
OO
cinnamaldehyde
O H
O O-
NH3+
O O- O O-
OH
O O-
OH
OMe
p-coumarate ferulate
piperine
OH
OH
OMe
PAL C4L C3H
CL/CCR
coniferyl alcohol
L-phenylalanine cinnamate
OH
OMe
eugenol
OMT
4CL/CCR/CAD
FLAVONOIDS AND
OTHER PRODUCTS
O O-
OH
O O-
OH
OMe
O O-
OH
OMeMeO
p-coumarate ferulate sinapate
OH
OH
OMeMeO
OH
OH
OMe
OH
OH
LIGNINS
LIGNANS
C3H/OMT F5H/OMT
4CL/CC/CAD 4CL/CCR/CAD 4CL/CCR/CAD
p-coumaryl
alcoholconiferyl
alcohol
sinapyl
alcohol
Antitumoral lignans from Podophyllum hexandrum
Clinically used for treatment of testicular/lung cancer,
and certain form of leukemia.
Ross et al. (1984) Cancer Res. 44, 5857.
teniposideetoposidepodophyllotoxin
OO
O
MeO
OH
OMe
O
O
O
OO
OH
HO
S
O
OO
OH
HO
Me
OO
O
MeO
OH
OMe
O
O
OO
O
MeO
OMe
OMe
HO
O
Lignans are dimers of coniferyl alcohol regardless
the position of linkage (Gottlieb 1974)
dibenzocyclooctaenearyltetralin dihydrobenzofuran
furofurandibenzylbutyrolactonediarylbutane
a
a
OH
Ar
OH
O
Ar
Ar
OH
OH
Ar
Ar
O
O
Ar
OH
OH
O
O
Ar
Ar
O
O
Tabela 1. Atividades biológicas observadas para lignóides
(McRae & Towers, 1984)
____________________________________________________
atividade antitumoral efeito catártico
atividade antimitótica ação alergênica
atividade antiviral ação hipotensiva
citotoxicidade atividade inseticida
proteção hepática atividade piscicida
ação no S.N.C. inibidor de germinação
atividade cardiovascular atividade fungistática
ação antifertilidade influência sobre ácidos
nucleicos
proteção ao estresse/ influência sobre atividades
antifadiga enzimáticas
____________________________________________________
Forsythia intermedia
Katayama et al. 1992Katayama et al. 1993Dinkova-Kostova et al. 1997
OHOMe
OH
O
O
OMeHO
OMeOH
O
OH
OMeHO
OMeOH
OH
OMeHO
OMeOH
HO
coniferyl alcohol (+)-pinoresinol (+)-lariciresinol (-)-secoisolariciresinol
2 x
Sesamun indicum
Kato et al . 1998.Jiao et al. (1998). (+)-sesamolin
(+)-sesamin
(+)-piperitol
OO
O
O
O
OO
O
O
OO
OO
O
O
OO
OMeOH
Examples of Neolignans
(sensu Gottlieb 1974)
ArAr
ArO
O
ArO
O
Ar
O
ArAr
Ar
Ar O
a
Ar ArO
diarylbutanetetrahydrofuran
dihydrobenzofuran
bicyclooctane spiro
benzodioxane
Ferula assa-foetida L.
Umbelliferae (Apiaceae)
Oleo-gum-resin : resin 40-64% (Ferulic acid
etc)
Feulic acid inhibit platelet aggregation
carminative, expectorant, antispasmodic
properties, fixative
export: Iran, Pakistan, Afghanistan
Melissa officinalis
Labiatae (Lamiaceae)
volatile oil 0.06-0.35% (rosmarinic acid > 4%)
sedative, spasmolytic, antibacterial, nervous
tension etc
export: Bulgaria, Roumania, Spain
Adulterant : Lemon oil
Thymus vulgaris, T. zygis
Labiatae
volatile oil 1.2% (thymol 36-55%, carvacrol 1-4%)
antiseptic, antitussive, expectorant
export : Spain H3C CH3
OH
CH3
H3C CH3
CH3
OH
thymol carvacrol
Syzygium aromaticum (Eugenia caryophyllus)
Myrtaceae volatile oil 14-21% (eugenol 84-
95%) flavouring agent, stimulant,
antiseptic
Flower bud : Madagascar, Indonesia, Brazil
Stem : Madagascar, Tanzania
Leaves : Madagascar, Tanzania, Indonesia
H3CO
HOeugenol
vanillinHO
H3COH
O
Opt : phenol content low, use in pharmacy
Strong : phenol content high, use in the manufacture of vanillin
Medicinol (clove) oil has a phenol content 85 - 90%
Deterioration
Zingiber officinale
Zingiberaceae
gingerol(an oily liquid consisting of homologous phenols)
pungency of ginger
inhibit prostaglandin synthetase (Anti-inflammatory)
antiplatelet aggregation
Humulus lupulus
Cannabaceae
humulone, lupulone
(phloroglucinol
derivative)
use in preparation of
beer
England, Germany,
Belgium, France, Russia,
California
OH
OHHO
phloroglucinol