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Antimicrobial Activity of Isopteropodine



Bioassay-directed fractionation for the determination of antimicrobial activity of Uncaria tomentosa, has led to the isolation of isopteropodine (0.3%), a known Uncaria pentacyclic oxindol alkaloid that exhibited antibacterial activity against Gram positive bacteria.
Antimicrobial Activity of Isopteropodine
´n Garcı
*, Cesia Cayunao
, Ronny Bocic
, Nadine Backhouse
Carla Delporte
, Mercedes Zaldivar
, and Silvia Erazo
Department of Pharmacological and Toxicological Chemistry, School of Chemical and
Pharmaceutical Sciences, University of Chile, P. O. Box 233, Santiago 1, Chile.
Fax: 56-2-222 7900. E-mail:
Department of Biochemistry and Molecular Biology, School of Chemical and
Pharmaceutical Sciences, University of Chile, Santiago, Chile
* Author for correspondence and reprint requests
Z. Naturforsch. 60 c, 385Ð388 (2005); received October 18/November 29, 2004
Bioassay-directed fractionation for the determination of antimicrobial activity of Uncaria
tomentosa, has led to the isolation of isopteropodine (0.3%), a known Uncaria pentacyclic
oxindol alkaloid that exhibited antibacterial activity against Gram positive bacteria.
Key words: Uncaria tomentosa, Isopteropodine, Antibacterial Activity
Uncaria tomentosa (Willd. ex Roemer and
Schultes DC.), commonly known as “cat’s claw”, is
a large climbing shrub, belonging to the Rubiaceae
family. Cat’s claw is indigenous to the Amazon
rainforest and other tropical areas of South and
Central America, including Peru, Colombia,
Ecuador, Guyana, Trinidad, Venezuela, Suriname,
Costa Rica, Guatemala, and Panama (Keplinger
et al., 1999; Lock de Ugaz, 1995).
The bark of cat’s claw is used in either folk
medicine or in procuring phytotherapeutic drugs.
This species contain several active compounds
which were tested widely for possible medicinal
value (rheumatism, tumors, anti-inflammatory ef-
fect and breast cancer) (Williams, 2001; Riva et al.,
2001; Aguilar et al., 2002; Gattuso et al., 2004).
Chemical studies on Uncaria tomentosa revealed
the presence of diverse compounds as quinovic gly-
cosides, polyoxygenated triterpenoids, catechins,
sterols and alkaloids, with diverse pharmacological
actions (Aquino et al., 1989; Wagner et al., 1985;
Keplinger et al., 1999; Kang et al., 2002; Sandoval et
al., 2002; Mur et al., 2002; Montoro et al., 2004).
However, of all the extensive biological activi-
ties investigated in this plant, specially for penta-
cyclic oxindol alkaloids (Kang et al., 2002; Lee
et al., 1999; Falkiewicz and Lukasiak, 2001) Ðonly
the quinovic glycosides were reported to have an-
timicrobial (antiviral) (Aquino et al., 1989 ; Wil-
liams, 2001) activity Ðreputed in folk medicine for
Uncaria tomentosa. These instances reinforced our
0939Ð5075/2005/0500Ð0385 $ 06.00 2005 Verlag der Zeitschrift für Naturforschung, Tübingen · ·
interest for evaluating the antimicrobial activity of
“cat’s claw” bark against bacteria and fungi.
Materials and Methods
General experimental procedures
The solvent used for NMR studies was CDCl
The measurements of the NMR spectra were
carried out on a Bruker AMX-300 [
(300 MHz),
C NMR (75 MHz)] spectrometer.
Column chromatography (CC) was carried out
using silica gel 60 G (Merck, 7734). TLC was per-
formed on silica gel GF 254 plates (Merck, 5554);
the spots were detected by UV light (254, 366 nm),
Liebermann Burchard test and/or p-anisaldehyde
and Dragendorf reagents.
