G-quadruplexes (G4) are DNA secondary structures that take part in the regulation of gene expression. Putative G4 forming sequences (PQS) have been reported in mammals, yeast, bacteria, and viruses. Here, we present PQS searches on the genomes of T. brucei, L. major, and P. falciparum. We found telomeric sequences and new PQS motifs. Biophysical experiments showed that EBR1, a 29 nucleotide long highly repeated PQS in T. brucei, forms a stable G4 structure. G4 ligands based on carbohydrate conjugated naphthalene diimides (carb-NDIs) that bind G4’s including hTel could bind EBR1 with selectivity versus dsDNA. These ligands showed important antiparasitic activity. IC50 values were in the nanomolar range against T. brucei with high selectivity against MRC-5 human cells. Confocal microscopy confirmed these ligands localize in the nucleus and kinetoplast of T. brucei suggesting they can reach their potential G4 targets. Cytotoxicity and zebrafish toxicity studies revealed sugar conjugation reduces intrinsic to...

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G-Quadruplex Identification in the Genome of Protozoan Parasites Points to Naphthalene Diimide Ligands as New Antiparasitic Agents

Design and synthesis of novel V-shaped AIEE active quinoxalines for acidochromic applications

We present G4-iM Grinder, a system for the localization, characterization and selection of potential G4s, i-Motifs and higher order structures. A robust and highly adaptable search engine identifies all structures that fit the user's quadruplex definitions. Their biological relevance, in vitro formation probability and presence of known-to-form structures are then used as filters. The outcome is an efficient methodology that helps select the best candidates for a subsequent in vitro analysis or a macroscopic genomic quadruplex assessment. As proof of the analytical capabilities of G4-iM Grinder, the human genome was analyzed for potential G4s and i-Motifs. Many known-to-form structures were identified. New candidates were selected considering their score and appearance frequency. We also focused on locating Potential Higher Order Quadruplex Sequences (PHOQS). We developed a new methodology to predict the most probable subunits of these assemblies and applied it to a PHOQS candidate. Taking the human average density as reference, we examined the genomes of several etiological causes of disease. This first of its class comparative study found many organisms to be very dense in these potential quadruplexes. Many presented already known-to-form-G4s and i-Motifs. These findings suggest the potential quadruplexes have as therapeutic targets for these diseases that currently kill millions worldwide.

/pdf/g4-im-grinder-when-size-and-frequency-matter-g-quadruplex-i-3n8micsnra.pdf

G4-iM Grinder: when size and frequency matter. G-Quadruplex, i-Motif and higher order structure search and analysis tool

Carbohydrate-naphthalene diimide conjugates as potential antiparasitic drugs: Synthesis, evaluation and structure-activity studies.

Herein, we describe novel iron-catalyzed transfer hydrogenation between alcohols and 1-(2-nitrophenyl)pyrroles for the synthesis of pyrrolo[1,2-α]quinoxalines. The tricarbonyl (η4-cyclopentadienone) iron complex catalyzed the oxidation of alcohols and the reduction of nitroarenes, and the corresponding aldehydes and aniline were generated in situ. The resulting Pictet-Spengler-type annulation/oxidation completed the quinoxaline structure formation. The protocol tolerated various kinds of functional groups and provided 29 samples of 4-substituted pyrrolo[1,2-α]quinoxalines. The developed method was also applied for the synthesis of additional polyheterocycles.

Direct Synthesis of Pyrrolo[1,2-α]quinoxalines via Iron-Catalyzed Transfer Hydrogenation between 1-(2-Nitrophenyl)pyrroles and Alcohols.

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.

Timothee Garnerin

Papers

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives.