Secondary Metabolites from Plants

David S.-Y. Wang Assistant Professor Department of Forestry, NCHU

Plant Secondary Metabolites

• Secondary metabolites are those metabolites which are often produced in a phase of subsequent to growth, have no function in growth (although they may have survival function), are produced by certain restricted taxonomic groups of microorganisms, have unusual chemicals structures, and are often formed as mixtures of closely related members of a chemical family. • The simplest definition of secondary products is that they are not generally included in standard metabolic charts.

1 Plant Secondary Metabolites

• A metabolic intermediate or product, found as a differentiation product in restricted taxonomic groups, not essential to growth and the life of the producing organism, and biosynthesis from one or more general metabolites by a wider variety of pathways than is available in general metabolism. • Secondary metabolites are not essential for growth and tend to be strain specific. They have a wide range of chemical structures and biological activities. They are derived by unique biosynthetic pathways from primary metabolites and intermediates.

Plant Secondary Metabolites

• Biochemical pathways that are not necessary for growth or reproduction of an organism, but which can be demonstrated genetically, physiologically or biochemically.

2 Plant Secondary Metabolites

• Plants produce as amazing diversity of low molecular

weight compounds.

• Of the estimated 400,000 – 500,000 plant species around

the globe, only a small percentage has been investigated

phytochemically and the fraction subjected to biological or

pharmacological screening is even lower.

Plant Secondary Metabolites

• The ability to synthesize secondary metabolites has been selected through the course of evolution in different plant lineage when such compounds address specific needs.

– Floral scent volatiles and pigments have evolved to attract insect pollinators and thus enhance fertilization.

– To synthesize toxic chemical has evolved to ward off pathogens and herbivores or to suppress the growth of neighboring plants.

3 Plant Secondary Metabolites

– Chemicals found in fruits prevent spoilage and act as signals (in

the form of color, aroma, and flavor) of the presence of potential

rewards (sugars, vitamins and flavor) for animals that eat the fruit

and thereby help to disperse the seeds.

– Other chemicals serve cellular functions that are unique to the

particular plant in which they occur (e.g. resistance to salt or

drought).

Natural Products Drug Discovery and Development

• Over the ages, human have relied on nature fro their

basic needs for the production of foodstuffs, shelters,

clothing, means of transportations, fertilizers, flavors and

fragrances, and not least medicine.

• Plants have formed the basis of sophisticated traditional medicine system that have been in existence thousands of years in countries such as China and India.

4 Natural Products Drug Discovery and Development

• About 25% of all prescriptions sold in the US are for natural products, while another 25% are for structural modifications of a natural products.

• According to Fransworth (1990) claims that 119 characterized drugs are still obtained commercially from higher plants and that 74% were found from ethnobotanical information.

. Fransworth, N.R. (1990) In bioactive compounds from plants. John and Wiley Co..

Primary and Secondary Metabolism

• Primary metabolism

– The biological reactions are essential to maintain life in living organisms and are known as primary metabolism.

– Plant convert sunlight energy to chemical energy, such as ATP, NADPH, by the mediation of chlorophyll in chloroplasts and

synthesize sugars and starch from CO2 by using ATP and NADPH+.

– These carbohydrates are stored and used for differentiation and formation of plant tissues.

5 Primary and Secondary Metabolism

• Secondary metabolism

– The metabolisms which are not directly related to maintaining

life, are known as secondary metabolisms.

– The products formed by secondary metabolism are called

secondary metabolites.

– Secondary metabolite play a role in reinforcement of tissue and

tree body (e.g. cellulose, lignin, suberin), protection against

insects, dieses, and plant regulation (plant hormones).

Primary and Secondary Metabolism

• All organisms need to transform and interconvert a vast number of organic compounds to enable them to live, grow and reproduce. • All organisms need to provide themselves with energy in the form of ATP, and a supply of building blocks to construct their own tissues. • An integrated network of enzyme-mediated and carefully regulated chemical reactions in used for this purpose, collectively referred to as intermediary metabolism, and the pathways involved are termed metabolic pathway.

6 Primary and Secondary Metabolism

• The pathways for generally modifying and synthesizing carbohydrates, proteins, fats, and nucleic acids are found to be essentially to same in all organisms, apart from minor variations.

– These processes demonstrate the fundamental unity of all living matter, and are collectively described as primary metabolism, with the compounds involved in pathways being termed primary metabolites.

