1
Terpenoids
• The widest biosynthetic group of secondary metabolites
– (> 22 000 of structures)
– From 70ies 2× more of described compounds
• Function in plant
– Hormons
– Pigments
– Electron transporters
– Intermediates in sugar metabolism
– Building material
– Communication
– Attractants
– Repelers
– Defensive compounds
• Relatively high levels in
• Essential oils
• Waxes
• Resins
• Many times volatiles – possibility of inhalation
• On the surface – possibility of contact
• Esters
– Hydrolysis to alcohols and
carboxylic acids
– Mostly in liver
• Products detoxified
– Primary by conjugation
with glucuronic acid –
excretion in urine
– Unsaturated alcohols 4oxidysed
at allyl
• polar metabolites – diols
• conjugation - excretion
• or excreted freely
• Primary alcohols could
be further oxidized
– Metabolites of acyclic
alcohols – oxidation to
CO2.
2
• Monoterpenes
– Volatile part of essential oils
– Lamiaceae, Cupressaceae, Asteraceae,
Apiaceae
– Sub-groups
• Iridoids
• Cyclic monoterpenes
• Acyclic monoterpenes
• Toxic iridoids
– Alamandin
• Allamanda cathartica
Apocynaceae
• South America
• Golden Trumpet
• Irritating after contact
• Per os only high
amounts
– Vomiting and
diarrhea
– Boschnialacton
• Boschniakia rossica
Orobanchaceae
• Parasitic plant
• Toxic for Felidae
(cats)
– excitation
O
O
O
O
OH
OO
H
H
O
OH
H
3
• Thujone
– Natural mixture of
isomers α,β (33% α,
67% β)
– Artemisia absinthium,
A. vulgaris, Salvia
officinalis, S. sclarea
– Tanacetum vulgare
– Thuja occidentalis
– Folk medicine:
• Abortive,
emenagogue,
digestive, carminative,
antiphlogistic,
anthelmintic
– Analgesic, analeptic,
antidepressive
O
CH3
CH3CH3
H
– Toxicity:
• CNS effect
– Tonic-clonic convulsions, cumulative effect
– Absinthism
» hyperexcitability, hallucination
• Nephrotoxicity (degenerative changes)
• Hepatotoxicity
– Dependence on dosage and sensitivity
– Mechanism of effect:
• Blockator of GABAA chloride channel (similarly to picrotoxine)
• α-thujone 2.3× more effective than β-thujone
• Low affinity to cannabinoid receptors
• Metabolism:
– Reduction of ketone to hydroxyl, excretion in urine
– 7-OH-thujon, dehydrothujon – also active
– Absinthism
– Oscar Wilde:
• "The first stage is like ordinary drinking, the second when you begin
to see monstrous and cruel things, but if you can persevere you will
enter in upon the third stage where your see things that you want to
see (what is the most horrible thing)."
4
Tanacetum vulgare Thuja occidentalis
• Toxic cyclic
monoterpenes
Ascaridol
• Chenopodium
ambrosioides var.
anthelmintikum
Chenopodiaceae
• Peumus boldus
Monimiaceae
• Vomiting, vertigo,
gastritis, muscular
weakness
• Affection of cardiac
activity and blood
pressure, CNS
depression, convulsions
• Cancerogene
O
O
5
• Toxic cyclic monoterpenes
– Camphora
– Cinamomum camphora (+)-form
– Tanacetum parhenium, Arthemisia,
Lavandula (-)-form
– Hydroxylation at many positions
• glucuronisation
– Nauzea, vomiting, headache, blue-red
vision
– Excitation of CNS
• Unassines, derangement,
hallucination, tremor
• Convulsions, respiratory
depression, coma
– Hyperaemic skin
– Cardiotoxicity
• Similarly to caffeine
– High toxicity for foetus
O
• Toxic cyclic monoterpenes
–Pyrethrins
•Pyrethryns I and II
•Cynerins I and II
•Jasmolins I and II
•Pyrethrum parthenium, syn.
