- Design, synthesis, and antiproliferative effect of 2,9-bis[4-(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline derivatives on human leukemic cells by targeting G-quadruplex
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Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G-quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine-rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives (1a–i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4-11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c-MYC, BCL-2, and K-RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g–i were tested for telomerase activity in HuT78 and MV4-11 protein extracts.
- Guillon, Jean,Denevault-Sabourin, Caroline,Chevret, Edith,Brachet-Botineau, Marie,Milano, Vittoria,Guédin-Beaurepaire, Aurore,Moreau, Stéphane,Ronga, Luisa,Savrimoutou, Solène,Rubio, Sandra,Ferrer, Jacky,Lamarche, Jeremy,Mergny, Jean-Louis,Viaud-Massuard, Marie-Claude,Ranz, Matthieu,Largy, Eric,Gabelica, Valérie,Rosu, Frédéric,Gouilleux, Fabrice,Desplat, Vanessa
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- Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives
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A series of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic-to-antiparasitic activities of 107 and 39 against a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G-quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.
- Guillon, Jean,Cohen, Anita,Das, Rabindra Nath,Boudot, Clotilde,Gueddouda, Nassima Meriem,Moreau, Stéphane,Ronga, Luisa,Savrimoutou, Solène,Basmaciyan, Louise,Tisnerat, Camille,Mestanier, Sacha,Rubio, Sandra,Amaziane, Sophia,Dassonville-Klimpt, Alexandra,Azas, Nadine,Courtioux, Bertrand,Mergny, Jean-Louis,Mullié, Catherine,Sonnet, Pascal
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- Design, Synthesis, and Evaluation of 2,9-Bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline Derivatives as G-Quadruplex Ligands
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Genomic sequences able to form guanine quadruplexes (G4) are found in oncogene promoters, in telomeres, and in 5′- and 3′-untranslated regions as well as introns of messenger RNAs. These regions are potential targets for drugs designed to treat cancer. Herein, we present the design and syntheses of ten new phenanthroline derivatives and characterization of their interactions with G4-forming oligonucleotides. We evaluated ligand-induced stabilization and specificity and selectivity of ligands for various G4 conformations using FRET-melting experiments. We investigated the interaction of compound 1 a (2,9-bis{4-[(3-dimethylaminopropyl)aminomethyl]phenyl}-1,10-phenanthroline), which combined the greatest stabilizing effect and specificity for G4, with human telomeric sequences using FRET, circular dichroism, and ESI-MS. In addition, we showed that compound 1 a interferes with the G4 helicase activity of Saccharomyces cerevisiae Pif1. Interestingly, compound 1 a was significantly more cytotoxic toward two human leukemic cell lines than to normal human blood mononuclear cells. These novel phenanthroline derivatives will be a starting point for further development and optimization of potent G4 ligands that have potential as anticancer agents.
- Gueddouda, Nassima Meriem,Hurtado, Miyanou Rosales,Moreau, Stéphane,Ronga, Luisa,Das, Rabindra Nath,Savrimoutou, Solène,Rubio, Sandra,Marchand, Adrien,Mendoza, Oscar,Marchivie, Mathieu,Elmi, Lilian,Chansavang, Albain,Desplat, Vanessa,Gabelica, Valérie,Bourdoncle, Anne,Mergny, Jean-Louis,Guillon, Jean
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- Diverse Proton-Conducting Nanotubes via a Tandem Macrocyclization and Assembly Strategy
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Macrocycles that assemble into nanotubes exhibit emergent properties stemming from their low dimensionality, structural regularity, and distinct interior environments. We report a versatile strategy to synthesize diverse nanotube structures in a single, efficient reaction by using a conserved building block bearing a pyridine ring. Imine condensation of a 2,4,6-triphenylpyridine-based diamine with various aromatic dialdehydes yields chemically distinct pentagonal [5 + 5], hexagonal [3 + 3], and diamond-shaped [2 + 2] macrocycles depending on the substitution pattern of the aromatic dialdehyde monomer. Atomic force microscopy and in solvo X-ray diffraction demonstrate that protonation of the macrocycles under the mild conditions used for their synthesis drives assembly into high-aspect ratio nanotubes. Each of the pyridine-containing nanotube assemblies exhibited measurable proton conductivity by electrochemical impedance spectroscopy, with values as high as 10-3 S m-1 (90% R.H., 25 °C) that we attribute to differences in their internal pore sizes. This synthetic strategy represents a general method to access robust nanotube assemblies from a universal pyridine-containing monomer, which will enable systematic investigations of their emergent properties.
