Monoterpenoid Indole alkaloids - faculty.psau.edu.sa · an indole or dihydroindole structure...
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aloidsids 22 11
Monoterpenoid Indole alkaloids
RAUWOLFIA (SNAKEWOOD)
roots and rhizomes of
Rauwolfia serpentina
( Apocynaceae).
total alkaloids (0.5-2.5%) form a
complex mixture of nearly 30
different compounds, mostly indoles.
used by
India to
ranging
the traditional healers of
treat a variety of ailments,
from snake-bite to insanity.
Three main groups of alkaloids are distinguished:
1- Yohimbane-type Derivatives.The most interesting ones are substituted at the 16- 17, and 18 positions):
reserpine (trimethoxybenzoate of methyl reserpate) and
recinnamine (trimethoxycinnamate of methylreserpate).
2- Heteroyohimbane Derivatives.very closely related to the previous ones, with heterocyclic E ring:
Ajmalicine (also known as raubasine), reserpiline, 10, 11-dimethoxy-
ajmalicine), reserpiline, isoreserpiline), and serpentine.
3- Dihydroindole derivativesThese are chiefly represented by ajmaline, a polycyclic indoline alkaloid
2
Reserpine:
Pale white to slightly yellow or colorless crystals, weak base,
insoluble in H2O, soluble in CHCl3
Salt such as reserpine sulfate are soluble in chloroform.
On treatment with sodium nitrite in the presence of sulfuric
acid, these alkaloids are oxidized to the corresponding 3,4-
dehydro- derivatives: these are colored and can be used for
quantitative estimation.
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- Rauwolfia alkaloids exert hypotensive effects by depletion of catecholamine
and serotonine stores in many organs, and by reduction of uptake of
catecholamines by adrenergic neurons.
- Their sedative and tranqulizing effect are thought to be related to depletion
of amines in CNS.
Reserpine (used for its neuroleptic properties and antihypertensive activity)
- It is used in combination with diuretics for treating arterial hypertension.
Rescinnamine has the same activity.
Ajmaline (antiarrhythmic agent)
- decrease the rate of depolarization of atrial and ventricular cells.
Ajmalicine (Raubasine) moderates the activity of the vasomotor centers,
the brain and is slightly anxiolytic.
Yohimbine (from the bark of the tree Pausinystalia yohimbe)
- It is hypotensive and a peripheral vasodilator.
- Has reputation as an aphrodisiac, (treated impotence in patients with
vascular or diabetic
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Catharanthus roseus (Fam. Apocynaceae)
- 0.2-1% alkaloids
- All of them have
(very complex mixture)
an indole or dihydroindole structure (indoline- the
principal constituents) e.g. catharanthine, vindoline and ajmalicine.
The alkaloids with antineoplastic activity belong to a new class of
bisindole derivatives (composed of an indole and a dihydroindole
unit) catharanthine and vindoline respectively.
About 20 binary alkaloids have been isolated from various C. roseus.
Several have cytostatic properties, especially:
-
-
-
1- Vincristine: 0.0003% (i. e 3 g per metric ton of dried drug)
2- Vinblastine: which is a little more abundant.
- These two alkaloids formally comprise a dihydroindole moity
(vindoline) and an indole moiety (velbanamine).
- Vincristine and vinblastine are antimitotics.
6
CH2CH3
COOCH3H
R HO OCCH3
R = CH3 Vinblastine
7
OH
N
N
N
CH2CH3
O
H3CO N OCCH3
O
R = CHO Vincristine
Nux vomica
-
-
ripe seed of Strychnos nux-vomica (Fam. Loganiaceae).
The drug contains from 1-3% total alkaloids chiefly
(strychinine and its dimethoxylated derivative brucine)
Strychinine was formerly used mainly to poison rodents, and
the galenicals obtained from the drug ingredients of tonic
preparation.
Few products based on nux vomica tincture are still used in
homeopathy.
-
-
- Brucine, which is less toxic than strychinie, has been used
commercially as bitters.
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Strychnine:
Monoacidic base, has no basic
properties, colorless prisms or white,
base and salts are very powerful
poison.
Brucine:
Dimethoxystrychnine, soluble in
alcohol and acetone, insoulble in
NaOH or KOH
Identification:
1-
2-
3-
4-
Strychnine
Strychnine
Strychnine
+
+
+
H2SO4 + K2CrO3 gives reddish-violet color
NH4-Vandate gives violet color (Mandelin’s reagent)
HNO3 gives yellow color
Brucine + HNO3 gives orange-red color
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R1 N
R2 N
OO
Strychnine = R1 =R2 = H
Brucine = R1 = R2 = OCH3
Separation of a mixture of strychnine
and brucine:1- Acetone dissolves brucine and leave
strychnine.
