introduction to natural products and bioactive...
TRANSCRIPT
CHAPTER-I
Introduction to natural products and bioactive compounds: A review
1.1. Introduction to natural products and bioactive compounds
Organic chemistry is an art executed science. The art of synthesis
and isolation of natural products and bioactive compounds makes it
one of the most interesting and finest areas of modern chemistry.
As an eminent scientist says, If we wish to catch with nature, we
shall need to use the same methods as she does, and I can foresee a
time in which physiological chemistry will not only make greater use of
natural enzymes but will actually resort to creating synthetic ones–
Emily Fischer, 1902. These words reflected an extensive chemical
synthesis and isolation of natural products and bioactive compounds
for the welfare of human kind in the future thereafter.
The key role played by plant-based systems in the healthcare of
different cultures has been extensively documented, and the World
Health Organization (WHO) has estimated that approximately 65-80%
of the world’s population rely mainly on plant-derived traditional
medicines for their primary health care.1 Most of these natural
products are secondary plant metabolites. Keeping this in view, we felt
an urge to synthesize some natural products and test their bioactivity
and also planned for the isolation of some bioactive natural
compounds.
Natural products have played a key role in health care and
prevention of diseases for the past thousands of years. Several ancient
civilizations, such as Indians, Chinese, and North Africans have
provided written evidence for the use of natural sources for curing
various ailments.2 Sumerian clay tablet is known to be the earliest
known written document that was used as a remedy for various
illnesses.3
The importance of natural products as anticancer agents can be
seen between the years 1981-2006, where about a hundred
anticancer agents have been developed, of which, nine were pure
natural products, eleven were derived from a natural product
pharmacophore, eighteen were natural product mimics, and twenty
five were natural product derivatives,4 thus making the natural
sources as significant contributors to the health care system.
A few words below convey a subtle idea about the importance of
natural products as medicines over the last 4000 years.
2000 BC: Here, eat this root.
1000 AD: That root is heathen! Here, say this prayer.
1850 AD: That prayer is superstition! Here, drink this potion.
1935 AD: That potion is snake oil! Here, swallow this pill.
1975 AD: That pill is ineffective! Here, take this antibiotic.
2000 AD: That antibiotic is poison! Here, eat this root.
-Anonymous
1.2. Characterization of natural products and bioactive compounds
The characterization of natural products and bioactive compounds
in the past decades has utilized spectroscopic techniques as well as
chemical methods to determine the structures. The use of ultraviolet-
visible and infrared spectrophotometry, nuclear magnetic resonance
spectroscopy (NMR), mass spectrometry (MS), high performance liquid
chromatography (HPLC), polarimetry, and circular dichroism can yield
complementary information that is used to determine the structures
of the compounds. When NMR data and degradative studies are
inconclusive, a total synthesis and spectroscopic comparison between
the synthetic and natural product is the easiest way for
stereochemical determination and confirmation.5
1.3. Dereplication
Dereplication is the rapid identification of known compounds
within a sample. These known compounds interfere with in vitro
assays, leading to false-positive results in bioassays. In order to avoid
known or interfering compounds, various dereplication methods are
applied to the bioactive samples. The currently used popular
dereplication methods include mass spectrometry (MS)-based
methods, NMR-based methods, chromatographic methods, and
activity profiling.
1.3.1. MS-based methods:
It includes liquid chromatography-MS (LC-MS), LC-UV-MS, and
LC-MS-NMR methods. These methods allow for an easy determination
of the molecular weights of compounds in either a purified or crude
sample.6 In some methods, the LC-MS, UV, and bioactivity profiles of
a particular crude extract can be compared with a library of
characterized compounds, and a particular known active compound
can be rapidly identified.7,8
1.3.2. NMR based methods:
These rely on the ability of NMR-based techniques to resolve
signals given by different functional groups within a molecule, or
different molecules in a mixture, and help in the rapid identification of
functional groups and structural motifs. DEPT, COSY or HSQC
spectra are some of them.9,10
1.3.3. Chromatographic methods:
Prefractionation methods depend on the ability to selectively
remove a few undesirable classes of compounds. Selective removal of
tannins by use of polyamide chromatography is one of the most widely
used prefractionation-dereplication methods. Sephadex LH-20 and
HP20 MCI gel11 were been reported to selectively remove tannins from
plant extracts. The remaining extract can then be evaluated for
bioactivity.