Chrysanthemum parthenium,
Tanacetum parthenium (řimbaba)
Asteraceae
•Metabolism:
–unchanged
–Metabolized to chrysanthemumic
acid and further
» Less toxic metabolites
» In liver, into bile
•Acute toxicity:
–Inhalation – asthmatic attack
–Neurotoxic poison – Na+ a Ca2+ a
Cl- channels
» lethargy, vomiting, tremor,
convulsions, irritability
» Hypersensitivity to stimules
» Paralysis, respiratory distress
•Chronic toxicity low
O
O
O
6
1. Pyrethrin I:
•Oxidation
2. Pyrethrin II:
•Oxidation after hydrolysis
3. Both via carboxylic
chrysanthemumic acid
4. Diol
– Menthol
• Mentha spp. Lamiaceae
• Toxic in high doses
– Stomach pain, vomiting
– Vertigo, coma
– Children:
– asphyxiation via spasm
of glottis
– Pulegone
• Mentha spp. Lamiaceae
• Toxic in high doses
– Stomach pain, vomiting
– Hepatotoxicity
– Kidney insufficiency
– Metabolite - menthofuran
O
OH
7
8
• Sesquiterpenes
– Mostly lactones
• Division:
– Guajanolides
– Eremophilanolides
– Pseudoguajanolides
– Xantholides
– Germacranolides
– Fragrant and bitter substances
– Toxicity
• Convulsants
• Irritation of GIT
• Alergenes
– Exocyclic methylene group
» Binding to amino acids
– Crossed reactivity
– Dependent on concentration, individual sensitivity
• Often observed cytotoxicity
– Family Asteraceae
• Toxic sesquiterpenic
lactones
– Absinthin
• Arthemisia absinthum
Asteraceae
• Neurotoxicity dubious
– Alantolactone
• Inula spp. Asteraceae
• Alergic contact dermatitidis
– Anisatine
• Illicium anisatum Illiciaceae
• Neoanisatine,
pseudoanisatine
• Picrotoxine type of toxin
– Non-competitive GABA
inhibitor
– Binding at picrotoxine site
• Neurologic and
gastrointestinal toxicity
– Nausea, vomiting
– Tremor, myoclony,
convulsions
OH
OH
OH
CH3
O
O
CH3
OH
O
O
9
– Coriamyrtine
•Coriaria spp. Coriariaceae
•Picrotoxine type
•Toxicity for mammals
•GABA inhibition
– Epileptiphormous convulsions
– Excitation of CNS
– Myosis, asthma
– Apnoe, coma
– Cardio-pulmonary failure, death
– Picrotoxine
•Picrotine and picrotoxinine 1:1
•Anamirta paniculata Fishberry
Menispermaceae
•Ichtyotoxine
– Paralysis of air bladder
– Intoxicated meat
•Inhibition of GABAA receptor
•Excitation of CNS
– Mainly medulla oblongata
•Myoclony, uncoordinated movements, stupor,
delirium, epileptiformous convulsions
•Coma, insensitivity
•Cardio-pulmonary failure, death
•Stimulation of glandular secretion
– GIT problems
•Slowering of cardiac function - arrest
OH
CH3 O
O
O
O
CH3
CH2
CH3
O
OH
O
O
O
OH
CH3
CH3
OH
CH3
O
OH
O
O
O
CH3
CH2
OH
10
– Helenaline
• Helenium (sneezeweed),
Arnica and further
Asteraceae
• Toxicity
– Aborts
– Vomiting, tachycardia
– Facial hyperemia
– Respiratory distress
– Death via circulatory
collapse
– α-santonin
• Artemisia cina Asteraceae