Primary Metabolisms

• Degradation of carbohydrates and sugars generally proceeds via the well characterized pathways, known as glycolysis and the kerbs / citricacid / tricarboxylic acid cycle, which release energy from the organic compounds by oxidative reactions.

• Oxidation of fatty acids from fats by the sequence called β-oxidation also provides energy.

7 Primary Metabolisms

• Aerobic organisms are able to optimize these processed by

adding on a further process, oxidative phosphorylation.

This improves the effeiciency of oxidation by incorporating

a more general process applicable to oxidation of a wide

variety of substrates rather then having to provide specific

process for each individual substrate.

Primary Metabolisms

• Proteins taken in via the diet provide amino acids, but

the proportions of each will almost certainly vary from the

organism’s requirements.

• Most organisms can synthesize only a proportion of the

amino acids they actually require for protein synthesis.

Those structures not synthesized, so-called essential

amino acids, must be obtained from external sources.

8 Secondary Metabolisms

• The compounds which synthesized from the secondary metabolisms are so-called secondary metabolites. • Secondary metabolites are formed in only specific organisms, or groups of organisms, ane are expressioin of the individuality of species. • Secondary metabolites are not necessarily produced under all conditions, and in the vast majority of cases the function of these compounds and their benefit to the organism is not yet known. • It is this area of secondary metabolism that provides most of the pharmacologically active natural products.

Secondary Metabolisms

• To make such compounds as sugars, waxes, lignin starch, pigments, or alkaloids, plants utilize very specific enzymes, each of which catalyzes a specific metabolic reaction.

– The enzymes are proteins called organic catalysts.

– These enzymes are coded by specific genes in the plants DNA and are made via processed we call transcription and traslation.

– When there is a series of enzymatically catalyzed reaction in a well- defined sequence of step, we have what is termed a metabolic pathway.

9 Biosynthetic Pathway

• Nucleoside diphosphate sugar pathway: cellulose, hemicellulose, glycosides.

• Shikimate-cinnamate pathway: lignin, lignans, hydrolyzed tannins.

• Mixed pathways of 3 and 4: some prenylflavonoids, quinones and stilbenes.

Primary and Secondary Metabolism

• Primary and secondary metabolites leave a “grey area” at the boundary, so that some groups of natural products could be assigned to either divisions.

• Primary metabolites → Biochemistry

Secondary metabolites → Natural products Chemistry

10 The Classes of Secondary Metabolites

• The majority of secondary metabolites belong to one of a number of families, each of which have particular structural characteristics arising from the way in which they are built up in nature (biosynthesis). • The classes of secondary metabolites are: – Polyketides and fatty acids – Terpenoids and steroids – Phenylpropanoids – Alkaloids – Others (specialize amino acids and carbohydrates)

Polyketide and Fatty acids

• Polyketides are formed by the linear combination of acetate units derived from the “building block” acetyl co- enzyme A. • The acetate origin of these compounds leads to a preponderance of even-numbered carbon chains. • Many plant oils and animal fats contain long-chain monocarboxylic acids know as fatty acids. • In the fatty acids, the carbonyl group of the acetate units is reduced during the course of the chain assembly process. Dehydrogenation and oxidative processed may subsequently give the unsaturated fatty acids.

11 Polyketide and Fatty acids

• The common fatty acids have an even number of

carbon atoms, typically C12 –C20, linked together in a straight chain with up four double bonds. • In plants the fatty acids and the corresponding alcohol are found in leave waxes and seed coating: – Myristic acid (C14) is found in nutmeg seeds. – Palmitic acid (C16) is found in almost all plant oils. – Stearic acid (C18) occurs in long amounts in animal fat.

Polyketide and Fatty acids

• Unsaturated fatty acids are important to us in food. – Oleic acid is the most widely distributed, and a major constituent of olive oil. – Linoleic and linolenic acids are most highly unsaturated and are found in linseed oil. – Linolenic acid is easily oxidized by air, and is one of the “drying oil” used in paint and varnishes.

12 Polyketide and Fatty acids

– Linolenic acid is oxidized

by plants to jasmonic acid,

which is a signaling

substances that stimulates

plant defense mechanisms.

– Arachidonic acid (C20) is a

precursors of the

prostaglandin hormones.

