Natural Products Chemistry:Major Classes of Medically Relevant Compounds from Plants

Emory UniversityEmory UniversityHLTH 385: Botanical Medicine & Health

Cassandra L. Quave, Ph.D.Center for the Study of Human Health

Learning Objectives

• What are the major classes of medically relevant natural products derived from plants?

• What are plant secondary metabolites and why do plants make them?

• How do indigenous people use sensory clues from plants to understand a plant’s chemistry and potential for medicinal value?

• Organic compounds not directly involved in basic survival of the organism (growth, development, or reproduction)

• In plants, these are used for:– Defense against predation and herbivory– Competitive “warfare” with other organisms in the

community – Pollinator attractors– Dispersal – Responsible for plant colors, flavors, and odors**Since plants are sessile, these compounds are critical in **Since plants are sessile, these compounds are critical in

either attracting or deterring other organisms as needed either attracting or deterring other organisms as needed and can increase survival of the plantand can increase survival of the plant

Secondary MetabolitesSecondary Metabolites

Fight off bacterial and/or viral invasion/infection (in roots and above-ground parts)

Secondary MetabolitesSecondary Metabolites

Deter other plant species from growing nearby

Fight off bacterial and/or viral invasion/infection (in roots and above-ground parts)

Secondary MetabolitesSecondary Metabolites

Deter other plant species from growing nearby

Fight off bacterial and/or viral invasion/infection (in roots and above-ground parts)

Attract pollinators

Secondary MetabolitesSecondary Metabolites

Deter other plant species from growing nearby

Fight off bacterial and/or viral invasion/infection (in roots and above-ground parts)

Defense against herbivory (ex. Tannins and HCN release in Acacia)

Attract pollinators

• Phenolics and Polyphenols

• Quinones• Flavones, Flavonoids,

and Flavonols• Tannins• Coumarins• Terpenoids and

Essential Oils

• Alkaloids• Lectins and

Polypeptides• Phenylpropenes• Lignans• Glycosides

Major Groups of Natural Products from PlantsMajor Groups of Natural Products from Plants

Phenolics and PolyphenolsPhenolics and Polyphenols

• Can be as simple as a single substituted phenolic ring – many exhibit antioxidant, antibacterial, antiviral, and antifungal activity

• The # and location of –OH groups on the phenolic ring is related to relative toxicity to microorganisms

Caffeic acid Catechol Pyrogallol

QuinonesQuinones• Aromatic rings with 2 ketone

substitutions• Responsible for “browning” when

fruit/veggies are cut (apples) – also related to melanin synthesis in skin

• Quinones provide a source of stable free radicals – and can inactivate proteins by irreversible complexing with nucleophilic amino acids

• antibacterial targets: surface-exposed adhesins, cell-wall polypeptides, & membrane-bound enzymes

Quinones found in Lawsonia inermis(plant source of henna) are responsible for henna’s dying properties1,2-benzoquinone

anthraquinone

QuinonesQuinones

Anthraquinones from Cassia italica (Fabaceae) are bacteriostatic for Bacillus anthracis, Corynebacterium pseudodiphthericum, & Pseudomonas aeruginosa. They are bacteriocidal for P. pseudomalliae.

Kazmi et al. 1994. Phytochemistry

Hypericin, an anthroquinone from St. John’s Wort acts as an anti-depressant and also demonstrates anti-staphylococcal activity (Gibbons et al. 2002. Fitoterapia)

hypericin

Hypericum perforatum

Flavones, Flavonoids, and FlavonolsFlavones, Flavonoids, and Flavonols

• Flavone: phenolic structures with 1 carbonyl group (as opposed to the 2 carbonyls in quinones)

• Flavonol: add a 3-hydroxyl group• Flavonoid: also hydroxylated, but as a C6-C3

unit linked to an aromatic ring

Flavone Flavonol

Flavones, Flavonoids, and FlavonolsFlavones, Flavonoids, and Flavonols

• Flavonoids are synthesized by plants in response to infection– Active against bacteria and viruses,

including HIV and respiratory syncital virus (RSV)

• Catechins have shown some notable antibacterial activity:– Streptococcus mutans, Shigella,

and Vibrio (also inactivating cholera toxin)

• Isoflavones are active against variety of microorganisms and have been used successfully to prevent schistosomal infection

Flavonoids:

Quercetin

Epicatechin

Flavonoids• These compounds occur as plant

pigments often yellow or orange (flavus = yellow)

• They are universal within the plant kingdom

• It is likely that one of their main roles in nature is as color attractants to insects and birds, or to affect the taste of plants (some are bitter and astringent and some are intensely sweet)

• Flavonoids have important dietary significance because, being phenolic compounds they are strongly antioxidant

