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Structure of the antiplasmodial compound 7,9-dinitrocryptolepine hydrochloride methanol solvate.Lisgarten, J.N., Potter, B.S., Pitts, J.E., Palmer, R.A., Wright, Colin W. January 2008 (has links)
No / The structure of C16H10N4O4[HCl,1.5CH3OH],
Mr = 406.80, has been determined from X-ray diffraction
data. The crystals are monoclinic, space group C2/c, with
eight molecules per unit cell and a = 21.482(4),
b = 7.131(1), c = 24.495(5) A ° , b = 111.01(3) , crystal
density Dc = 1.546 g/cm3. The material was difficult to
crystallize and crystals produced were found to be poor
diffractors. Intensity data were measured at liquid nitrogen
temperature using a weakly diffracting crystal typical of
the batch. However the X-ray analysis has finally enabled
the chemical constitution of this cryptolepine derivative,
which was previously incorrectly assigned, to be
unequivocally established. Direct methods were used to
solve the structure which was refined by full-matrix least
squares to a conventional R-index of 0.0798 for 2,861
reflections and 268 parameters. The 7,9-dinitrocryptolepine
molecule is highly planar with a strong intramolecular
hydrogen bond between N(10) in ring C and O(92) of a
nitro group. There are a number of intermolecular hydrogen
bonds involving the cryptolepine derivative the
hydrochloride and both solvated methanols. One of the
methanol solvate molecules (methanol 2) is unusually
disordered with its C atom lying exactly on a crystallographic
twofold axis. Consequently the methanol OH and
H3 groups are at 0.5 occupancy and repeated by the twofold
symmetry.
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The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites.Lisgarten, J.N., Coll, M., Portugal, J., Wright, Colin W., Aymami, J. January 2001 (has links)
No / Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode.
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X-ray crystallographic structure of the potent antiplasmodial compound 2,7-dibromocryptolepine acetic acid solvate.Potter, B.S., Lisgarten, J.N., Pitts, J.E., Palmer, R.A., Wright, Colin W. January 2008 (has links)
No / The structure of 2,7-dibromocryptolepine acetic
acid solvate, C16H11N2Br2 [1.5(C2H4O2)][C2H3O2
-]
[0.5H2O], Mr = 460.17, has been determined from X-ray
diffraction data. The crystals are monoclinic, space group
P21/c with Z = 4 molecules per unit cell and a =
7.3243(3), b = 18.7804(6), c = 15.8306(7) A ° , b = 94.279(1) ,
Vc = 2171.5(2) A ° , crystal density Dc = 1.667 g/cm3. The
structure was determined using direct methods and refined
by full-matrix least-squares to a conventional R-index of
0.0496 for 4,908 reflections and 258 parameters. The cryptolepine
nucleus of the 2,7-dibromocryptolepine molecule
is highly planar and the two Br atoms are in this plane
within 0.06 and 0.01 A ° , respectively. The crystal structure
is maintained via hydrogen bonding between N(10) in the
cryptolepine nucleus and the oxygen of one of the three
solvated acetic acid molecules. The acetic acid molecules
also form hydrogen bonded chains. Acetic acid B is
deprotonated and its two C¿O bond lengths are equivalent,
unlike those in A and C. Acetic acid C lies very close to a
crystallographic centre of symmetry. To avoid overlap the
two repeats cannot exist together and are subject to 50%
statistical disorder. O(1C) of this methanol is furthest from
the two-fold axis and its occupancy refines to a value of 1.0
and is assumed to exist alternately as a water oxygen
hydrogen bonding to methanol O(1C) across the two-fold
axis at a distance of 2.775 A ° .
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Genomewide expression profiling of the cryptolepine-induced toxicity in Saccharomyces cerevisiae.Rojas, M., Wright, Colin W., Pina, B., Portugal, J. January 2008 (has links)
No / We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo
to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds
in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of
cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by
either increasing cell permeability ( erg6 or ISE2 strains) or disrupting DNA damage repair ( rad52 strains).
These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA
lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC20 and
IC40]) were analyzed by comparing the gene expression profiles of treated and untreated erg6 yeast cells.
Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated).
General stress-related genes constituted the only recognizable functional cluster whose expression was increased
upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the
characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron
transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The
effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of
function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the
interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this
finding supports the utility of S. cerevisiae in drug-developing schemes.