Polyketide and Fatty acids

• Polyacetylenes

– They are a group of naturally Falcarinol occurring hydrocarbon OH

derivatives characterized by O

one or more acetylenic groups O COOH in their structures. Wyerone acid

– Araliaceae(五加科), OH

Campanulaceae(桔梗科), Safynol HO Apiaceae(繖形花科),

Asteraceae, Pittosporaceae(海 OH

桐科), and some fungi. 1,2-dihdroxytrideca-5,7,9,11-tetrayne OH

13 14 Terpenes

• The terpenes are among the most widespread and

chemically diverse groups of natural products.

• Terpenes are a unique group of hydrocarbon-based

natural products whose structures may be derived from

isoprene.

• Terpenes are classified by the number of 5-carbon units.

15 Terpenes

• Isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) combined to yield geranyl pyrophosphate (GPP), leading to monoterpenes. Similarly, compounds derived from farnesyl pyrophosphate (IPP) lead to sesquiterpenes, and triterpenes are formed from two equivalents of FPP, and triterpenes are formed from two equivalents of FPP.

Terpenes

• The function of terpenes in plants is generally

considered to be both ecological and physiological

– Allelophathy

– Insecticidal

– Insect pollinators

– Plant hormone (Abscisic acid, gibberlellin)

16 Myrcene

Greek Bay (Laurus nobilis) Hops (Humulus lupulus)

Myrcene is found in the essential oil of bay leaves as well as hops. It is used as an intermediate in the manufacture of perfumes.

Geraniol and Linalool

OH OH

Geraniol Linalool

Geraniol is isomeric with linalool, constitutes the citronella major part of the oil of roses and is also found in essential oils of citronella, lemon grass, and others.

17 Menthol

Menthol is a well-known monoterpenewhich is found in the essential oil of peppermint and other members of the mint family.

Sesquiterpenoids

• More than 10000 sesquiterpenoids have been identified, representing a wide variety compounds of different skeletal types from acyclic to tetra cyclic systems.

α-cedrene α-muurolene δ-cadinene α-cadinol

logifloene juniperol nootkatin chanootin

18 cadinenes

Wormwood (Artemisia maritima)

O O O santonin

caryophyllene Dandelion (Taraxacum officinale )

Cloves (Syzygium aromaticum) OH

O O

tetrahydroridentin B

19 Bioactive Compounds Contributing to Decay Resistance of Taiwania Wood • Fungi and termites are two of the most harmful organisms to wooden structures worldwide • To develop methods for prolonging the service life of wood is one of challenges of wood utilization researchers

•As regards decay resistance, Taiwania is classified as the species with an excellent durability in Taiwan •There are several papers dealing with the antifungal and antitermitic activities of Taiwania: .For. Prod. Industries. 1998, 17, 287. .Holzforschung. 1999, 53, 487. .Holzforschung. 2000, 54,241. . J. Chem. Eco. 2001, 27, 717.

20 Commonly Occurring Brown-rot and White-rot Fungi

White rot fungi Brown rot fungi Coriolus versicolor Laetiporus sulphureus

Lenzites betulina Antrodia taxa

Pycnoporus coccineus Fomitopsis pinicola

Trichaptum abietinum Phaeolus schweinitzii

Oligoporus lowei

Extractives of Taiwania against White- rot Fungi

Taiwania Heartwood

MeOH extraction

MeOH Extractives

Hex Fr.

Chl. Fr.

EtoAc Fr. MeOH Fr.

21 Extractives of Taiwania against Brown-rot Fungi

Taiwania Heartwood

MeOH extraction

MeOH Extractives

Hex Fr. Chl. Fr.

EtoAc Fr. MeOH Fr.

Antifungal Indices of Compounds Isolated from Taiwania Heatwood

Suginol Hinokiol C. v. Ferruginol α-Cedrol α-Cadinol Helioxanthin Taiwanin C L. s. Savinin Taiwanin A

0 20406080100 Antifungal index

22 Effectiveness of α-Cadinol against White-rot and Brown-rot Fungi

• Among the compounds isolated from Taiwania heartwood, α-cadinol has demonstrated to possess the highest antifungal effectiveness.

OH OH H H OH

H H H

23 Quantification of the Cadinane Skeletal Sesquiterpenoids Distribution in Different Parts of Taiwania

H T-cadinol The amounts of hexane extractives and essential OH H 1 oils distilled from various parts of Taiwania

H T-muurolol

2 H OH

H α-cadinol

GC chromatograms of essential oils distilled from Taiwania heartwood.