• Anthelmintic
• Mainly for children
• Headache, apathy,
disorders of hearing
• Cardiovascular and
respiratory collapse
• Irritation of CNS
– Convulsions,
hallucination
CH3
OCH3
O
CH3
O
• Other toxic sesquiterpenes
– Gossypol
• Gossipium spp., Montezuma
spp. Bombacaceae
• Pigment of bissesquiterpene
type
• Reproductional toxicity:
– Oligospermy, abnormality of
spermatozioides
– Destruction of seminiferous
tubules
• Neurosis of GIT, changed libido,
hypokalemia
• Important hepatotoxicity
• Acute toxicity:
– Loss of weight, diarrhea,
bleeding, dysrythmia
OH
OH
CH3
CH3
CH3
OH
O
OH
OH
O
OH
CH3CH3
11
Ledol a palustrol
• Ledum palustre Ericaceae
• Tricyclic sesquiterpene
• Toxicity
– Central stimulation
– Psychomotoric excitation
– Convulsions to paralysis
CH3
CH3
CH3
OH CH3
CH3
CH3
OH
CH3
CH3
H
– Miotoxin C, roridin A
• Baccharis cordifolia Asteraceae
• Sesquiterpene of trichothecene
type
• Probably metabolite of symbiotic
fungus (Fusarium)
• Toxic for sheep and cattle
– GIT disorders
– Neural disorders
• Antileukemic properties
O
O
O
O
O
CH3
O
O
CH3
OH
O
O
CH3
OH CH3
H H
12
– Ptachiloside
• Norsesquiterpenic
glucoside of iludane type
• Different types of ferns
– Pteridium, Pteris,
Chelanthes
Dennstaedtiaceae
• Potent cancerogene
– Urinary bladder
– Guts
– Esophagus
• Hepatotoxicity
• Cattle pasturing these
ferns
– Transfer to milk
O
CH3
O
O
CH3
O
OH
OH
OH
OH
• Diterpenes
– Compounds containing 20 carbon atoms (4 ×
5)
– Toxikologically important families:
• Ericaceae (grayanotoxins)
• Euphorbiaceae (Euphorbia factors)
• Asteraceae
• Rubiaceae
13
•Toxic diterpenes
– Atractylosides A-I
• Xanthium (cocklebur), Atractylis,
Wedelia Asteraceae
• Derivative carboxyatractylosid, in
Wedelia wedeloside
• Glycosides
– Carboxyl derivative 10x
effective
– Aglycone low effectiveness
only
• Strychnine-like effect
• Inhibitors ADP/ATP
transportation through membrane
of mitochondria
– Binding to carrier – block at
outer side of membrane –
block of transfer to matrix –
block of oxidative
phosphorylation
• Nephrotoxicity – necrosis of
proximal tubulus
• Hepatotoxicity – centrilobular
necrosis
O
O
OO
O
O
O
O
S
O
OS
O
O
O
O
O
O
H
H
K
+(I)
• Toxic diterpenes
– Daphnetoxin, mezerein
• Daphne mezereum and other
Thymelaceae species
• Poisonous fruits and leaves
• Mainly children – to 30% mortality
• Contact – irritation
• GIT – ulceration, damage of mucose
– Convulsions, vomiting, diarrhea
• Hepatotoxicity
– Interaction with mitochondrial
phosphorylation
– Increases the transition of membranes for
ions
• Neurologic symptoms
– Convulsions
– Headache, vertigo
• Arrhythmias
OCH3
O
O
OH
O
OH
O
CH3
OH
CH3
CH2
H
14
– Gnidilatine and its
derivatives
• Gnidia factors
– simplexine
• Gnidia spp.