2- K[Fe3(CN)6]-solution when added to
the mixture, strychnine gives ppt
quickly from its salts than brucine.
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Quinoline AlkaloidsAlkaloids containing quinoline as their principle nucleus include
those obtained from cinchona (quinine, quinidine,
cinchonidine).
Cinchona
cinchonine and
- bark of C. pubescens (C. succirubra) or
of its varieties (Fam. Rubiaceae).
7-15% alkaloids which occur in
combination with special organic acids
chiefly quinic acid and cinchotannic acid.
Used in the treatment of malaria fever for
many years.
Over doses of cinchona products results in
temporary loss of hearing and in impaired
sight. Ringing in the ears is a symptom of
toxicity (Cinchonism).
-
-
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Chemistry:
-9-rubanol is the
from the parent
- Ruban nucleus
basic skeleton of these alkaloids, which is derived
compound named ruban.
is composed of quinoline ring system attached
through a methyllene group to a bicyclic ring system named
quinuclidine.
- The principal alkaloids are the stereoisomers, quinine and quinidine,
and their 6'-demethoxylated homologs cinchonine and cinchonidine.
H
HO
R = OCH3 (-_ ) Quinine R = OCH3 ( _ ) Quinidine
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HHO
N N
R H R H
N N
-
R = H ( _ ) Cinchonidine R = H ( _ ) Cinchonine
Quinine:
- a diastereoisomer of quinidine, occurs as
crystals.
- Quinine is antimalaria agent.
white, odorless, bitter
Quinidine:
- an antiarrththmic class I (sodium channel blockade).
- inhibits the rapid sodium influx,
depolarization, contractility, and
conduction velocity.
- used for treating various cardiac
decreases the rate of
the atrial and intraventricular
arrhythmias e.g. premature atrial,
ventricular contraction, atrial and ventricular tachycardia, and atrial
flutter and atrial fibrillation.
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The current indications of quinine include the following:
1- treating of pernicious malaria and of cases of malaria resistant
to 4-aminoquinolines.
2- The symptomatic treatment of fevers, aches and flu-like states.
3- Quinine ascorbate, combined with vitamins, used in programs
quit smoking (60-80mg/day in four doses).
to
4- in combination with thiamine, to relieve muscle cramps.
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Identification:1- With oxygenated acids (e.g. sulphric and acetic acid)
Quinine and quinidine produce a strong blue fluorescence when
dissolved in these acids.
2- Thalleioquin reaction
Quinine and quinidine in solution in dilute H2SO4 can be
treated by Br2 until the fluorescence disappears.
The addition of aqueous NH3 causes the development of an
emerald green color, which can be extracted with chloroform.
3- The addition of K[Fe3(CN)6]-solution in alkaline medium leads
to a purplish red color that can also be extracted with chloroform.
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Ramzi MM loidsids 22
Camptotheca acuminata (Fam. Nyssaceae)
The bark, and the fruits of this large tree indigenous to southern China
-
-
-
-
contain 0.01-0.03 % camptothecine.
It is characterized by a pyrrol [3,4b]quinoline sequence.
It is a neutral lactam, which does not react with the general reagents for alkaloids
Camptothecine exert cytotoxic and antitumor activity, but because of its
toxicity, its synthetic analogs such as Topotecan and CPT11 have been used.
There was evidence that this compound had some activity on topoisomerase I-
(an enzyme involved in
transcription).
the uncoiling of DNA, a prerequisite for replication and
N
N
16
9 7
10 O
11
12
20 O
OH O
Camptothecine
Histidine- derived Alkaloids
Alkaloids of the Imidazole group
►Alkaloids that possess an imidazole
nucleus are very rare.
► found in some Rutaceae (leaves of
the Pilocarpus of South America)
Jaborandi
► It consists of the leaflets of
Pilocarpus jaborandi, P. microphyllus,
and P. Pinnatifolius (Fam. Rutaceae).
► 0.7 – 1.0 %, the chief constituents is
(3S, 4R)-(+)-pilocarpine and
stereoisomer isopilocarpine.
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Ramzi MMothanothanaa AlkaloAlkaloidsids 22
► Pilocarpine is a tertiary base containing a lactone group as well
as an imidazole nucleus.
It is an oily syrupy liquid, easily soluble in water, alcohol and
chloroform, but almost insoluble in ether.
The lactone ring is opened by caustic alkali, which forms salts
with the resulting pilocarbic acid (unaffected by ammonia or
alkali carbonates) (destroys the physiological activity)
►
►
► it is demethylated and converted to pilocarpidine, when heated
with acids.