1.3.4. Activity profiling:
It is a dereplication method where the bioactivity of an extract is
profiled in several different assays. The COMPARE algorithm used
with the NCI's sixty-cell line panel is one of the most well-known
methods. COMPARE method considers IC50 values, which represent
the concentration of a compound inhibiting the cell growth by 50%.12
1.4. Biogenesis and classification of natural products:
The classification of natural products can be made on the basis of
biogenesis where the process of photosynthesis plays a lead role.
Carbohydrates, the initial products of photosynthesis undergo
alterations and leads to the formation of low molecular weight pool of
organic compounds. The final natural product is formed from a
sequence of biosynthetic reactions and the process is termed as
biogenesis (Fig. 1.1).13
CO2 hν
photosynthesis
H2O
erythrose-4 phosphate
glucose
mono-, oligo-, polyosides
glycosides
phenols, quinones, polyacetylenes, macrolides, fatty acids, lipids...
phospho-enolpyruvate
shikimate
flavonoids, anthocyanins, tannins
shikimates
cinnamates,lignans,coumarins,quinones...
pyruvate
acetyl-CoA
Krebs cycle
amino acids
mevalonate
terpenoids and steroids
alkaloids
essential oils,sesqui- and diterpenes,saponins...proteins
polyacetates
Fig. 1.1
1.5. Sources:
Natural products generally have a prebiotic origin or they originate
from plants, microbes, or animal sources (Fig. 1.2).14,15 Plants and
microorganisms such as fungi, bacteria have proven to be an excellent
source of novel natural products including peptide antibiotics,
polyketides and classes of other bioactive compounds.16 Some of the
microbial metabolites are used as antineoplastic agents, antimicrobial
agents and bioinsecticides.17
Natural Product SourcesMicrobial sources
Marine sources
Plant sources
Animal sources
Fig. 1.2
The marine environment is a rich source of natural bioactive
compounds as more than 70% of earth’s surface is covered by
oceans.18-20 Thus we broadly have four categories of natural product
sources.
1.5.1. Natural products from plant sources:
Since ages, plants have been an excellent source for the bioactive
natural products. Several plant extracts were used as medicines in the
treatment of various diseases. Higher plants are extremely popular for
the production of variety of biologically active compounds that
include, paclitaxel 1, morphine 2 and others.21,22
NHO
OH
O
O
O
OO
H
O
O
HOO HO
OH
H
Paclitaxel (1)
Source: T axus brevif ol ia
HO
O H
HO
HN
morphine (2)
Source: Papaver somnif erum
1.5.2. Natural products from marine organisms:
Spongouridine (3) and spongothymidine (4)23 were known to be the
first bioactive nucleotide compounds to be isolated from the Carribean
sponge Cryptotheca crypta in 1950’s. These compounds were potent
anticancer and antiviral agents. Some of the marine organisms lead a
sedentary lifestyle, and thereby synthesize several complex and
extremely potent chemicals for their defense from predators.20 The
potential of these chemicals can be utilized to treat various ailments,
especially cancer. Discodermolide (5), isolated from the marine sponge
Discodermia dissoluta, is one such example which has a similar mode
of action when compared to that of paclitaxel and possesses a strong
anticancer activity. Infact, a combination therapy of the above two
drugs has led to reduced tumor growth in certain cancers.24
O
OH
HON
HN
O
O
Spongouridine (3)
HO
O
OH
HON
HN
O
O
Spongothymidine (4)
HO
O
O
H2N
OH
OH
OH
O
HO O
Discodermolide (5)
1.5.3. Natural products from microorganisms: The discovery of penicillin in 1929 opened the gates for
microorganisms as a source of potential drug candidates. Since then,
a large number of microorganisms were screened for drug discovery
which led to the discovery of antibacterial agents like cephalosporins-
cefprozil (6), antidiabetic agents like acarbose (7), and anticancer
agents like epirubicin (8).25
NH2
HO
NH
O N
O
S O
OH
H
Cefprozil (6)
HN
HO
OH
OH
OH
O
O
OH
HO
HO
HO
OH
OH
OH
OH
Acarbose (7)
O
O
OH
OMe OH
O
OH
O
OHO
H2N
Epirubicin (8)
HO
1.5.4. Natural products from animal sources:
Animals also form a source of some interesting bioactive
compounds. Epibatidine (9), a nitrogen containing heterocyclic
compound isolated from the skin of an Ecuadorian poison frog, was
