SHIKIMATES
Phenylpropane Derivative-Containing Drugs
1. BIOSYNTHETIC ORIGIN OF THE AROMATIC RING (Shikimic Acid Pathway)
Since numerous works and reviews are devoted to this reaction sequence and to the mechanisms involved, we shall only present here a succinct summary of the pathway leading from the products of glycolysis and of the Calvin cycle to aromatic amino acids (phenylalanine and tyrosine) and to cinnamic acids.
coo-
coo-
hq
OH
coo-
coo-
cr ~y oh 6h
3-Dehydroquinate
cr  y 'oh 6h
3-Dehydroshikimate
OH
Erythrose 4-phosphate
3-Dehydroshikimate formation
1. DAHP synthase, NAD* 2.3-dehydroquinate synthase 3.3-dehydroquinase
The first reaction is the condensation of phosphoenolpyruvate (= PEP) with erythrose-4-phosphate which yields a C7 compound, 3-deoxy-D-arabinoheptulo-sonate-7-phosphate (= DAHP). The cyclization of DAHP to 3-dehydroquinate is a
234
PHENOLICS
Enz-B:
coo-
Conversion of 3-dehydroquinate to 3-dehydroshikimate (enzyme: 3-dehydroquinate dehydratase)
3-Dehydroshikima te
catalyzed by an enzyme which forms a transient Schiff base between a lysine residue and the carbonyl group of 3-dehydroquinate, and induces a stereospecific cis elimination of a water molecule. Following the reduction of 3-dehydroshikimate and shikimate phosphorylation, condensation with another molecule of PEP yields an enol ether, 5-enolpyruvylshikimate 3-phosphate (= EPSP). This leads, via an unusual trans 1,4-elimination, to chorismate.
coo-
coo-
1
coo-
ÖH OH
3-Dehydroshikimate Shikimate
coo-
oh
o xoo-
OH
Shikimate 3-phosphate
Formation of chorismate from
3-dehydroshikimate
1. shikimate oxydoreductase, NADP+
2. shikimate kinase, ATP
3. EPSP synthase, PEP
4. chorismate synthase
o coo-
OH
Chorismate
Chorismic acid holds a key position in metabolism and has multiple fates:
• Claisen-type pericyclic rearrangement to prephenate. This pathway leads, via phenylpyruvate, to phenylalanine and tyrosine. This rearrangement is catalyzed by an enzyme, chorismate mutase, which transfers the side chain derived from PEP to the carbocycle, and thereby generates the skeleton of phenylpropanes. The enzyme is thought to control the conformation by favoring a chair transition state with pseudoaxial substituents;
• amination and anthranilate (= 2-aminobenzoate) formation. Anthranilate is the required intermediate of the biosynthesis of tryptophan, which is the starting point of
the formation of all indole alkaloids. It is also the (direct) precursor of most
UbNbKALl 1 lfci>
coo-
Pericyclic rearrangement of chorismate; Formation of aromatic amino acids
-Hydroxy phenylpyruvate
-ooc
O '/COO- -OOQ,
OH
Chorismate
OH
Prephenate
OH
L-Arogenate
OH
L-Tyrosine
1. chorismate mutase
2. chorismate mutase-prephenatedehydratase
3. phenylpyruvate aminotransferase
4. prephenate aminotransferase
5. arogenate deshydratase
■ 6. arogenate deshydrogenase, NADf 7. prephenate deshydrogenase, NAD*
Phenylpyruvate
L-Phenylalanine
coo-
C02h
p-Coumaric acid
*o coo
iso-Chorismic acid
Salicylic acid
C02H
NH2
(Ror
(OR)
Cinnamates and derivates
,C02h C02h
Anthranilic acid
H
L-Tryptophan
OSB 0
(-> quinones)
Fate of chorismic acid (main pathways)
236
PHENOLICS
hydroxylation and dehydration to isochorismate, from which arise phenol n Cg-Cj (e.c naphthoquinones.
acids in Cg-Cj (e.g., salicylic acid), and via o-succinylbenzoic acid (= OSB), certain
Prephenate decarboxylation, aromatization, and reductive deamination yield L-phenylalanine. If the hydroxyl in the C-4 position is conserved (formation of 4-hydroxy-phenylpyruvate by prephenate dehydrogenase), then the reductive animation yields L-tyrosine. Another biogenetic pathway to aromatic amino acids is also known, in which the initial step is the reductive animation of the a-ketoacid; the resulting amino acid (L-arogenate) is subsequently decarboxylated and aromatized to L-phenyl-alanine (by arogenate dehydratase) or else to-L-tyrosine (by arogenate dehydrogenase).
2. ORIGIN AND FATE OF CINNAMIC ACIDS
Compounds with a C6-C3 unit, often collectively referred to as phenyl-propanoids, are the most common of all shikimic acid metabolites. No matter the degree of oxidation of their side chain (alcohol, aldehyde, propene, or other), they arise from cinnamic acids. These are virtually universal and may occur in the free or combined state (as esters, amides, or glycosides); they frequently acylate the most diverse metabolites. Furthermore, the phenylpropanoid moiety may cyclize (coumarins), dimerize (lignans), polymerize (lignins), or undergo side chain elongation (stilbenes, flavonoids).