GC-MS analyses were made on a Fisons MB 800
mass spectrometer (MS) coupled with a Hewlett-
Packard mod. 5890 series II gas chromatograph
(GC), equipped with a 25 m ¥0.2 mm i.d. HP U-2
column, with 0.25 µm film thickness. The initial
oven temperature was held at 40 C for 6 min, it
was then increased at 7 /min up to 200 C, at
110 KPa with helium as carrier gas.
HPLC was performed on a Shimadzu LC-10
AD, with a Shimadzu SPD-10 AV UV-VIS detec-
tor. Column: C
(Phenomenex); solvent system:
acetonitrile/buffer K
(pH 7) 50:50 with a
flow of 0.75 ml/min to 27 C.
Plant material
U. tomentosa bark was kindly provided by
Hochstetter Laboratory (collected from Peruvian
386 R. Garcı
´aet al. · Antimicrobial Activity of Isopteropodine
rainforest), and a voucher is kept at the botany
faculty laboratory.
Extraction and isolation
Ground dried bark (720 g) was sequentially ex-
tracted at room temperature with n-hexane, di-
chloromethane and methanol, yielding after re-
moval of the solvents in vacuo, 2.10 g (0.3%),
2.86 g (0.4%) and 82.5 g (11.5%), respectively.
Dichloromethane and methanol extracts were
active in the preliminary bio-assay, showing the
presence of a single bioactive alkaloid substance.
The extracts were separately worked up dissolving
the dried extracts in acetic acid (2 n), filtering, ba-
sifying with concentrated ammonia solution, and
extracting with chloroform (5 ¥25 ml). The chlo-
roform extracts were joined and subjected to CC
over silica gel, eluting an unpurified alkaloid with
dichloromethane/ethyl acetate 9.5:0.5 to dichloro-
methane/ethyl acetate 8:2, in fractions 49Ð72,
respectively. Preparative TLC on silica gel led to
the isolation of the purified alkaloid compound.
The purity of this substance was evaluated by gas
chromatography-mass spectroscopy, showing a sin-
gle peak at the retention time (Rt) of 21.5 min.
Crystallization from MeOH gave colorless needles.
Isopteropodine: M.p. 207Ð209 C. Ð[α]
(c= 0.764, CHCl
). ÐUV(MeOH): λ
= 208, 243,
283 nm (sh). ÐMS: m/z (% rel. int.) = 368 (4.5)
], 223 (13), 208 (11), 180 (13), 146 (55), 130
(61), 117 (58), 103 (25), 77 (72), 69 (100), 55 (74);
C NMR (ppm): δ= 181.43,
167.64, 154.98, 140.23, 133.76, 127.67, 124.53,
122.52, 109.82, 109.70, 72.14, 71.25, 56.93, 54.14,
53.51, 51.02, 37.83, 34.84, 30.17, 30.42, 18.65. Ð
NMR (ppm): δ= 8.56 (1H, brs), 7.42 (1H, s), 7.28
(1H, d, J= 7.5 Hz), 7.19 (1H, t, J= 7.6 Hz), 7.02
(1H, t, J= 7.5 Hz), 6.93 (1H, d, J= 7.6 Hz), 4.35
(1H, m), 3.60 (3H, s), 3.29 (2H, m), 2.46 (5H, m),
2.01(1H, m), 1.59 (2H, m), 1.41 (3H, d, J= 6.2 Hz),
0.87 (1H, appq, J= 12.8 Hz) (* brs: broad singlet;
appq: apparent quartet).
Antimicrobial assays
The antimicrobial activity of the extracts was de-
termined against Escherichia coli (ATCC 8739),
Klebsiella pneumoniae (isolated from a patient),
Salmonella aviatum (ATCC 2228), Pseudomonas
aeruginosa (ATCC 14207), Staphylococcus aureus
(ATCC 6538P), Micrococcus flavus (ATCC 10290)
and Bacillus subtilis (ATCC 6633), Candida albi-
cans and Saccharomyces cerevisiae.
Dilutions of 100 and 200 µg/ml of DMSO ex-
tract’s solution were added to a fixed volume of
Plate Count Agar (PCA) and Tryptic Soy Broth
(TSB). They were then superficially inoculated
with a single line of an overnight culture of the
different microorganisms and incubated at 37 C
for 24 h for bacteria and 28 C for fungi. Results
were recorded as growth or growth inhibition at
each extract concentration.
The active extracts were submitted to a bio-
autography agar overlay bioassay in order to deter-
mine the active compounds (Rahalison et al., 1995).