Amounts of Cadinanes in Various Parts of Taiwania 8

t-cadinol 6.49 t-muurolol 6 α-cadinol total cadinols

1.77 2

Amounts of cadinanes (mg/kg) of cadinanes Amounts 0.04 0.36 0 n-Hex Essential oil extracts Leafs Sapwood Heartwood Heartwood

24 Antifungal Indices of α-Cadinol, T-Cadinol, and T-Muurolol equatorial hydroxyl group

trans ring junction

Fungi α-Cadinol T-Cadinol T-Muurolol

C. v. 100 47.1 38.8

L. s. 100 100 82

Diterpenoids

• Diterpenoids constitute a major part of oleoresin.

• This group can be divided into geranyl-linalool β-epimanool acylic, bicyclic, tricyclic, tetracyclic, and macrocyclic structural types. cis-abienol manoyloxide • Diterpenoids are present either as hydrocarbons or as derivatives with hydroxyl, pimaral cembrene carbonyl, or carboxyl groups. pimarol

25 Phenolic Constituents

• Heartwood and bark contain a large variety of complex aromatic extractives. Most of them are phenolic compounds, and many are derived from the phenylpropanoid structure.

Classification of Phenolic Compounds

Numbers of C Basic skeleton Name

6 C6 Benzoquinones 10 C6-C4 Naphthoquinones

14 C6-C2-C6 Stilbenes

15 C6-C3-C6 Flavonoids

17 C6-C3-C2-C6 Norlignans

18 (C6-C3)2 Lignans n (C6-C3-C6)n Condensed tannins

26 Phenolic Compounds

H2COH CH CH 2 CH CH CHO CH2

OCH OCH 3 3 OCH3 OH O GLUCOSE OH

Vanillin Coniferin Eugenol

CHO O CH3O OCH3

OCH CH3O OCH3 3 OH OH O Syringaldehyde Guaiacol 2,6-Dimethoxy benzoquinone

Summery of the Biogenetic Connection between a Selection of Familiar Phenolic metabolites

27 Summery of the Biogenetic Connection between a Selection of Familiar Phenolic metabolites

Summery of the Biogenetic Connection between a Selection of Familiar Phenolic metabolites

28 Lignans Isolation Procedures

• Lignans can be isolated from the bark, fruit, heartwood, leaves, roots and resin of plants • Most isolation procedures involve solvent extraction, chromatography separations, and crystallization • Lignan yields can vary from 0-30%

29 Lignans Commercialization

• Large amount of research devoted to investigating medicinal properties of lignans – Particularly from tropical hardwoods and grasses • Example 1999 reference: 35 lignans isolated from the twigs of Tazus mairei – Antiviral – Antitumor – Biocidal – Bioactive Agents

30 • The heartwood of Taiwania is yellowish red with distinguished purplish pink streaks, which fascinates people very much.

• The yellowish red color in Taiwania is susceptible to change to dull black after exposure it to nature environment.

31 Optical Micrographs of Different Parts of Taiwania

Optical Micrograph Observation of Discoloration in Red Taiwania Heartwood

2 weeks 4 weeks

After exposed Taiwania heartwood under indoors condition, its color changed from red to dull black.

32 Color Compounds Isolated from Taiwania Heartwood

O O O O HO O O O O O O O O O HO O

O O O O O O O O Taiwanin A Savinin Helioxanthin Pluviatolide

OH OH OH HO H HO O

CHO H CHO OMe O O

Taiwanin I Ferruginol T-Cadinol Secoabietane dialdehyde

33 Cytotoxicity of Lignans and Sesquiterpenoids from Taiwania

Heartwood (ED50 values in mM)

Taiwanin A

Taiwanin E

Dimethylmatairesinol α-Cadinol

Cytotoxicity of Dibenzyl-γ-butyrolactone Type of Lignans Isolated from Taiwania Heartwood

O O • An unsaturated double bond O O O O O between C7-C8 and/or C7’-C8’ is associated with stronger OO O cytotoxicity. O • The presence of two 3, 4- O R O dimethoxyphenyl groups in R lignans may increase the cytotoxicity, as dimethyl- R R matairesinol was stronger than arctigenin and hinokinin

34 Cytotoxicity of Dibenzyl-γ-butyrolactone Type of Lignans Isolated from Taiwania Heartwood

Cytotoxicity of Dibenzyl-γ-butyrolactone Type of Lignans Isolated from Taiwania Heartwood

O O • An unsaturated double bond O O O O O between C7-C8 and/or C7’-C8’ is associated with stronger OO O cytotoxicity. O • The presence of two 3, 4- O MeO O dimethoxyphenyl groups in MeO lignans may increase the cytotoxicity, as dimethyl- OMe MeO matairesinol was stronger than arctigenin and hinokinin

35 Cytotoxicity of Arylnaphthalide Type of Lignans Isolated from Taiwania Heartwood

• Taiwanin E showed the OH O strongest cytotoxicity O O O O O O O O in this group. O O O • It appears that the O O O O O O hydroxyl group at the C7 position enhances the cytotoxicity.