The stereospecific elimination of ammonia from phenylalanine yields (£)-cinnamic (= fra?«-cinnamic) acid. The reaction is catalyzed by phenyl ammonia lyase (PAL), and the elimination of ammonia is facilitated by the reaction between the NH2 function and a dehydroalanine residue on the prosthetic group of the enzyme. In the majority of cases, 4-mono- and 4,5-dihydroxylated cinnamic acids (e.g.,4-coumaric and caffeic acids, respectively) arise from cinnamic acid hydroxylation. Thus, cinnamate 4-hydroxylase (a cytochrome P450-dependent monooxygenase) catalyzes cinnamic acid hydroxylation.
Subsequent reactions of cinnamic acids, especially ester formation, require their preliminary activation, either as esters of coenzyme A, or as esters of glucose, with the latter functioning as acylating reagent as well as acylation substrate.
Cinnamic aldehydes and alcohols arise from stepwise enzymatic reduction of the esters of cinnamic acids and of coenzyme A.
Among the most important cinnamic acid metabolites are phenylpropanoids,
especially ally 1- and propenylphenols. Their formation mechanisms remain
GENERALITIES
237
ArCH=CH-COSCoA
ArCH=CH-CHO
\
ArCH=CH-CH2OH
(o a
ArCH^CH-CH2-O^P-OH
H"
ArCH=CH-CH3
—- ArCH2—CH=CH2
H"
" Likely origin of allyl- and propenylphenols j
Shortening of the side chain yields benzoic acids and their derivatives or simple phenols.
. Benzoic acids and their derivatives. Ar-Cj-type compounds (e.g., vanillin, benzoic acid) can arise directly from 3-dehydroshikimic acid (like gallic acid) or from chorismic acid (like salicylic acid), but as a general rule, they result from side chain degradation of the corresponding cinnamic acids. Although some Ar-C2-type compounds are formed from cinnamates, most benzophenones arise from the metabolism of acetate and malonate.
COSCoA
Possible origin of
kr-C2orkr-Ci
compounds
COSCoA
COSCoA
. Simple phenols. These seldom occur naturally. In all likelihood, they arise from benzoic acid decarboxylation (oxidative or not). For example, arbutm may arise from the decarboxylation of peroxidized 4-hydroxybenzoic acid.
COzH
C02H
C02H
HOO, C02H
238
PHENOLICS
Chief drugs containing phenylpropanoids include sources of essential oils whose major constituents are allyl- and propenylphenols (e.g., essential oils of clove, sassafras or Apiaceae): their structures and the biological properties that some of them impart to the drugs containing them will be indicated in the corresponding chapter (see essential oil-containing drugs). In addition, esters of gallic acid and glucose (i.e., hydrolyzable tannins), since they have physico-chemical and biological properties similar to those of condensed tannins, will be studied together (see tannin-containing drugs).
Accordingly we shall cover: first, simple phenols and phenolic acids, then balsams, coumarins, and lignans; and second, chain elongation products of phenylpropane.
3. BIBLIOGRAPHY
Dewick, P.M. (1998). The Biosynthesis of Shikimate Metabolites, Nat. Prod. Rep., 15,17-58. Harborae, J.B. (1989). General Procedures and Measurement of Total Phenolics, in "Methods
in Plant Biochemistry", vol 1, Plant Phenolics, (Harbome, J.B., Ed.), p. 1-28, Academic
Press, London.
Waterman, P.G. and Mole, S. (1994). Analysis of Phenolic Plant Metabolites, Blackwell Scientific Publications, London.
Phenols and Phenolic Acids
1. Generalities..................................................................................................................240
2. Physico-chemical Properties, Characterization, and Extraction..................................242
3. Pharmacological Applications and Uses.....................................................................243
4. Simple Phenol-containing Drugs.................................................................................243
Bearberry ..........................................................................................................243
Other Ericaceae...................................................................................................246
Hydroquinone......................................................................................................246
5. Phenolic Acid-containing Drugs..................................................................................247
A. Caffeic Acid Derivative-containing Drugs....................................................247
Artichoke..........................................................................................247
Rosemary..........................................................................................249
Orthosiphon......................................................................................250
B. Salicylic Acid Derivative-containing Drugs..................................................251
Queen-of-the-meadow......................................................................251
Willow..............................................................................................252
C. Other Phenolic Acid-containing Drugs..........................................................253
European Goldenrod........................................................................253
6. Benzoic and Cinnamic Ester-containing Drugs: Balsams and Benzoins...................254
Peruvian Balsam..................................................................................................254
Tolu Balsam........................................................................................................257
Siam Benzoin......................................................................................................257
Sumatra Benzoin.................................................................................................258
7. Bibliography................................................................................................................259