The turbidimetric method (Balows et al., 1991)
was used for determining MIC values of the iso-
lated substance against S. aureus and B. subtilis. It
consisted in preparing serial dilutions of the com-
pound (Table I) in TSB culture medium. Each
tube (carrying the same volume) was inoculated
with a fixed volume of the culture medium to ob-
tain 2 ml of final volume. Each dilution of the sam-
ple in study was assayed in triplicate.
Results and Discussion
U. tomentosa active extracts (dichloromethane
and methanol extracts) showed antimicrobial ac-
tivity only against M. flavus and B. subtilis and was
inactive against C. albicans and S. cerevisiae.
The methanol extract presented the major anti-
bacterial activity at concentrations of 100 µg/ml and
200 µg/ml. A bioautographic agar overlay in TLC of
the extracts and the isolated alkaloid was carried
out on a silica gel 60 F
plate developed with di-
chloromethane/ethyl acetate 1:1. The bioautograms
were sprayed with an aqueous solution of thiazolyl
blue (MTT). A positive antimicrobial reaction was
observed as a clear inhibition zone against a purple
background (Rahalison et al., 1995).
The isolated alkaloid was identified unambigu-
ously as isopteropodine (Uncarine E), by its mass
C NMR and literature
data (Chan et al., 1966; Shamma and Foley, 1967;
Wagner et al., 1985; Seki et al., 1993).
The isopteropodine bark quantification (0.3%)
was assayed by HPLC using the isolated alkaloid as
internal reference (Rt: 12.1; Ganzera et al., 2001).
Isopteropodine was inactive, in the same way as
Uncaria extracts, against C. albicans and S. cerevi-
siae, and was active only against the Gram positive
bacteria S. aureus and B. subtilis, with a MIC value
R. Garcı
´aet al. · Antimicrobial Activity of Isopteropodine 387
Table I. Isopteropodine MIC value determinations.
Bacteria Isopteropodine concentration [µm]
353 380 408 435 462 489 516 543 571 598 625 652 679
B. subtilis ++++++++++++Ð
+, Bacterial growth.
Ð, No bacterial growth.
of 150 µg/ml (408 µm) and 250 µg/ml (679 µm),
respectively (Table I) [ampicillin: MIC 5 µg/ml
(14 µm) for S. aureus and 10 µg/ml (29 µm) for B.
In conclusion, these results support scientifically
the use of this species in popular medicine as anti-
microbial, despite its weaker activity compared
with the standard antibiotic.
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... 3,6,7,12 The UT contain some active compounds that have been previously associated with an antimicrobial effect, including dichloromethane and methanol extracts. 2,6 Moreover, isopteropodine has shown antibacterial activity against Gram-positive bacteria, and is considered the strongest antimicrobial component of the UT species. 6 Further studies are needed to evaluate the correlation between the chemical compounds that compose UT and antimicrobial activity, in addition to its specific mechanism of action. ...
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... Some pharmacological activities, such as cytotoxic (Mena-Rejon et al. 2009), antiinflammatory (Gomez-Beloz et al. 2003), uterotonic (Reyes-Chilpa et al. 2004), and antiparasitic (Suarez et al. 2008), have been found using the plant extracts. Also, pure MOAs, mainly pteropodine, isoteropodine, and uncarine F exhibited antiproliferative, pro-apoptotic (Bacher et al. 2006), antioxidant, immunostimulant (Kang et al. 2002;Paniagua-Perez et al. 2009) and antimicrobial properties (Garcia et al. 2005). ...
