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See detailG-Quadruplex DNA Assemblies: Loop Length, Cation Identity, and Multimer Formation
Smargiasso, Nicolas ULg; Rosu, Frédéric ULg; Hsia, Wei et al

in Journal of the American Chemical Society (2008), 130(31), 10208-10216

G-rich DNA sequences are able to fold into structures called G-quadruplexes. To obtain general trends in the influence of loop length on the structure and stability of G-quadruplex structures, we studied ... [more ▼]

G-rich DNA sequences are able to fold into structures called G-quadruplexes. To obtain general trends in the influence of loop length on the structure and stability of G-quadruplex structures, we studied oligodeoxynucleotides with random bases in the loops. Sequences studied are dGGGWiGGGWjGGGWkGGG, with W = thymine or adenine with equal probability, and i, j, and k comprised between 1 and 4. All were studied by circular dichroism, native gel electrophoresis, UV-monitored thermal denaturation, and electrospray mass spectrometry, in the presence of 150 mM potassium, sodium, or ammonium cations. Parallel conformations are favored by sequences with short loops, but we also found that sequences with short loops form very stable multimeric quadruplexes, even at low strand concentration. Mass spectrometry reveals the formation of dimers and trimers. When the loop length increases, preferred quadruplex conformations tend to be more intramolecular and antiparallel. The nature of the cation also has an influence on the adopted structures, with K+ inducing more parallel multimers than NH4+ and Na+. Structural possibilities are discussed for the new quadruplex higher-order assemblies. [less ▲]

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See detailStructural and electrical properties of tellurovanadate glasses containing Li2O
Krins, Natacha ULg; Vertruyen, Bénédicte ULg; Lepot, Laurent et al

Conference (2006)

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See detailInteraction of the 106-126 prion peptide with lipid membranes and potential implication for neurotoxicity.
Dupiereux-Fettweis, Ingrid ULg; Zorzi, Willy ULg; Lins, Laurence ULg et al

in Biochemical and Biophysical Research Communications (2005), 331(4), 894-901

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the ... [more ▼]

Prion diseases are fatal neurodegenerative disorders characterized by the accumulation in the brain of an abnormally misfolded, protease-resistant, and beta-sheet rich pathogenic isoform (PrP(SC)) of the cellular prion protein (PrP(C)). In the present work, we were interested to study the mode of prion protein interaction with the membrane using the 106-126 peptide and small unilamellar lipid vesicles as model. As previously demonstrated, we showed by MTS assay that PrP 106-126 induces alterations in the human neuroblastoma SH-SY5Y cell line. We demonstrated for the first time by lipid-mixing assay and by the liposome vesicle leakage test that PrP 106-126, a non-tilted peptide, induces liposome fusion thus a potential cell membrane destabilization, as supported by membrane integrity assay (LDH). By circular dichroism (CD) analysis we showed that the fusogenic property of PrP 106-126 in the presence of liposome is associated with a predominantly beta-sheet structure. These data suggest that the fusogenic property associated with a predominant beta-sheet structure exhibited by the prion peptides contributes to the neurotoxicity of these peptides by destabilizing cellular membranes. The latter might be attached at the membrane surface in a parallel orientation as shown by molecular modeling. [less ▲]

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See detailApoptosis of HL-60 leukemia cells induced by the bisindole alkaloids sungucine and isosungucine from Strychnos icaja
Lansiaux, A.; Bailly, Christian; Houssier, Claude ULg et al

in Planta Medica (2002), 68(7), 591-595

Sungucine and isosungucine are two bisindole alkaloids isolated from the roots of the African plant Strychnos icaja Baillon. They both exhibit antiplasmodial activities but also show cytotoxic effects ... [more ▼]