found to be ten times more potent than morphine.26 Venoms and
toxins from animals have played a significant role in designing a
multitude of cures for several diseases. Teprotide, a toxic venom,
extracted from a Brazilian viper, has led to the development of
cilazapril (10) and captopril (11), which were found to be effective
against hypertension.27
NCl
HN
Epibatidine (9)
N
N
HO
NH
OOOO
Cilazapril (10)
HS N
O
Captopril (11)
HOOC
1.6. Bioassay:
Once a compound is synthesized or isolated, it needs to be
screened for its biological activity. Screening is an attractive and key
area towards the drug discovery programmes.28 It is crucial for
successful isolation of bioactive compounds. Generally, bioassays are
broadly classified into two types. They are mechanism based assays
and cell based assays.29
1.6.1. Mechanism based assays:
It involves the testing of a specific drug against a specific enzyme,
DNA, receptor etc. As these assays are conducted in artificial
environment which is different from physiological environment, it
must be properly configured for accuracy. A properly handled assay
can determine the activity of a compound even at lower
concentrations.30 Though these assays are useful in determining the
biological activity of the compounds, the disadvantage is that they
approximate the in vivo environment due to incomplete system
generated from the absence of certain pathways.
1.6.2. Cell based assays:
It involves a drug-cell interaction with the complete intact cell
rather than just isolated system and is by far more superior to the
mechanism based assay. This method has the advantage of screening
of compounds that cannot pass through the cell membrane.
Though several classifications of bioassays are seen, one of the
easier schemes31 to represent a screening is depicted below (Fig. 1.3).
Screening models for natural products
in vivo in vitro
Animal models
Serum pharmacology
Tissue models
Cell models
Receptor/enzyme models
Biochromatographicmodels
Genomic models
Molecularchromatography
Cell membranechromatography
Immobilized liposomechromatography
Immobilized artificialmembraneschromatography
Microdialysischromatography
Fig. 1.3
Screening or bioassay is a powerful tool to analyze the activity and
thus can give an idea of a compound to become a pharmacophore. It
is done in combination with separation techniques (chromatography)
and structural elucidation methods (spectroscopy). It is said that
pharmacology at a lower dose is toxicology and toxicology at a higher
dose is simply pharmacology. One of the bioassays is the test against
brine shrimp model. In vivo lethality towards an organism can be used
as a convenient method for screening of bioactive compounds.32
1.7. Bioactive natural products:
Natural products play a major role in organic chemistry. Some of
these may possess biopotency, selectivity and pharmacokinetic traits
making them drug agents. In some cases their analogues are accessed
through modification that serves the requirements.
Natural source
separationtechniques
Isolation and characterization
based onrequirements
synthesis
bioassay?
yes nobiologically active biologically inactive
can be a pharmacophore
can be tailored?
yes noanalogues
bioassay?
yes no
biologically active biologically inactive
Fig. 1.4
The small molecule natural products are evolutionarily optimized
to interact with either enzymes or receptors and other
biomacromolecules making a pharmaceutical connection.33 As these
SMNP are valuable sources, these can either be isolated in smaller
quantities from the natural source, or can be synthesized to meet the
required needs (Fig 1.4). For the purpose of preparing these
compounds the notion of diverted total synthesis approach was
developed (Fig. 1.5).34-36
Synthonschemical
synthesisIntermediate
Total
synthesisNatural Product Biosynthesis
Analog 2
addcomplexity
reduce complexity
Analog 1
Fig. 1.5
Polyketides are one of the good examples for small molecule
natural products. These are secondary metabolites from bacteria,
fungi, plants and animals that are biosynthesized through the
decarboxylative condensation of acetyl coenzyme A, as well as the
compounds derived from them by further condensations. Some of
these polyketides have attractive biological activities and are used as
pharmacophores.