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Characterization of the cytotoxic activity of the indoloquinoline alkaloid cryptolepine in human tumour cell lines and primary cultures of tumour cells from patients.Laryea, D., Isaksson, A., Wright, Colin W., Larsson, R., Nygren, P. January 2009 (has links)
No / The plant derived indoloquinoline alkaloid cryptolepine was investigated for its cytotoxic properties in 12 human tumour cell lines and in primary cultures of tumour cells from patients. The fluorometric microculture cytotoxicity assay was used to assess cytotoxicity and DNA mocro-array analysis to evaluate gene expression. Cryptolepine mean IC50 in the cell line panel was 0.9 microM compared with 1.0 and 2.8 microM in haemaotological and solid tumour malignancies respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as sensitive as haematological malignancies, respectively. Among patient solid tumour samples, those from breast cancer were the most sensitive and essentially as senstive as haematological malignancies. Cryptolepine activity showed highest correlations to topoisomerase II and microtubule targetting drugs. In the cell lines cryptolepine activity was essentially unaffected by established mechanisms of drug resistance. A number of genes were identified as associated with cryptolepine activity. In conclusion, cryptolepine shows interesting in vitro cytotoxic properties and its further evaluation as an anticancer drug seems warranted.
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Anti-inflammatory properties of cryptolepine.Olajide, O.A., Ajayi, A.A., Wright, Colin W. 07 December 2010 (has links)
No / Cryptolepine is the major alkaloid of the West African shrub, Cryptolepis sanguinolenta. Cryptolepine has
been shown to inhibit nitric oxide production, and DNA binding of Nuclear Factor-kappa B following
inflammatory stimuli in vitro. In order to validate the anti-inflammatory property of this compound in vivo,
we investigated its effects on a number of animal models of inflammation. Cryptolepine (10¿40 mg/kg i.p.)
produced significant dose-dependent inhibition of the carrageenan-induced rat paw oedema, and carrageenaninduced
pleurisy in rats. These effects were compared with those of the non-steroidal anti-inflammatory drug
indomethacin (10 mg/kg). At doses of 10¿40 mg/kg i.p., cryptolepine inhibited lipopolysaccharide (LPS)-induced
microvascular permeability in mice in a dose-related fashion. Oral administration of up to 40 mg/kg of the
compound for four consecutive days did not induce gastric lesion formation in rats. Analgesic activity was also
exhibited by cryptolepine through a dose-related (10¿40 mg/kg i.p.) inhibition of writhing induced by i.p.
administration of acetic acid in mice. The results of this study reveal that cryptolepine possesses in vivo
anti-inflammatory activity.Copyright © 2009 John Wiley & Sons, Ltd.
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Low Temperature X-Ray Crystallographic Structure of the Antiplasmodial Compound 5-N-Hydroxyethanequindoline Hydrochloride 0.5CH3OH.Hampson, Hannah C., Ho, Chung Y., Palmer, R.A., Potter, B.S., Helliwell, M., Wright, Colin W. January 2011 (has links)
No / The structure of 5-N-hydroxyethanequindoline hydrochloride methanolate, C17H15ON2 Cl·½CH3OH, M r = 314.78, has been determined from X-ray diffraction data. The crystals are monoclinic, space group C2/c, with Z = 8 molecules per unit cell and a = 18.179(11), b = 7.317(5), c = 24.125(15) Å, β = 110.155(10)°, V c = 3012(3) Å3, crystal density D c = 1.388 Mg m−3. The structure was solved by direct methods, and the asymmetric unit comprises the 5-N-hydroxyethanequindoline hydrochloride and ½CH3OH moiety. The methanol is unusually disordered over a twofold axis with the C atom slightly removed from the twofold axis. Restraints were applied to the bond lengths of the two components of the disordered CH3OH, and to the anisotropic thermal displacement parameters of the disordered CH3OH carbon atom. The heterocyclic quindoline ring system and the first C atom of the hydroxyethane side chain are planar within 0.02 Å, with the terminal C–OH atoms of the side chain significantly out of the plane. The crystal structure is maintained via three hydrogen bonds all involving the chlorine atom an oxygen in the hydroxyethane side chain, a nitrogen in the quindoline moiety and the methanol oxygen.