COOH HNN
H
4 34 3 NN
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4 3
O
N NH2
N O
Histidine Pilocarpidine
H3C H3C
O O
N O N O
(3S, 4R)-Pilocarpine (3R,4R)-Isopilocarpine
Pharmacology:
►
►
Pilocarpine is a parasympathomimetic.
It induces salivary glands, gastric, and sweat hyper-secretion,
it increases intestinal motility, induces broncho-constriction, and
bradycardia.
It directly stimulates the muscarinic receptors in the eye, causing
constriction of the pupil (myosis) and contraction of the ciliary
muscle.
It used in the treatment of narrow-angle glaucoma
Alone or in combination with beta-blocker (timolol) also for
treating intraocular pressure.
Pilocarpine can be used as a sialagogue to relieve dryness of the
mouth (for example, that due to the radiotherapy of mouth and
throat cancers).
►
►
►
►
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Chemical tests:1- Helch’s test (H2SO4 + H2O2 + KCr2O7)
gives violet color
2- Ekkert’s test (Na-nitroprusside + NaOH)
leave for a period in HCl-solution, it gives
red color
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Ornithine derived Alkaloids
► 4-aminobutanal and N-methyl-4-aminobutanal which are derived
from ornithine, represent the
alkaloids, namely:
1- Pyrrolizidine alkaloids
2- Tropane alkaloids
precursors of two groups of
Pyrrolizidine alkaloids
pyrrolizidine basic structure.
the Asteraceae and Boraginaceae.►
►
essentially isolated only from
they were found in many genera: Eupatorium, Senecio, Tussligo,
and Echium, Heliotropium Symphtum.
They are hepatotoxic, carcinogenic and mutagenic►
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► Pyrrolizidine alkaloids have a
Alkaloids of Tropane group
► Tropane alkaloids have in commn a nitrogen-containing bicyclic
structural element, namely azabicyclo-[3,2,1]octane (Tropane).
► They are 8-methyl-8-azabicyclo(3,2,1)octanes.
7
35
7 3
6
Distribution:
►Approximately 200 alkaloids are
in Solanaceae, Erythroxylaceae
convulvulaceae, Euphorbiaceae,
known in
and more
this group, distributed
sporadically in
Brasicaceae and Olacaceae.
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8
H3C N 1 2 1 2
4
= 8 N CH 3
6 5 4
Tropane
Structure:
► Tropane alkaloids are esters of tropane alcohols and of acids of
different structures, either aliphatic or aromatic.
►These tropane alcohols are divided into two series based on the
orientation of hydroxyl group at the 3- position:
1- derivatives
2- derivatives
of
of
tropan-3α-ol
tropan-3β-ol
(the most common)
(specific to the Erythroxylaceae)
1
3 CH8 N= 33
► The tropanols (Tropins) are often hydroxylated at the 6- or
7-position or both, and sometimes 6,7-epoxidized.
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H3C N
OH OH
5
Pseudotropine
H3C N 1
= 8 N CH3 OH
5
HO
Tropanol or Tropine (3-Hydroxytropane)
33
o
The acids may be aliphatic (acetic, butyric, isovaleric, tiglic and
angelic acids) or aromatic (tropic, truxillic, cinnamic, benzoic acids).
HO
(Atropic acid)
COOH
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HO O H
COOH COOH
OH
Tropic acid Apotropic acid O
alpha-truxillic acid
COOH
COOH
Angelic acid Tiglic acid Isovaleric acid
H3C N 1 H3C N COOH
= O 8 N CH OH OH
OH 5 Ecgonine
Scopine
The principal alkaloids of medicinal interest in this group are
1- (-) Hyoscyamine. This fragile ester is rapidly converted, in acidic
as well as basic conditions, to tropanol and tropic acid, and the
latter is transformed by intramolecular dehydration, into apotropic
(atropic acid), which is optically inactive.
2- Racemate of hyoscyamine: a simple reflux in chloroform is
enough to transform hyoscyamine into (±) atropine.
3- Hyoscine (scopolamine), which is converted by acidic or basic
hydrolysis to osine (scopine) and tropic acid.
OCH3N OO CHN
25
CH2OH CH2OH
3
O O
Hyoscyamine, Atropine Scopolamine (Hyoscine)
Characterization of tropane alkaloids.
1- Vitali-Morin reaction
After treating with fuming nitric acid and redissolving the residue
with acetone, by adding solution of potassium hydroxide in
methanol, purple color is developed, which is changed to red.