Picromycin (12), the first isolated macrolide showed interesting
antibiotic properties.37-39 Sporostatin (13) and xestodecalactones A–C
(14-16) are ring keto lactones that bear a fused 1,3-dihydroxybenzene
ring. Sporastatin or M5032 was isolated from Sporormiella sp. and
was shown to be an inhibitor of cyclic adenosine 3,5-monophosphate
phosphor- diesterase40 (cAMP-PDE) and epidermal growth factor (EGF)
receptor tyrosine kinase.41 Xestadecalactones A–C were first isolated
from the Penicillium fungus which in turn is found in the marine
sponge Xestospongia exigua.42 Xestadecalactone B (15) was shown to
be active against Candida albicans.
O
O
OH
O
O
O OHO
N(CH3)2
Picromycin (12)
HO
OH O
OHO
OH O
O
X
( )-Sporastatin (13)
(+)-Xestadecalactone A (X = H) (14)(+)-Xestadecalactone B (X = a-OH) (15)(+)-Xestadecalactone C (X = b-OH) (16)
Apart from these polyketides several other compounds isolated
from various sources have shown potent biological activities. For
instance, a cyclic octapeptide, curcacycline-A43 (17) isolated from
Jatropha species showed immuno-suppressive activity and another
compound curcacycline-B44 (18) from the same source enhanced
rotamase activity of cyclophilin B. Chevalierin-A45, (19) a cyclic
peptide isolated from Jatropha chevalieri was found to possess
antimalarial activity.
O
NO
N
N
O
N
O
H
N
O
N
N
NO
O
O
H
H
H
H
HH
H
NN
N
O
N
O
N
O
N
HO
O
N
O
O
NO
N
O
O
HH
H
H
H H H
H
Curcacyclin-A (17) Curcacyclin-B (18)
O
N
N
N
O
N
N
NO
O
O
H
H
H
HH
O
O N
ON
H
H
S
Chevaliren-A (19)
Quinine (20), isolated from the Cinchona bark is one of the earliest
natural compounds in the fight against malaria which also served as a
template for the development of analogues such as chloroquine (21),
primaquine (22), mepacrine (23) and mefloquine (24).46,47 These
analogues were proved to be efficient antimalarials (Fig 1.6).
N
H3CO
HO N
H
H
Quinine (20)
N
N
N
N
HN
Cl
NEt2
H3CO
HNNH2
Cl
HNNEt2
CF3
CF3
HO
HN
OCH3
Primaquine (22)
Mepacrine (23)
Chloroquine (21)
Mefloquine (24)
Fig. 1.6
Artemisinin (25),48-50 isolated from Artemesia annua, is an
antimalarial used successfully against chloroquine resistant malarial
parasites. Its poor solubility led to the development of analogues
artemether (26)51 and artesunate (27)52 that were oil and water
soluble respectively.
O
O
O
H
H
O O
O
O
OMe
H
H
O O
O
O
O
H
H
O O
CO2Na
Artemisinin (25) Artemether (26) Sodium artesunate (27)
Apart from the several natural products that show varied biological
activities, there are other bioactive compounds that are synthetically
prepared either resembling few natural products or keeping in view of
the active core fragment of the natural products. Substituted
pyrrolidines,53 pyrimidines54 are one of them. The substituted spiro
pyrrolidines (28-32 and 33-38) (Fig. 1.7) that were prepared
synthetically has shown a good antibacterial activity against various
pathogens.53
NH
N
O
HR
R = H (33)R = p -CH3 (34)R = p -OCH3 (35)R = p -Cl (36)R = p -N(Me)2 (37)R = m-NO2 (38)
N
N
HR H
NH
N
O
OH R R = H (28)
R = p-CH3 (29)R = p-OCH3 (30)R = p-Cl (31)R = 3,4,5(OCH3)3 (32)
Fig. 1.7
Substituted piperidines are amongst the most ubiquitous
heterocyclic building blocks in both natural products and synthetic
compounds with important biological activities.55,56 Considering the
extensive range of biological activities these compounds exhibit, it is
not surprising that between 1988 and 1998 thousands of piperidine-
derived compounds were mentioned in clinical and preclinical
studies.57
Simple 2,6-disubstituted piperidines [solenopsins (39) and
isosolenopsins (40)], isolated from fire ant venom, are reported to
possess a broad range of activities such as antibacterial, necrotic,