Sungucine and isosungucine are two bisindole alkaloids isolated from the roots of the African plant Strychnos icaja Baillon. They both exhibit antiplasmodial activities but also show cytotoxic effects against human cancer cell lines. In order to elucidate their mechanism of action, we have investigated the interaction of the alkaloids with DNA and their capacity to inhibit nucleic acids and protein synthesis in the human HL-60 promyelocytic leukemia cell line. Cell treatment with both sungucine and isosungucine leads to the appearance of a hypo-diploid DNA content peak. Western blotting analysis reveals that the two alkaloids induce cleavage of the poly(ADP-ribose) polymerase (PARP) and promote the cleavage of a caspase-3 DEVD peptide substrate. The activation of the caspase cascade is accompanied with a fragmentation of DNA in cells, as revealed by the TUNEL assay. Altogether, the results shed light on the mechanism of action of these two plant alkaloids and identify signaling factors involved in (iso)sungucine-induced apoptosis in HL-60 cells. [less ▲]

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See detailTriplex and quadruplex DNA structures studied by electrospray mass spectrometry
Rosu, Frédéric ULg; Gabelica, Valérie ULg; Houssier, Claude ULg et al

in Rapid Communications in Mass Spectrometry : RCM (2002), 16(18), 1729-1736

DNA triplex and quadruplex structures have been successfully detected by electrospray ionization mass spectrometry (ESI-MS). Circular dichroism and UV-melting experiments show that these structures are ... [more ▼]

DNA triplex and quadruplex structures have been successfully detected by electrospray ionization mass spectrometry (ESI-MS). Circular dichroism and UV-melting experiments show that these structures are stable in 150 mM ammonium acetate at pH 7 for the quadruplexes and pH 5.5 for the triplexes. The studied quadruplexes were the tetramer [d(TGGGGT)](4), the dimer [d(GGGGTTTTGGGG)](2), and the intramolecular folded strand dGGG(TTAGGG)(3), which is an analog of the human telomeric sequence. The absence of sodium contamination allowed demonstration of the specific inclusion of n-1 ammonium cations in the quadruplex structures, where n is the number of consecutive G-tetrads. We also detected the complexes between the quadruplexes and the quadruplex-specific drug mesoporphyrin IX. MS/MS spectra of [d(TGGGGT)](4) and the complex with the drug are also reported. As the drug does not displace the ammonium cations, one can conclude that the drug binds at the exterior of the tetrads, and not between them. For the triplex structure the ESI-MS spectra show the detection of the specific triplex, at m/z values typically higher than those typically observed for duplex species. Upon MS/MS the antigene strand, which is bound into the major groove of the duplex, separates from the triplex. This is the same dissociation pathway as in solution. To our knowledge this is the first report of a triplex DNA structure by electrospray mass spectrometry. [less ▲]

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See detailSynthesis, cytotoxicity, and antiplasmodial and antitrypanosomal activity of new neocryptolepine derivatives.
Jonckers, Tim H M; van Miert, Sabine; Cimanga, Kanyanga et al

in Journal of Medicinal Chemistry (2002), 45(16), 3497-508

On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology ... [more ▼]

On the basis of the original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting from easily accessible educts, this approach allowed the synthesis of hitherto unknown compounds with a varied substitution pattern. As a result of steric hindrance, preferential formation of the 3-substituted isomers over the 1-substituted isomers was observed when cyclizing N-(3-substituted-phenyl)-N'-[2-(2-trimethylsilylethynyl)phenyl]carbodiimides. All compounds were evaluated for their activity against chloroquine-sensitive as well as chloroquine-resistant Plasmodium falciparum strains, for their activity against Trypanosoma brucei and T. cruzi, and for their cytotoxicity on human MRC-5 cells. Mechanisms of action were investigated by testing heme complexation using ESI-MS, inhibition of beta-hematin formation, DNA interactions (DNA-methyl green assay and linear dichroism), and inhibition of human topoisomerase II. Neocryptolepine derivatives with a higher antiplasmodial activity and a lower cytotoxicity than the original lead have been obtained. This selective antiplasmodial activity was associated with inhibition of beta-hematin formation. 2-Bromoneocryptolepine was the most selective compound with an IC(50) value against chloroquine-resistant P. falciparum of 4.0 microM in the absence of cytotoxicity (IC(50) > 32 microM). Although cryptolepine, a known lead for antimalarials also originally isolated from Cryptolepis sanguinolenta, was more active (IC(50) = 2.0 microM), 2-bromoneocryptolepine showed a low affinity for DNA and no inhibition of human topoisomerase II, in contrast to cryptolepine. Although some neocryptolepine derivatives showed a higher antiplasmodial activity than 2-bromocryptolepine, these compounds also showed a higher affinity for DNA and/or a more pronounced cytotoxicity. Therefore, 2-bromoneocryptolepine is considered as the most promising lead from the present work for new antimalarial agents. In addition, 2-bromo-, 2-nitro-, and 2-methoxy-9-cyanoneocryptolepine exhibited antitrypanosomal activity in the micromolar range in the absence of obvious cytotoxicity. [less ▲]