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Introduction Hamelia patens is a perennial shrub native from Mexico which is used in traditional medicine to treat chronic wounds and tumors. Bioactive monoterpenoid indole alkaloids (MIAs) and monoterpenoid oxindole alkaloids (MOAs) have been isolated from this species, associated with the ethnomedical use. Objectives In order to study the biosynthesis and production of these alkaloids, H. patens plants were treated with the stress hormone jasmonic acid. Methods Nuclear magnetic resonance-based metabolic profiles and multivariate data analysis were applied to explore changes or variability in elicited and control plants. Results According to the partial least square-discriminant analysis from MeOH/H2O fractions, sucrose, tryptophan, glutamic acid, glutamine, strictosidine, p-coumaric acid, chlorogenic acid, and the MOAs isopteropodine, palmirine and pteropodine were predominant in the treated plants, while glucose, aspartic acid, acetic acid, and loganic acid concentrations were higher in control plants. HPLC analysis showed that accumulation of pteropodine, isopteropodine, speciophylline, rumberine, hameline and palmirine in elicited plants was preceded by an increase in the transcription level of 1-deoxy-d-xylulose-5-phosphate synthase (DXS, EC and strictosidine synthase (STR, EC, and STR activity during a time course. However, no inductions of transcription and enzyme activity of strictosidine β-glucosidase (SGD, EC were observed in elicited plants. Conclusion Correlations between primary and secondary metabolism biosynthetic pathways, such as the alkaloid and chlorogenic acid biosynthesis were found. Also, their implications in the plant fitness to stress are proposed. Confirmation of tryptophan as a precursor of MIA and MOA, via shikimate pathway, was done by L-[3′-14C]-tryptophan feeding.
Introduction Rapidly emerging diseases, such as viral infections, cancer, and autoimmune disorders are becoming an increasing global health concern. Natural products, including plant extracts and compounds, possess an enormous spectrum of pharmacological activities, including antiviral, anticancer, immunomodulatory, anti-asthma, anti-diabetic, anti-hypertension, and anti-rheumatism activities. Among them, the genus Uncaria (Rubiaceae family), rich in alkaloids and triterpenes, is believed to have vast therapeutic potential. This genus is mostly found in tropical regions, such as Africa, Southeast Asia, and Southeast America. In this review, we aim to summarize the studies on plant substances of genus Uncaria showing promising antimicrobial, anticancer, and immunomodulatory activities. Methodology A total of 814 studies were identified through database searches, of which 681 studies were excluded due to duplication and irrelevance to antimicrobial, immunomodulatory, and pharmacology activity. 133 studies were included, out of which 16 studies were related to antimicrobial and 117 studies related to the pharmacology of Uncaria. Conclusion According to the collected data Uncaria species proved to have a broad range of pharmacological activities, which makes it more interesting for further studies, to explore more about its antimicrobial, immunomodulatory, and other potential pharmacological properties.
Uncaria tomentosa (Willd) DC., commonly known as uña de gato or Cat's claw, is the botanical name of a liana from the Peruvian Amazon. Cat's claw is one of the most important medicinal plants in that area, where steam bark and the root bark are traditionally used for the treatment of inflammatory diseases. The main constituents of the bark are oxindole alkaloids, triterpene glycosides and proanthocyanidins. The antioxidant, antiinflammatory, antimutagenic, immunostimulant, antitumoral and antiviral activities of cat's claw bark have been demonstrated in different experimental models. Pharmacological, toxicological and clinical data showed that cat's claw bark is useful and safe for the treatment of osteoarthritis and rheumatoid arthritis.
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This Paper describes an improved HPLC method for the determination of pentacyclic oxindole alkaloids in Uncaria tomentosa (Cat's Claw). Six of the isomeric compounds could be baseline separated at room temperature within less than 30 min by using 3 microm C-18 column material and a mobile phase consisting of 10 mM phosphate buffer at pH 7.0 and acetonitrile. At a wavelength of 245 nm all standard compounds could be detected at concentrations as low as 0.63 microg/ml. Different samples of U. tomentosa bark and market products containing Cat's Claw were extracted with a modified procedure ensuring the integrity of the alkaloids and analyzed successfully. The results indicated accuracy and consistency of the new method, and showed variations in the total alkaloid content in products from 0.156 to 0.962%.
We have performed 27Al and 55Mn nuclear magnetic resonance (NMR) measurements on a single crystal of YMn4Al3 at 8 T. The 27Al NMR spectrum showed two sets of five satellites from two different Al sites. Based on the difference in NMR shift, linewidth and relaxation rates, two sets of NMR resonance peaks are assigned to the respective Al sites. The NMR shift and spin‐lattice and transverse relaxation rates, 1 T 1 and 1 T 2, were measured down to 4 K at 8 T. The shift and linewidth for the 27Al and 55Mn NMR followed the temperature dependence of the susceptibility, confirming that the hyperfine field from the Mn 3d spins dominates the local electronic structures at both the Al and Mn sites. The 1 T 1 of the 27Al and 55Mn NMR rapidly decrease at low temperature, which is indicative of a gap opening.