insecticidal, antifungal and anti-HIV.58 4-Hydroxy-2,6-disubstituted
piperidine alkaloid, dendrobate alkaloid-241D (41), isolated from
methanolic skin extracts of poison frog Dendrobates speciosus and
Dendrobates pumilio possess potent biological activity.59,60 Synthetic
racemic alkaloid-241D and the parent 4-piperidone (42) were found to
be potent inhibitors for binding of perhydrohistrionicotoxin to
nicotinic receptor channels of electroplax membranes.61 In addition,
racemic alkaloid-241D has been proved to be a non-competitive
blocker of acetylcholine to ganglionic nicotinic receptor channels.62
NH
OH
C9H19NH
O
C9H19
NH
H3C(CH2)n NH
H3C(CH2)n
41 42
Solenopsins (39) Isosolenopsins (40)
n = 8, 10, 12, 14 n = 8, 10, 12, 14
1.8. Natural products as anticancer drugs:
Natural products serve as the mother for several anticancer agents
available in the market today. Podophyllotoxin (43), isolated from
Podophyllum peltatum in 1944 was one of the early known compounds
that worked as anticancer agent.63 Initially it served therapeutically as
a purgative and in the treatment of venereal warts.64 Later studies
proved that it acts as an anticancer agent by binding irreversibly to
tubulin.65 Etoposide (44) and teniposide (45), were the modified
analogs of podophyllotoxin, that cause cell death by inhibition of
topoisomerase II, thus preventing the cleavage of the enzyme- DNA
complex and arresting the cell growth.66 These analogs are used in the
treatment of various cancers.67
O
OO
MeO
OMe
OMe
OH
O
Podophyllotoxin (43)
O
OO
MeO
OH
OMe
O
O
OOO
HO
Etoposide (44)
O
OO
MeO
OH
OMe
O
O
OOO
S HO
Teniposide (45)
Catharanthus roseus, a member of the Apocynaceae family, is a
rich source of indole alkaloids which include the anticancer
vincristine (46) and vinblastine (47), and also the antihypertensive
alkaloid, ajmalicine (48). Both vinblastine and vincristine are known
to prevent cell division by inhibiting mitosis in the cell cycle and bind
irreversibly to tubulin, thereby blocking cell multiplication and
eventually causing cell death.68
NH
N
HO
MeOOC
MeO N
N
OAc
OHCOOMeH
R
H
Vincristine R = Me (46)Vinblastine R = CHO (47)
NH
N
O
H H H
O
OMeAjmalicine (48)
Camptothecin (49), isolated from Camptotheca acuminata, is an
anticancer agent which has a unique mode of action. The low water
solubility nature of camptothecin was overcome by preparing its
water-soluble analogs, namely, topotecan (50) and irinotecan (51). All
of these compounds are topoisomerase-I inhibitors, and cause cell
death by DNA damage.69
N
NO
O
O
HO
N
NO
O
O
HO
N
Camptothecin (49) Topotecan (50)
N
NO
O
O
HO
O
O
NN
Irinotecan (51)
An extract of the Pacific yew tree, Taxus brevifolia was found to
possess excellent anticancer properties. The active component,
paclitaxel (1), was isolated from the extract by Monroe Wall and
Mansukh Wani.70,71 Paclitaxel promotes microtubule stabilization by
binding irreversibly to β-tubulin.72 Cell multiplication requires
equilibrium between tubulin-microtubule and its stabilization causes
programmed cell death.73 Paclitaxel was the first compound to
promote microtubule formation. It has been used in the treatment of
ovarian and breast cancers as well as non-small cell lung tumors. The
epothilones (52, 53), isolated from Sorangium cellulosum, possess
potential anticancer properties and also activity against taxane-
resistant cell lines.
O
O
N
S
H
OH
HO
O O
Epothilone A (52)
O
N
S
OH
HO
O O
Epothilone D (53)
1.9. Natural products as antimicrobial drugs:
Canthin-6-one (54) isolated from Allium neapolitanum and
Zanthoxylum chiloperone displayed a broad spectrum of activities
against Aspergillus fumigatus, A. niger, A. terreus, Candida albicans, C.