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See detailDNA intercalation, topoisomerase II inhibition and cytotoxic activity of the plant alkaloid cryptolepine
Bailly, Christian; Laine, W.; Baldeyrou, B. et al

in Anti-Cancer Drug Design (2000), 15(3), 191-201

Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic ... [more ▼]

Cryptolepine and neocryptolepine are two indoloquinoline alkaloids isolated from the roots of the African plant Cryptolepis sanguinolenta. Both drugs have revealed antibacterial and antiparasitic activities and are strongly cytotoxic to tumour cells. We have recently shown that cryptolepine can intercalate into DNA and stimulates DNA cleavage by human topoisomerase II. In this study, we have investigated the mechanism of action and cytotoxicity of neocryptolepine, which differs from the parent isomer only by the orientation of the indole unit with respect to the quinoline moiety. The biochemical and physicochemical results presented here indicate that neocryptolepine also intercalates into DNA, preferentially at GC-rich sequences, but exhibits a reduced affinity for DNA compared with cryptolepine. The two alkaloids interfere with the catalytic activity of human topoisomerase II but the poisoning activity is slightly more pronounced with cryptolepine than with its isomer. The data provide a molecular basis to account for the reduced cytotoxicity of neocryptolepine compared with the parent drug. [less ▲]

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See detailThe plant alkaloid usambarensine intercalates into DNA and induces apoptosis in human HL60 leukemia cells
Dassonneville, L.; Wattez, N.; Mahieu, C. et al

in Anticancer Research (1999), 19(6B), 5245-5250

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See detailStimulation of topoisomerase II-mediated DNA cleavage by three DNA-intercalating plant alkaloids: cryptolepine, matadine, and serpentine.
Dassonneville, L.; Bonjean, K.; De Pauw, Marie-Claire ULg et al

in Biochemistry (1999), 38(24), 7719-26

Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina ... [more ▼]

Cryptolepine, matadine, and serpentine are three indoloquinoline alkaloids isolated from the roots of African plants: Cryptolepis sanguinolenta, Strychnos gossweileri, and Rauwolfia serpentina, respectively. For a long time, these alkaloids have been used in African folk medicine in the form of plant extracts for the treatment of multiple diseases, in particular as antimalarial drugs. To date, the molecular basis for their diverse biological effects remains poorly understood. To elucidate their mechanism of action, we studied their interaction with DNA and their effects on topoisomerase II. The strength and mode of binding to DNA of the three alkaloids were investigated by spectroscopy. The alkaloids bind tightly to DNA and behave as typical intercalating agents. All three compounds stabilize the topoisomerase II-DNA covalent complex and stimulate the cutting of DNA by topoisomerase II. The poisoning effect is more pronounced with cryptolepine than with matadine and serpentine, but none of the drugs exhibit a preference for cutting at a specific base. Cryptolepine which binds 10-fold more tightly to DNA than the two related alkaloids proves to be much more cytotoxic toward B16 melanoma cells than matadine and serpentine. The cellular consequences of the inhibition of topoisomerase II by cryptolepine were investigated using the HL60 leukemia cell line. The flow cytometry analysis shows that the drug alters the cell cycle distribution, but no sign of drug-induced apoptosis was detected when evaluating the internucleosomal fragmentation of DNA in cells. Cryptolepine-treated cells probably die via necrosis rather than via apoptosis. The results provide evidence that DNA and topoisomerase II are the primary targets of cryptolepine, matadine, and serpentine. [less ▲]