Cytotoxicity of Arylnaphthalide Type of Lignans Isolated from Taiwania Heartwood

• Taiwanin E showed the

OH O strongest cytotoxicity O O O O O O O O in this group. O O O • It appears that the O O O O O O hydroxyl group at the C7 position enhances the cytotoxicity.

36 Flavonoids/Tannins Isolation of Flavonoids

• Isolation of flavonoids accomplished through solvent extraction – Hot water – Alcohols • Solvent fractionation of extract • Salting out • Crystallization

Flavonoids/Tannins Isolation of Flavonoids

• Flavonoids concentrated in certain parts of plants • Plant sources – Pulp of fruits – Broccoli, green peppers, onions, etc. – Green tea, red wine – Herbs – Tree bark

37 Blockade of tumor induction by EGCG

OH OH

HO O OH OH O OH C OH O OH

(-)-epigallocatechin-3- gallate RH: procarcinogens (aflatoxins, poly-cyclic aromatic hydrocarbons, and nitrosamines)

GST: glutathione S-transferase GlcT: UDP-glucuronyl transferase ROS: reactive oxygen (superoxide anion, hydrogen peroxide, hydroxyl radical, nitric oxide, peroxynitrite, and nitric dioxide anion)

Chemical Composition of Tea

•Caffein: 3-4 %

•Catechins (including Tannin): 15-30 %

•Flavonols and Metal: 5 %

¾P,K, Ca, Mg, Mn, Zn, Cu, Al

•Vitamins: A, B1, B2, C, E, Nicotinic acid

38 Flavonoids/Tannins Polymerization Reactions • Condensed tannins are formed through the O

polymerization of flavan-3-ol OH (catechin) and flavan–3,4- OH Flavan-3,4-diols diols (leucoanthocyanidins) (Leucoanthocyanidins) – In tree, polymerization

through acidic enzymatic O non-oxidative coupling OH – 2-50 units Flavan-3-ols • Typically 2-8 (Catechins) – Linkages can be through a variety of sites

Flavonoids/Tannins Polymerization Reactions

3' 2' • Examples of linkages 4' 8 B – 4 alpha – 8 O 2 7 5' – 4 beta – 8 A C 6' – 4 beta – 6 6 3 5 4 • Stereochemistry • A variety of monomers

39 Flavonoids/Tannins Polymerization Reactions

OH OH OH OH OH OH

O O HO O HO O

-H2O OH OH (H+) OH OH OH OH OH

OH OH + H+ OH OH HO O OH OH OH OH OH HO O HO O OH + HO O - H OH OH OH OH OH (+) OH

Flavonoids/Tannins Polymerization Reactions

• Flavan-3-ols are OH incapable of HO O OH polymerizing without OH OH flavan 3,4-diol HO HO • Flavan-3-ol form

O OH O terminating unit OH

HO OH OH OH

40 Flavonoids/Tannins Polymerization Reactions

OH OH • All 4-8 linkages HO O • This structure has OH OH OH OH been isolated from HO O

OH pine bark OH OH OH

HO O

OH OH

Flavonoids/Tannins Polymerization Reactions

• Flavan-3-ols can OH polymerize through OH an oxidative HO O

enzymatic coupling OH OH reaction forming OH O oligo and polymeric HO O materials OH O – Linkages 8-6’ – Causes loss of brightness in wood

41 Flavonoids/Tannins Location in Tree: Tannins

• Western hemlock – Bark: 18% tannins – Wood: 2% tannins • Quebracho – In wood, tannins found in heartwood – Majority (80%) located in vessel lumina – Tannins deposit in dead cell starting at CML and ending in secondary wall

42 Condensed Tannins Properties

• The term condensed tannins refers to a mixture of polyflavonoids of different MW (500-5000) characterized by different linkages, functional groups, and stereochemistry. • Protein binding capacity: tannins will bind with proteins causing them to precipitate. – This was the definition of tannins: compound which will precipitate proteins.