tropicalis, Cryptococcus neoformans, Geotrichum candidum,
Saccharomyces cerevisiae, Trichosporon beigelii, Trichosporon
cutaneum and Trichophyton mentagrophytes var. interdigitale with MIC
values between 1.66 and 10.12 mg mL-1 whereas 5-Methoxycanthin-6-
one (55) displayed selective activity against only T. mentagrophytes
var. interdigitale, with an MIC value of 3.075 mg mL-1.74
N
N
O
N
N
O
HO
Canthin-6-one (54) 5-Methoxycanthin-6-one (55)
YM-215343 (56), a cytotoxic compound found in the bacterial
culture of Phoma sp. exhibited antifungal activity against some
pathogenic fungi C. albicans, C. neoformans and A. fumigatus, with
MIC values of 2–16 mg mL-1.75 Zheng et al. isolated five
epidithiodioxopiperazines, bionectins A (57), B (58) and C (59) and
verticillins D (60) and G (61), from the cultures of the fungus
Bionectra byssicola F120. Out of these compounds, 57, 58 and 60
exhibited antibacterial activity against S. aureus including methicillin
resistant S. aureus (MRSA) and quinolone-resistant S. aureus (QRSA),
with MIC values of 10–30 mgmL-1, while 59 showed no antibacterial
activity even at 100 mg mL-1.76
NH
OHO
O
O
O
H H
HOH
YM-215343 (56)
NH
N N
NH
O R
O
S S
H
OH
NH
N N
NH
O
O
H
OH
S
S
R = H, Bionectin A (57)R = CH(OH)CH3 Bionectin B (58) Bionectin C (59)
NH
N N
O CH(OH)CH3
O
S S
H
OH
HNNN
HO
O
O
H3C(HO)HC
S S
NH
N N
O
O
H
OH
NHN
N
O
O
O
SS
H
OH
S
SH
Verticillin D (60) Verticillin G (61) Ratjadone 62, a polyketide isolated from cultures of Sorangium
cellulosum strain Soce36077 displayed potent in vitro antifungal
activity with MIC values in the range from 0.004 to 0.6 µg/mL for
Mucor hiemalis, Phythophthora drechsleri, Ceratocystis ulmi, and
Monilia brunnea.
O OOH
O
OH
(+)-Ratjadone (62)
1.10. Natural Products as anti-HIV agents:
(E)-3-(3-Hydroxymethyl-2-butenyl)-7-(3-methyl-2-butenyl)-1H
indole (63), a diprenylated indole alkaloid, isolated from the twigs and
leaves of Glycosmis montana exhibited potent anti-HIV activity with an
IC50 value of 1.17 mg/mL and an SI of 11.68.78 Anibamine (64), a
novel pyridine quaternary alkaloid, was isolated from the stems of an
Aniba species as a TFA salt, competed for the binding of 125I-gp120
to human CCR5 with an IC50 of 1 mM.79
NH
OH
63
N
TFA
Anibamine (64)
NH
R2 OCH3
R1
R1 = CHO, R2 = H (65)R1 = CHO, R2 = OCH3 (66)R1 = COOH, R2 = OCH3 (67)
A few carbazole alkaloids, O-methylmukonal (65), 3-formyl-2,7
dimethoxycarbazole (66) and clauszoline J (67), isolated from the
rhizomes and roots of Clausena excavata showed anti-HIV-1 activity
in a syncytial assay, with EC50 values of 12.0, 29.1 and 34.2 mM and
TI of 56.7, 8.0 and 1.6, respectively.80 Gomisin J (68), (-)-gomisin M1
(69), (+)-gomisin M2 (70) and schisanhenol (71) were isolated from the
fruits of Schisandra rubriflora. These were found to be
dibenzocyclooctadiene lignans. Out of these lignans, (-)-gomisin M1
(69) exhibited the most potent anti-HIV activity, with EC50 and TI
values of <0.65 mM and >68, respectively. It was found from the
studies that compounds with aromatic hydroxyl groups were more
active than those lacking aromatic hydroxyls, suggesting the
importance of the aromatic hydroxyl groups for the anti-HIV activity of
dibenzocyclooctadiene lignans. The position of the hydroxyl group was
also a key for enhancing the anti-HIV activity, as 69 (with a 3′-OH),
was more potent than 70 (with a 3-OH).81
H3CO
H3CO
OH
H3CO
H3CO
OH
R1O
R2O
H3CO
OCH3
OO
HO
H3CO
H3CO
OCH3
H3COOCH3
R1 = CH3, R2 = H (69)R1 = H, R2 = CH3 (70)
68 71
Thus the study of natural products and bioactive compounds
becomes an interesting area of organic chemistry.
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