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See detailThe DNA intercalating alkaloid cryptolepine interferes with topoisomerase II and inhibits primarily DNA synthesis in B16 melanoma cells.
Bonjean, K.; De Pauw, Marie-Claire ULg; Defresne, Marie-Paule ULg et al

in Biochemistry (1998), 37(15), 5136-46

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including ... [more ▼]

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including antibacterial, antiviral, and antimalarial properties. To date, the molecular basis for its diverse biological effects remains largely uncertain. Several lines of evidence strongly suggest that DNA might correspond to its principal cellular target. Consequently, we studied the strength and mode of binding to DNA of cryptolepine by means of absorption, fluorescence, circular, and linear dichroism, as well as by a relaxation assay using DNA topoisomerases. The results of various optical and gel electrophoresis techniques converge to reveal that the alkaloid binds tightly to DNA and behaves as a typical intercalating agent. In DNAase I footprinting experiments it was found that the drug interacts preferentially with GC-rich sequences and discriminates against homo-oligomeric runs of A and T. This study has also led to the discovery that cryptolepine is a potent topoisomerase II inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA covalent complexes and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. Taking advantage of the fluorescence of the indoloquinoline chromophore, fluorescence microscopy was used to map cellular uptake of the drug. Cryptolepine easily crosses the cell membranes and accumulates selectively into the nuclei rather than in the cytoplasm of B16 melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is also shown that the alkaloid is more potent at inhibiting DNA synthesis rather than RNA and protein synthesis. Altogether, the results provide direct evidence that DNA is the primary target of cryptolepine and suggest that this alkaloid is a valid candidate for the development of tumor active compounds. [less ▲]

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See detailComparative study of the condensation of chicken erythrocyte and calf thymus chromatins by di- and multivalent cations.
Marquet, R.; Colson, Pierre ULg; Matton, Anne-Marie ULg et al

in Journal of Biomolecular Structure & Dynamics (1988), 5(4), 839-57

The condensation of chicken erythrocyte (CE) and calf thymus (CT) chromatins upon addition of di- and multivalent cations has been studied using turbidity, precipitation and electric dichroism ... [more ▼]

The condensation of chicken erythrocyte (CE) and calf thymus (CT) chromatins upon addition of di- and multivalent cations has been studied using turbidity, precipitation and electric dichroism measurements. For all the cations investigated (Mg2+, Tb3+, Co(NH3)6(3+), spermidine Spd2+ and spermine Sp4+) condensation of CE chromatin occurred before the onset of aggregation, while aggregation of CT chromatin started before condensation with all cations except Mg2+ and Tb3+. Precipitation of CE chromatin required lower di- and multivalent cations concentrations than CT chromatin. The electric dichroism data for both chromatins, at low ionic strength in the absence of di- or multivalent cations, indicated that the nucleoprotein molecules were not totally decondensed but that a "precondensed" state was already present. A positive electric dichroism was observed for the most condensed chromatin fibers, in agreement with the "cross-linker" models. Tb3+ led to less compact condensed particles as judged from the electric dichroism observations, but electron microscopy revealed that "30 nm fibers" were formed. Very little aggregation was produced by Tb3+. On the contrary, spermine produced very large networks of condensed molecules, but large spheroidal particles were also observed. The condensation of CE chromatin happened without changes of solution conductivity upon cation salt addition, regardless of the condensing cation, indicating a cooperative uptake of the ions during this process. [less ▲]

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See detailLocalisation of the phosphoester bond hydrolyzed by the major apurinic/apyrimidinic endodeoxyribonuclease from rat-liver chromatin.
Verly, Walter G; Colson, Pierre ULg; Zocchi, Germaine ULg et al

in European Journal of Biochemistry (1981), 118

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