Flavonoids• Many disease states are induced or aggravated by

free radicals such as superoxide. Flavonoids have the ability of scavenge these oxidizing species

• Foods rich on flavonoids have been proposed to be important on ameliorating diseases such as cancer and hearth disease

• Flavonoids occur both free (aglycone) and as glycosides

• Flavonoids are important components of the human diet. Average consumption is estimated at approximately 1 g/per day/per person

Flavonoids• proanthocyanidins and anthocyanins

Bilberries are a rich source of anthocyanins

Anthocyanins have superoxide radicals scavenging effects in vitro and in vivo. They have been associated with collagen-stabilizing activity.Cyandin is an example of an anthocyanin. proanthocyanin

They are dimers

Flavonoids

• Resveratrol is naturally occurring compound found in various plant species including grapevines

• Given that it is present in grape berry skins but not in flesh, white wine contains very small amounts of resveratrol, compared to red wine

• The concentrations in the form of trans- and cis- isomers of aglycone and glucosides are subjected to numerous variables.

• In red wine, the concentrations of the trans-isomer, which is the major form, generally ranges between 0.1 and 15 mg/L

Flavonoids

• The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process.

• Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted

• Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 µg of resveratrol, compared to peanuts, which average 73 µg per ounce

TanninsTannins

• Polymeric phenolic compounds with the ability to “tan” leather (astringent properties)

• Found in almost every plant part• Formed by condensations of flavan

derivatives or by polymerization of quinone units

• Act by complexing with proteins via hydrogen bonding, hydrophobic effects, and covalent bond formation - inactivating microbial adhesins, enzymes, and cell envelope transport proteins

PentagalloylglucoseProcyanidine B-2

Image: Eygentliche Beschreibung aller St.

Tannins• Tannins represent a very large group

of polyphenolic natural products• They are widely distributed in the

bark, insect galls, leaves, stems and fruits

• They are the main constituent for astringency

• They have the ability to precipitate proteins into insoluble complex (used to “tan” animal hides

Tannins• Hydrolysable tannins are derived from simple phenolic

compounds and there are linked to a sugar by esterification

• Hydrolysable tannins can be hydrolyzed by base to produce simple acids and sugars

• Non hydrolysable tannins or condensed tannins that are formed by the polymerization of flavonoids

• They are used mainly because of their astringent properties, for example as antdiarrheic properties

• Consumption of tannins may lead to reduce absorption of proteins and other nutrients

• They can precipitate other components in herbal preparations

CoumarinsCoumarins

• Phenolics made of fused benzene and α-pyrone rings

• Best known for their anithrombotic, anti-inflammatory, and vasodilatory activity

• Coumarins stimulate macrophages – which could help clear infections

• Coumarin has also been used to prevent recurrences of viral cold sores caused by HSV-1

Coumarin

CoumarinsCoumarins

• Psoralens– Coumarins that have a furan

ring– Readily absorb light– Typical in Rutaceae (citrus)

and Apiaceae (carrot) families– Carcinogenic and mutagenic– Used in treatment of vitiligo

(melanin deficient skin patches), eczema and psoriasis

Xanthotoxin

(Trade name: Oxsoralen , Dltasoralen , Meladinine)

Furanocoumarins

Furanocoumarins have furan ring at C-6 C-7 or C-7 C-8. Psoralen have photosensitizing activity utilized on the treatment of psoriasis in combination with UV light (PUVA). It is also used to promote skin pigmentation in vitiligo

Psoralen is one of the oldest known chemotheraputic drugs--the use of a psoralen containing Nile weed to treat skin ailments was described in Ebers papyrus, an early Egyptian medical text published around 1550 BC (the front page is reproduced above). The drug photocrosslinks DNA and is shown in this figure to induce the formation of a four-stranded Holliday junction (reference, Eichman, et al., J. Mol. Biol., 2001, 308: 15-26).

lactonefuran

Terpenoids and Essential OilsTerpenoids and Essential Oils

• Terpenes (C10H16) – also occur as di-, tri-. tetra-, hemi-, and sesqui-terpenes

• Terpenoids contain additional elements (usually oxygen)

• Responsible for plant fragrance

• Exhibit activity against: viruses, fungi, bacteria, and protozoa

Limonene Camphor

Monoterpenes

Farnesol

Artemisin

Sesquiterpenes

AlkaloidsAlkaloids• Heterocyclic nitrogen

compounds• Best known for psychoactive

effects:– Opiate analgesics from poppy– Stimulants (caffeine & related

structures)– MAO Inhibitors (harmala alkaloids

permit hallucinations by making DMT orally active)