- Strauss, Michael J.,Jia, Manping,Evans, Austin M.,Castano, Ioannina,Li, Rebecca L.,Aguilar-Enriquez, Xavier,Roesner, Emily K.,Swartz, Jeremy L.,Chavez, Anton D.,Enciso, Alan E.,Stoddart, J. Fraser,Rolandi, Marco,Dichtel, William R.
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supporting information
p. 8145 - 8153
(2021/06/21)
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- COVALENT ORGANIC FRAMEWORKS WITH A WOVEN STRUCTURE
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The disclosure provides for covalent organic frameworks (COFs) that constructed from weaving a plurality of long organic threads together. In particular, the disclosure provides for the construction of woven COFS, where long organic strands are connected
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- Synthesis of new copper(I)-complexed rotaxanes via click chemistry
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The Cu(I)-catalyzed dipolar cycloaddition of azides and terminal alkynes ('click' chemistry) has been used as a mild and efficient stoppering reaction for the preparation of new copper(I)-complexed rotaxanes.
- Durot, Stéphanie,Mobian, Pierre,Collin, Jean-Paul,Sauvage, Jean-Pierre
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p. 8496 - 8503
(2008/12/21)
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- Multiporphyrinic rotaxanes: Control of intramolecular electron transfer rate by steering the mutual arrangement of the chromophores
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A [2]-rotaxane Zn2-Au+ made from a dumbbell component ended by Zn(II) porphyrin stoppers and a ring component incorporating a Au(III) porphyrin has been assembled in 13% yield using the transition metal templating route. 1
- Linke,Chambron,Heitz,Sauvage,Encinas,Barigelletti,Flamigni
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p. 11834 - 11844
(2007/10/03)
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- Self-assembling, chromogenic receptors for the recognition of medically important substrates and their method of use
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A chromogenic receptor comprises a self-assembled chromogenic compound having at least one intrinsic binding site. The chromogenic compound is characterized by the property of producing a reversible color change responsive to binding a target substrate to
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- Spectral Sensitization of Large-band-gap Semiconductors (Thin Films and Ceramics) by a Carboxylated Bis(1,10-Phenanthroline)copper(I) Complex
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Photoelectrochemical cells based on colloidal films of titanium dioxide and zinc oxide ceramic electrodes sensitized by a bis(2,9-diphenyl-1,10-phenanthroline)copper(I) complex modified at the para positions with NaO2C groups, were investigated in an aque
- Alonso-Vante, Nicolas,Nierengarten, Jean-Francois,Sauvage, Jean-Pierre
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p. 1649 - 1654
(2007/10/02)
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- Synthesis of bis-porphyrins containing a 2,9-diphenyl-1,10-phenanthroline spacer
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The synthesis of bis-porphyrins disposed in an oblique fashion is described. The tetrapyrrole rings are linked via a 2,9-diphenyl-1,10-phenanthroline spacer. Two routes have been investigated: a step wise procedure and a direct strategy involving a double cyclisation step. From the bis-free base porphyrin, synthesized with an overall yield of 1% from 2,9-di(p-tolyl)-1,10-phenanthroline, an unsymmetrical zinc (II) porphyrin free base system was prepared and isolated in view of excited state energy and electron transfer.
- Chabdon-Noblat, Sylvie,Sauvage, Jean-Pierre
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p. 5123 - 5132
(2007/10/02)
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