Thymelaceae
• Skin irritants
• Convulsants
• Carcinogens
• Cattle disease
– St. Georg desease –
cardio-pulmonal
syndrom
O
O
O
O
O
O
O
O
O
O
H
H
O
O
O
O
O
O
O
O
O
O
H
H
15
• Toxic diterpenes
– Phorbol and its esters
• Croton, Sapium, Euphorbia Euphorbiaceae
• Tetracyclic diterpen
• In plant latex
• Skin and mucosal irritation
• Conjunctivitis
• Irreversible damage of lysosomal and mytochondrial
membranes
• Acute toxicity
– burning, edema, mucoses turning red
– Vomiting, paralysis of veins in GIT
– Mydriasis, vertigo, collapse
• Potent inductor of carcinogenesis
– Ingenol esters
• Rod Euphorbia Euphorbiaceae
• Latex
• Inflammation of skin and mucosa
• Monoesters more aggressive
OHCH3
OH
CH3
CH3
OH
OH
CH3
O
OH
OH
O
CH3
OH
OH
CH3
OH
CH3
CH3
16
– Resiniferatoxine
• So called Euphorbia
factors
– One of most active
irritants
– Carcinogen
– Lowers body
temperature
– Analogue of capsaicin
1000 × stronger
– Neurotoxicity
» Terminal
hypoalgesia
» Inhibition of
potassium
channels
O O
O
O
O
O
O
O
O
H
H
17
–Grayanotoxine, Asebotoxine II
• Hepatotoxicity (mainly sheep)
• Andromeda, Rhododendron
spp. Ericaceae
• Pieris japonica Ericaceae
• Similar to aconitine intoxication
– Progressive paralysis from
numbs to diaphragm
• Ionotropic effect
– Increase of Na+ transition
through membrane of
cardiocytes
• Stimulation – paralysis of
nervus vagus
• Salivation, nausea, vomiting,
diarrhea, GIT disorders,
bradycardia
O
OH
OHOH
O
OH
OH
H H
– Taxol 0.01-0.03%
– Pacific - Taxus brevifolia
– Europe - Taxus baccata
– Japon - Taxus cuspidata
– Himalaya - Taxus wallichiani
• Taxaceae
• Cephalomanine
– Taxus baccata
• Mitotic poison
– Suport of microtubule
formation
– Inhibition of depolimerisation
• Neutropenia
• Neurotoxicity
– Peripheral neuropathy
• Myalgia, alopecia
• Ulceration of GIT O
O
O
OO
O
O
O
O
O
O
O
O
N
O
H
18
O
O
O
O
O
O
O
O
O
O
O
N
O
OH
O O
O
O
OO
O
O
O
O
O
O
O
O
N
O
H
Cephalomanine Taxol
O
O
O O
O O
O
O
O
O
O
O
N
H
Paclitaxel
– Salvinorin A
• Diterpene of clerodadiene type
• Salvia divinorum Lamiaceae
• Hallucinogenic
• Shamanic plant
O O
O
O
OO
O
O
HH
19
• Triterpenes
– Different structural forms
– Different biologic activity
– Cucurbitaceae, Verbenaceae
20
• Toxic triterpenes
– Cucurbitacines A-V, Q1
• Tetracyklic triterpenes
– Several keto groups
– Free or glycosides
• Cucurbitaceae
– Citrullus
– Cucumis
– Luffa
– And further
• Toxicity
– Neurotoxicity (up to 24 hours)
– Drastic laxative (up to 3 days)
• Cucurbitacine D
– Relative long latention (including high
dosages)
– Diarrhea, exhaustion, tachypnoe
– Persisting bloody diarrhea, necrosis of gut
– Circulatory collapse, coma, death
– Nephrotoxicity, hepatotoxicity
» Histological changes of liver,
pancreas, guts, kidneys, lungs
– Conjunctivitidis, cataract, blindness
– Icterus
Cucumis myriocarpus
Luffa aegyptiaca
OH
OH
O
O
OH
O
OH
O
Cucurbitacine
21
– Lantadenes
• Triterpenes of oleanane type
• Lantana camara, Lippia
rehmanii Verbenaceae
• Acute toxicity
– Hepatotoxic
– Gastroenteritides
» Bloody and watery
diarrheas
• Chronic toxicity
– Photosenzibilization
O
O
O
O
O
Lantadene A
22
• Glycosides
– Various structures
• Sugar part
– D-β-sugar
– L-α-sugar
• Ester, ether, thioether, amide, C-C bond
– Hydrolysis
• Activation
– Nitrotoxines, cyanogennic glycosides
• Deactivation
– Polycyclic aglycons
• Cyanogennic glycosides
– 2-hydroxynitriles + β-D-glucose
– Hydrolysis produces:
• HCN
• Sugar
• Residue (acetone, benzaldehyde)
– Widely distributed
• Rosaceae
• Fabaceae
• Euphorbiaceae
• Passifloraceae
– Toxic concentration of HCN 0.5-3.5 mg/kg
• Massive consumation
• Hydrolysis in GIT
– Rapid detoxication in organism
• Production thiocyanate
– Toxicity
• Cytotoxic anoxia
– Bonds at cytochrome c
– Disabling of O2 utilization
23
• Three phases of intoxication:
1. Dispnoe and irritation
2. Convulsions
3. Terminal adynamy
• Mild intoxication
– Headache
– Anxiety and respiratory distress
– Vomiting, palpitation
– Tachycardia, dyspnoe
• Higher doses
– Peripheral anesthesia
– Insane mind
– Cyanosis, stupor, tonic-clonic convulsions
– Respiratory arrest, death
• Alimentary intoxications
– Manioc
– Sorghum
– Bitter almonds
– Several Asian and American species of beans
• Manioc
– Manihot esculenta Euphorbiaceae
– Linamarine, lotaustraline
– Inhibition of Na+/K+ ATPase
• Loss of potassium, ion disbalance
– Damage of kidneys and liver
– Acute intoxication
• Stomach pain, diarrhea
• Coma, cardiopulmonary failure
– Chronic intoxication
• Tropical neuropathic ataxia
– Damage of skin and mucosa
– Damage of optic and auditory
nerve
– Depletion of sulphur-containing
AMA
N
O beta-D-Glucose
24
25
• Sorghum
– Sorghum spp.
Poaceae
– Dhurrin
• p-hydroxymandelonitril-
β-glucoside
– High content in young
shoots
– Hydrolysis releases
HCN
O
O
OHOH
OH
OH
N
OH
• Toxic glucosinolates
(thioglycosides)
• Brassicaceae
• Capparaceae
• Tropelolaceae
• Resedaceae
– Strumigens
– Glucose residue
– Sulphate group
– Aglycone
• Aliphatic
• Aromatic
• Heteroaromatic
– Enzymatic hydrolysis
• Myrozinase
– Isothiocyanates or
nitriles
– Glucose + sulphate
26
• Cyclic products of
decomposition
–Oxazolidinthiones
–The most toxic
• Goitrine and its precursors –
progoitrines
• Inhibition of incorporation of
inorganic iodine into thyroxin
precursors
– Insufficient production of thyroidal
hormones
– Histomorphologic changes
» Goiter - hyperplasia
- hypertrophy
– Retardation of growth
– Liver damage
– Toxic amount 2-5 mg/1g of food
O
N
S
• Toxic anthraquinone glycosides
– Many families
• Aloe Liliaceae
• Cassie, Gleditchia Caesalpiniaceae
• Andira Fabaceae
• Polygonum, Rheum, Rumex Polygonaceae
• Frangula, Rhamnus Rhamnaceae
– Aglycon
• Derivatives of 9,10-anthraquinone
• Reduction
– Rise of anthrones, anthranoles and dimers
• Substitution of aromatic carbons
– OH, -OCH3, -CH2OH, -COOH
– Intoxication
• Usually overdose of laxative
• Disturbance of balance of water absorption
– Active transport of sodium
• Disturbance of water secretion
– Hydrostatic pressure
– Prostaglandins released chloride secretion
• Anthrones are produced via reduction
mediated by gut microflora
– 100× cytotoxic than precursors
– Cytotoxic for gut mucosa
27
• Metabolism
– Aglycons
• Rapid absorption
• Detoxification in liver
– Excretion as glucuronides and
sulphates
– Glycosides
• Do not absorbed
• Transport to colon
– Colon microflora metabolism
– Chronic intoxication
• Laxative abuse syndrome
– Loss of electrolytes
– Changes of gut mucosa
– Melanosis coli
– Degenerative changes of
inervation of colon
– Acute intoxications
• Loss of water and electrolytes
– Hypocalemia
– Tubular nephropathy
– Lowering of muscular activity
– Arrhythmia, bradycardia
– Mutagenicity
• Chrysophanol, emodine…
– Hypericismus
• Photosenzibilisation
• Formation of singlet oxygen