2- Gerrard reaction
Atropine and hyoscyamine react with 2% solution of mercuric
chloride in 50% alcohol to produce a red color. Scopolamine
gives white precipitate.
3- Schaer’s reaction
Tropane alkaloids gives with a prepared solution of 1 volume of
30%H2O2 mixed with 10 volumes of conc. H2SO4 a green color.
26
Drugs containing tropane alkaloids:
Datura stramonium
Atropa belladonna Hyocymus niger
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Pharmacological activity of the alkaloids:
Atropine and Hyoscyamine
►Atropine and hyoscyamine have the same activity.
► They are parasympatholytics (block the muscarinergic and
cholenergic receptors by forming cationic, anionic and polar
bonds with the receptors).
► It increases the heart rate, induces relaxation and motor
inhibition, decreases intestinal tone and peristalsis, paralyzes the
ureters, increases bladder pressure,
and blocks the bronchoconstricting
Secretions of saliva, sweat, gastric,
decreases biliary duct tone,
effect of acetylcholine.
pancreatic, bronchial, and
lachhrymal secretions
mydriasis.
are all decreased. Atropine induces
Scopolamine
► parasympatholytic activity,
possesses sedative, depressant,
especially of the myocardium. It
and hypnotic with amnesia.28
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Coca alkaloids
Coca or coca leaves are the dried
leaves of Erythroxylum coca and E.
novogranatense var. truxillense
(Fam. Erythroxylaceae).
► 0.5-1.5% alkaloids
► The leaves contain three basic types
of alkaloids according to the
principal nucleus in the molecule:
1- Deivatives of ecgonine:
e.g. cocaine, cinnamylcocaine
Derivatives of pseudotropine:
e.g. Tropacocain
Deivatives of pyrrolidine:
e.g. hygrine
2-
3-
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H3C N COOCH3
► The chief alkaloid (30-50%) is the cocaine, which is an ester,
volatile as a free base, colorless crystals, cause numbness to the
lips and tongue, soluble in alcohol and CHCl3.Pharmacology
► Cocaine is a local anesthetic. (It blocks ion channels in neuron
membranes, and interrupts the propagation of action potentials
corresponding to the sensory message).
sympathomimetic. It acts as an adrenergic
reuptake blockade (hyperthermia,
► Cocaine is also
stimulant by noradrenaline
mydriasis and vasoconstriction)
a
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O
Cocaine: R =
O R O
Cinnamoycocaine: R =
Identification of Cocaine:
1- solution of cocaine + gold-chloride (AuCl4) gives stellate rods
2- solution of cocaine + PtCl6 gives yellow needles
3- Solution of cocaine + KMnO4 + alum (50%-solution) gives
violet crystals of cocaine-pemenganate.
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Alkaloids derived from aspartic acid
Alkaloids of the Pyridine group
This group of alkaloids could be divided into 4 subgroups
nucleus of the molecule is one of the following nuclei:
1- Pyridine alone:
e.g. trigonelline
and the
2- Pyridine with other nitrogenous rings (e.g. pyrrol-ring)
3- Tetrahydropyridine
e.g. areca alkaloids
Pyridone
e.g. ricinine
4-
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Biogenesis of pyridine alkaloids:
COOH
N COOHH
COORL- lysine COOR
Guvacoline(R = CH3)N
Guvacine(R = H)N
Anabasine N
N
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O P COOH
HO CH2 H
CHO NH2 COOH quinolinic acid
glyceraldehyde aspartic acid
OCH3 COOH
CN
NN O nicotinic acid
CH3
Ricinine
L-Ornithine N N
CH3 H
N
H Arecoline (R = CH3)
H Arecaidine (R = H)
CH3 N
Nicotine N
Nicotelline
Drugs containing pyridine alkaloids:
Tobaccos
► The leaves of the tobacco plant
Nicotiana tabacum (Fam: Solanaceae)
are used for production of Cigarettes.
► They are toxic plants which contain
alkaloids, chiefly represented by
nicotine.
►Other close structurally alkaloids have
been found such as nornicotine,
the N-oxidized derivatives of nicotine,
e.g. nicotyrine, anabasine and anatabine.
35
Tobacco-alkaloids:
► 4-6% several volatile, non-volatile and crystalline alkaloids:
1- Volatile liquid alkaloids
e.g. nicotine, nor-nicotine, anabasine
2- Non-volatile liquid alkaloids
e.g. nicoteine and nicotyrine
3- Solid-alkaloids
e.g. nicotelline
and anatabine.
Identification1- Nicotine + p-dimethylaminobenzaldehyd
rose-red color
+ HCl gives
2-
3-
aq. Solution of nicotine + acidic vanillin gives red color
aq. Solution of nicotine + formaldehyde + HNO3 gives red color
36
Pharmacology►Nicotine possesses a high affinity to the gangionic-cholinergic
(nicotinic) receptors.