• Some can intercalate with DNA • Microbiocidal effects – including

against Giardia and Entamoeba species

Caffeine

Morphine

AlkaloidsAlkaloids

• Pyridine, piperidine & pyrrolizidine alkaloids– Pyridine alkaloid class:

• Nicotine from Nicotiana tabacum– Stimulant component to tobacco

– Piperidine alkaloid class:• Coniine from Conium maculatum

– Poison Hemlock Socrates was forced to drink

• Arecoline from Areca catechu – betel nuts addictive due to presence of this stimulant

– Pyrrolizidine alkaloid class:• Senecionine from Symphytum officinale (comfrey) and

Senecio vulgaris (groundsel)– Hepatotoxic properties

AlkaloidsAlkaloids

• Phenylalkylamine alkaloids– Ephedrine from Ephedra sinica (Ma Huang)

• CNS stimulant, vasoconstrictor, and bronchodilatory– Mescaline from Lophophora williamsii (peyote)

• Contributes to hallucination & vivid dream effects of peyote

• Quinoline alkaloids– Quinine from Cinchona spp. (Cinchona bark)

• Anti-malarial activity

• Isoquinolone alkaloids– Morphine from Papaver somniferum (opium poppy)

• Narcotic pain medication

AlkaloidsAlkaloids• Indole alkaloids

– Reserpine from Rauvolfia serpentina (snake root)• antihypertensive

– Inogaine from Tabernanthe iboga (iboga) • Hallucinogenic and anticonvulsant

• Tropane alkaloids– Hyoscamine/atropine from Atropa belladonna (deadly

nightshade)• Anticholinergic, mydriatic (pupil dilation), and used to treat acute

cardiac arrhythmias• Xanthine alkaloids

– Caffeine from Coffea arabica (coffee)• CNS stimulant and diuretic

• Imidazole alkaloids– Pilocarpine from Pilocarpus jaborandi (jaborandi)

• Cholinergic and used to treat glaucoma, causes miosis (pupillaryconstriction)

Lectins and PolypeptidesLectins and Polypeptides

• Peptides – often +-charged with disulfide bonds

• May act by forming ion channels in microbial membrane or competitive inhibition of adhesion of microbial proteins to host receptors

• Thionin peptides (45-50 a.a. long) found in barley and wheat are toxic to yeast and gram positive bacteria

• Fabatins (found in fava beans) are 47a.a. long and inhibit gram + and – bacteria (Zhang & Lewis, FEMS Microbiology Letters, 2006)

Vicia faba – the source of a popular Mediterranean food (fava beans) and the antimicrobial fabatinpeptides

PhenylpropenesPhenylpropenes• Consist of an aromatic

ring with an unsaturated 3-carbon chain attached

• Common components to spices

• Highly aromatic or pungent aromas

• Many are broadly antimicrobial (yeasts and bacteria)

EugenolClove oil & cinnamon leaf

MyristicinNutmeg (hallucinogenic component)

SafroleStar anise Fennel

GlycosidesGlycosides

• Glycoside = general term for natural product bound to a sugar– 2 parts: aglycone

(terpene, coumarin, flavonoid, etc) + sugar

• Cyanide Glycosides– Amygdalin found in seeds

of Prunus species– Cyanide glycosides found

in cassava tuber (Manihot esculenta) yield HCN

amygdalin

Glycosides• Glycosides are naturally occurring chemicals

formed by sugar moiety attached to a non-sugar portion

glycosideaglycone – glycone

• C-glycosides• O-glycosides• N-glycosides• S-glycosides

Glycosides

• Many glycosides remain bio-inactive until they are hydrolyzed and the aglycone is released “prodrugs’

• Classification of glycosides is based on the nature of the aglycone

• This is a heterogeneous group with little in common besides their physicochemical properties, e.g. they are very hydrophilic, and hygroscopic

GlycosidesGlycosides

• Glucosinolates– Found in

cabbage/mustard family (Brassicaceae)

– Glycosides with sulfur & nitrogen

– Responsible for strong odor of mustards

– Mustard oils used for external treatment of muscle pain

• Cardiac glycosides– Have a profound effect of

heart rhythm (ex. Digoxin & digitoxin from Digitalis)

– Common in these genera:• Convallaria• Nerium• Helleborus• Digitalis

sinigrin

digoxin

GlycosidesGlycosides• Anthraquinone glycosides

– Known for laxative properties due to increased peristaltic action & reduced water reabsorption

Cascara

Rhamnus purshiana

Aloe

Aloe vera

barbaloin

Cascaroside

Alexandria Senna

Cassia senna Sennoside A

Summary Points

• Great diversity in secondary plant metabolites– Structurally complex– Many are biologically active – Certain classes are associated with specific

effects/actions• Classes have specific structural characteristics• Many important current drugs derived from

these plant metabolites