Condensed Tannins Sources

• Condensed tannins more prevalent in hardwoods but present in softwoods

– Wattle (Acacia - Southern Africa)

– Quebracho (Schnopsis - South America)

– Mangrove (Rhizophora -)

– Hemlock (North America)

43 Condensed Tannins Biological Significance – Insects/Animals • Protection of plants against insects/animals – Some evidence for/some against • Bad Taste/Astringency (bitter taste) • Appears to be major factor • Particularly bad for insects not used to tannins • Animals: tannins reduce digestion of food – Interaction with digestion enzymes • Toxic to bacteria

Condensed Tannins Biological Significance - Fungus

• Pine calluses: created by fungal invasion – Tree forms calluses as protective tissue – Calluses contain high levels of tannins (Chinese 50-80%) – Concentrations of tannins as low as 0.1% or 0.8 % have been shown to retard the growth of a large number of parasitic fungi • Quote: Edwin Haslam (tannin chemist) – “serious and nagging fear that a part at least of (their) scientific career(s) has been spent inspecting the loot in the garbage bin of plant metabolism”

44 Hydrolyzable Tannins Structure • Polymers of a sugar (usually glucose) with one or more polyphenolic carboxylic acids: linked through ester linkages • Gallotannins: Gallic acid polymer • Ellagitannins: Ellagic Acid polymer OH HO OH OH HO

O C O C O OH O O C O HO OH OH

OH HOOC OH COOH OH Ellagic Acid Gallic Acid Digallic Acid

Hydrolyzable Tannins Polymer Structure Example

OH OH OH Sugar O OH HO O HO O O O O OH O O O OH HO O OH

HO HO O OH OH O OH n

OH O

45 Hydrolyzable Tannins Tree Information

• Rare to nonexistent in softwoods

• Hardwoods which contain large amounts:

– Oak (gallic and ellagic tannins)

– Eucalyptus (Ellagitannins)

– Chestnut (gallic tannins)

– Myrobalan fruits (cherry plum)

• Hydrolyzable tannins located in heartwood

Condensed Tannins Uses • Leather tanning: 10,000+ year old industry – Vegetable tannins & chrome – Tannins interacting with proteins in hides • Adhesives – In phenol formaldehyde systems, tannins speed up the set: • Oil well drilling fluids: old but effective use: taken over by chrome lignosulfonates

46 Stilbene 二苯乙烯類之化合物是以α，β-Diphenyl ethylene 為骨架之化合物稱之，廣泛地分佈在針葉樹皮及闊葉樹之許多樹種。由於具有共軛雙鍵，此類化合物為反應性極強之化合物，除了在製漿蒸煮過程中會與藥劑反應外，並會阻止可溶性之木質素磺酸鹽的形成，阻礙木質素的溶解。此外，二苯乙烯類亦與木材之抗蟻性有密切的關係。

Alkaloids

• Derived from plants

• With a basic character (hence the term alkaloid from alkali)

• Contained a nitrogen based heterocylic ring within their molecules

47 • Alkaloids can be sub-categorized according to: – Monocyclic alkaloids – Bicyclic alkaloids – Polycyclic alkaloids

48 Opium Narcotic analgesics Papaver somniferum - used for 5000 years. Arabs introduced opium to China in 7th century. Opium addiction became a problem so Chinese officials outlawed it. England traded opium to China for goods even though it was illegal in their own country and in China. China and England fought two wars over the English import of opium, China lost both, ceded Hong Kong to British at end of first war. Use of opium in China did not drop until Communist Revolution in 1949. Most opium is OR currently grown in SE Asia. O Morphine is purified from N CH3 opium and is a very potent R = H morphine HO painkiller. R = CH3 codeine

Ma Huang or Ephedra has been used in China since 2800 BC It was used primarily for colds, asthma, hayfever, bronchitis, edema, arthritis, fever, hypotension and hives. Potency is based upon the herb's alkaloid content. Side effects include increased blood pressure, heart rate and Ma huang anxiety. FDA suggest that those with heart (disease or high blood pressure), thyroid, Ephedra sinica, diabetes or prostrate problems may be Ephedra intermedia, affected adversely. It should definitely NOT Ephedra equisetina be taken with antihypertensive or antidepressant drugs.

CH3 CH3 H C N CH H C N CH H 3 H 3 H C OH HO C H

l-ephedrine d-pseudoephedrine

49 Catharanthus roseus 長春花

Vinblastine is a drug used in the treatment of cancer. It interferes with the multiplication of cancer cells and slows or stops their growth and spread in the body.

Berberis fremontii 小檗

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