► So, it stimulates all autonomic ganglia,
► it
► it
► It
acts on the CNS causing tremors and convulsions,
also stimulates the respiratory and vomiting centers.
acts on the smooth muscle of the intestine, by increasing
tone and motor activity.
► It acts on the cardiovascular system, by inducing vasoconstriction
and an increase in arterial blood pressure.
cardiovascular, pulmonary diseases.
► It is used in the form of chewing gum or transdermal
relieving the symptoms of withdrawal of cigarettes.
► It is also used as insecticide.
system for
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Alkaloids derived from Lysines
1- Alkaloids of the Piperidine group
Black Pepper
► dried fruits of Piper nigrum (Fam.
Piperaceae), a perennial plant in
(India and cultivated also in Indonesia,
Sri Lanka and South America).
► the pungent taste to piperidine amides
(5-10 %).
► The chief constituent is piperine
(insecticide), an amide of piperidine
and of piperic acid.
► The other amides are piperidines
(piperanine, piperettine) piperolein A and
Piperolein B, pyrrolidines (piperyline).
38
O
ON
O
Piperoleine B (n = 5)
H
39
O OH O
NO N
CH3 O
Lobeline Piperine
O
O (CH2)n N
O
Piperyline Piperoleine A (n = 3)
O
N
Pelletriene
Piperine:► Colorless, odorless, needles or prisms with burning taste,
insoluble in H2O, soluble in alcohol, chloroform and ether.
exhibits only weak basicity
On hydrolysis, gives piperidine and piperic acid
Used as stomachic and insecticide
Has CNS depressant and anticonvulsant effects in rats
►
►
►
►
Identification of Piperine:
1- On the addition of Wagner’s reagent, steel blue needle crystals
of piperine periodide are formed.
Piperine on treating with platiniumchloride solution gives
orange red needles.
Piperine on treating with H2SO4 gives a red color.
2-
3-
40
PomegranateThe plant is a shrub widespread Punica
granatum (Fam. Punicaceae).
► The bark contains 0.5- 0.7% total
alkaloids: (-) pelletierine,
isopelletierene, and N-methylated
analogs.
► The plant was used as anthelmintic.
H
41
O
N
Pelletriene
Alkaloids derived from Glycine
Purine Alkaloids
► Purines are derivatives of a heterocyclic nucleus consisting
of the six-membered pyrimidine ring fused to the five
membered imidazol ring.
► Purine itself does not occur in the nature but numerous
derivatives are biologically well-known such as Adenin and
guanin.
► The purine nucleus is not very common in higher plants.
► Purine alkaloids are secondary metabolites of methylated
xanthines (2,6-dioxopurine).
42
R1 R3N N Caffeine: CH CH CH
► Caffeine
isolated
is 1,3,7-trimethylxanthine,
in 1820,
the first purine base to be
► occurs in the seeds of coffee plant, of Cola plant and in Tealeaves.
► Theophyline is 1,3-methylxanthine, which occurs in small
quantities in Tea leaves and in Cola nuts.
► Theobromine is 3,7-dimethylxanthine, which accumulates
(0.9-3%) in cacao beans other purine base are (E)-zeatin,
cytokinin, and its derivatives.
► caffeine and theophylline are used in therapeutics.
43
O
R1 R2 R3
3 3 3
Theophylline: CH3 CH3 H
O N N Theobromine: H CH3 CH3
R2
Caffeine
1,3,7-trimethylxanthine
White powder, bitter taste, very weak base, soluble in hot
water, in alcohol and CHCl3, sparingly in
Doesn’t precipitate with Mayer’s reagent
ether.
Theophyline
1,3-dimethylxanthine
White, odorless, bitter crystalline, soluble in H2O, alcohol
Sparingly soluble in ether and CHCl3
Theobromine
3,7-dimethylxanthine (mainly in seeds of Theobroma cacao
White, odorless, bitter crystalline, sparingly soluble H2O
)
Insoluble in ether 44
PharmacologyCaffeine
► stimulation of CNS, effect on the psychic centers
► Causes flow of thought, lessen drowsiness,
gives a sense of comfort and well-being
relieve headaches and
Theobromine
►Diuretic effect and used in the treatment of various types of edema
Theophylline
► smooth muscle relaxant, myocardial stimulant and diuretic
Identification:Murexide reaction
Alkaloids + H2O2 + HCl
which turns to red-violet
gives after evaporation yellow-red color
upon addition of NH3.
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