A reinvestigation of the bark of Uncaria tomentosa afforded, in addition to the major quinovic acid glycosides 1-3, three further glycosides 4-6. The structures were elucidated by spectral and chemical studies. Furthermore, a series of antiviral tests were performed on all these glycosides and on the related glycosides 7-9, previously isolated from Guettarda platypoda.
Two new alkaloids designated as pteropodine and isopteropodine have been isolated from Uncaria pteropoda and characterised. They are stereoisomeric with mitraphylline and uncarine-A and -B and have been shown to have the same structure as these alkaloids on the basis of structural and degradative evidence.
Bioassay-guided fractionation of the EtOH extract of the bark of Uncaria guianensis (Aubl.) Gmel (Rubiaceae) using a yeast-based assay for DNA-damaging agents has furnished the two weakly but selectively active indole alkaloids uncarine C (1) and uncarine E (2) as the major bioactive constituents in this assay.
We assessed in vivo the anti-inflammatory activity of two Cat's claw bark extracts, by comparing a spray-dried hydroalcoholic extract against an aqueous freeze-dried extract, to determine which extract was more effective. We used the carrageenan-induced paw edema model in mice. In addition, to assess the molecular mechanism of action, we determined the inhibition of NF-kappa B through the Electrophoretic Mobility Shift Assay (EMSA) and the effects on cycloxygenase-1 and -2. Results showed that the anti-inflammatory activity was significantly higher using the hydroalcoholic compared with the aqueous extract (P<0.05). The extracts also showed little inhibitory activity on cyclooxygenase-1 and -2. It cannot be excluded that the slight inhibitory activity on DNA binding of NF-kappa B is due to cytotoxic effects.
Cat's claw is an herbal medicine from the Amazon that is used widely to treat inflammatory disorders. The purpose of this study was to characterize the antioxidative and antiinflammatory properties of cat's claw, Uncaria tomentosa (UT) and Uncaria guianensis (UG). Alkaloids and flavanols were determined using reversed-phase HPLC; scavenging of 1,1-diphenyl-2-picrilhydrazyl (DPPH), hydroxyl radicals, and lipid peroxidation by spectrophotometry; and TNFalpha production by ELISA. Anti-inflammatory activity was assessed in vitro by inhibition of TNFalpha and nitrite production from RAW 264.7 cells exposed to LPS (50 ng/ml) and in vivo using the indomethacin-induced gastritis model. Apoptosis was assessed using the TUNEL technique and TNFalpha mRNA by in situ RT-PCR. In each of the antioxidant assays tested, UG was more potent than UT (P < 0.01). The total oxindole and pentacyclic alkaloid content of UT was 35-fold > UG. The IC50 value for inhibition of TNFalpha production was significantly (P < 0.01) higher for UT (14.1 ng/ml) vs UG (9.5 ng/ml), yet at concentrations that were considerable lower than that required for antioxidant activity. Non-alkaloid HPLC fractions from UT decreased LPS-induced TNFalpha and nitrite production in RAW 264.7 cells (P < 0.01) at a concentration range comparable to the parent botanical. Oral pretreatment for 3 d with UT protected against indomethacin-induced gastritis, and prevented TNFalpha mRNA expression and apoptosis. These results indicate that while both species of cat's claw provide effective antioxidant and anti-inflammatory activities, U. guianensis is more potent. In conclusion, the presence of oxindole or pentacyclic alkaloids did not influence the antioxidant and anti-inflammatory properties of cat's claw.
The two main classes of secondary metabolites, alkaloids and quinovic acid glycosides, of Uncaria tomentosa (Willd.) DC. (Rubiaceae), a Peruvian plant commonly known as 'uña de gato', have been analysed. Separation of the alkaloidal fraction was achieved using a solid phase extraction method based on cationic exchange, and an analytical method employing HPLC-ES/MS has been developed. Quantitative data for commercial wild bark, cultivated bark and leaves are reported. The analysis of quinovic acid glycosides was performed directly on the crude extract using both a fast analytical method based on flow injection ES/MS, and a more complete analytical technique using HPLC-MS.