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Inhibition of Neuroinflammation in LPS-Activated Microglia by Cryptolepine.Olajide, O.A., Bhatia, H.S., de Oliveira, A.C.P., Wright, Colin W., Fiebich, B.L. January 2013 (has links)
No / Cryptolepine, an indoloquinoline alkaloid in Cryptolepis sanguinolenta, has anti-inflammatory property. In this study, we aimed to evaluate the effects of cryptolepine on lipopolysaccharide (LPS)- induced neuroinflammation in rat microglia and its potential mechanisms. Microglial activation was induced by stimulation with LPS, and the effects of cryptolepine pretreatment on microglial activation and production of proinflammatory mediators, PGE2/COX-2, microsomal prostaglandin E2 synthase and nitric oxide/iNOS were investigated. We further elucidated the role of Nuclear Factor-kappa B (NF-κB) and the mitogen-activated protein kinases in the antiinflammatory actions of cryptolepine in LPS-stimulated microglia. Our results showed that cryptolepine significantly inhibited LPS-induced production of tumour necrosis factor-alpha (TNFα), interleukin-6 (IL-6), interleukin-1beta (IL-1β), nitric oxide, and PGE2. Protein and mRNA levels of COX-2 and iNOS were also attenuated by cryptolepine. Further experiments on intracellular signalling mechanisms show that IκB-independent inhibition of NF-κB nuclear translocation contributes to the anti-neuroinflammatory actions of cryptolepine. Results also show that cryptolepine inhibited LPS-induced p38 and MAPKAPK2 phosphorylation in the microglia. Cell viability experiments revealed that cryptolepine (2.5 and 5 μM) did not produce cytotoxicity in microglia. Taken together, our results suggest that cryptolepine inhibits LPS-induced microglial inflammation by partial targeting of NF-κB signalling and attenuation of p38/MAPKAPK2.
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Identification of cryptolepine metabolites in rat and human hepatocytes and metabolism and pharmacokinetics of cryptolepine in Sprague Dawley ratsForkuo, A.D., Ansah, C., Pearson, D., Gertsch, W., Cirello, A., Amaral, A., Spear, J., Wright, Colin W., Rynn, C. 2017 December 1922 (has links)
Yes / Background: This study aims at characterizing the in vitro metabolism of cryptolepine using human and rat
hepatocytes, identifying metabolites in rat plasma and urine after a single cryptolepine dose, and evaluating the
single-dose oral and intravenous pharmacokinetics of cryptolepine in male Sprague Dawley (SD) rats.
Methods: The in vitro metabolic profiles of cryptolepine were determined by LC-MS/MS following incubation with
rat and human hepatocytes. The in vivo metabolic profile of cryptolepine was determined in plasma and urine
samples from Sprague Dawley rats following single-dose oral administration of cryptolepine. Pharmacokinetic
parameters of cryptolepine were determined in plasma and urine from Sprague Dawley rats after single-dose
intravenous and oral administration.
Results: Nine metabolites were identified in human and rat hepatocytes, resulting from metabolic pathways
involving oxidation (M2-M9) and glucuronidation (M1, M2, M4, M8, M9). All human metabolites were found in rat
hepatocyte incubations except glucuronide M1. Several metabolites (M2, M6, M9) were also identified in the urine
and plasma of rats following oral administration of cryptolepine. Unchanged cryptolepine detected in urine was
negligible. The Pharmacokinetic profile of cryptolepine showed a very high plasma clearance and volume of
distribution (Vss) resulting in a moderate average plasma half-life of 4.5 h. Oral absorption was fast and plasma
exposure and oral bioavailability were low.
Conclusions: Cryptolepine metabolism is similar in rat and human in vitro with the exception of direct glucuronidation
in human. Clearance in rat and human is likely to include a significant metabolic contribution, with proposed primary
human metabolism pathways hydroxylation, dihydrodiol formation and glucuronidation. Cryptolepine showed extensive
distribution with a moderate half-life. / Funded by Novartis Pharma under the Next Generation Scientist Program.
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Synthesis and evaluation of cryptolepine analogues for their potential as new antimalarial agents.Wright, Colin W., Addae-Kyereme, Jonathan A., Breen, Anthony G., Brown, John E., Cox, Marlene F., Croft, S.L., Gokcek, Yaman, Kendrick, H., Phillips, Roger M., Pollet, Pamela L. January 2001 (has links)
No / The indoloquinoline alkaloid cryptolepine 1 has potent in vitro antiplasmodial activity, but it is also a DNA intercalator with cytotoxic properties. We have shown that the antiplasmodial mechanism of 1 is likely to be due, at least in part, to a chloroquine-like action that does not depend on intercalation into DNA. A number of substituted analogues of 1 have been prepared that have potent activities against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum and also have in common with chloroquine the inhibition of ß-hematin formation in a cell-free system. Several compounds also displayed activity against Plasmodium berghei in mice, the most potent being 2,7-dibromocryptolepine 8, which suppressed parasitemia by 89% as compared to untreated infected controls at a dose of 12.5 mg kg-1 day-1 ip. No correlation was observed between in vitro cytotoxicity and the effect of compounds on the melting point of DNA (¿Tm value) or toxicity in the mouse¿malaria model.
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