Quilamine HQ1-44, an iron chelator vectorized toward tumor cells by the polyamine transport system, inhibits HCT116 tumor growth without adverse effect

International audienceTumor cell growth requires large iron quantities and the deprivation of this metal induced by synthetic metal chelators is therefore an attractive method for limiting the cancer cell proliferation. The antiproliferative effect of the Quilamine HQ1-44, a new iron chelator vectorized toward tumor cells by a polyamine chain, is related to its high selectivity for the Polyamine Transport System (PTS), allowing its preferential uptake by tumoral cells. The difference in PTS activation between healthy cells and tumor cells enables tumor cells to be targeted, whereas the strong dependence of these cells on iron ensures a secondary targeting. Here, we demonstrated in vitro that HQ1-44 inhibits DNA synthesis and cell proliferation of HCT116 cells by modulating the intracellular metabolism of both iron and polyamines. Moreover, in vivo, in xenografted athymic nude mice, we found that HQ1-44 was as effective as cis-platin in reducing HCT116 tumor growth, without its side effects. Furthermore, as suggested by in vitro data, the depletion in exogenous or endogenous polyamines, known to activate the PTS, dramatically enhanced the antitumor efficiency of HQ1-44. These data support the need for further studies to assess the value of HQ1-44 as an adjuvant treatment in cance

Recent advances in cancer treatment by Iron Chelators

International audienceThe development of new therapeutic alternatives for cancers is a major public health priority. Among the more promising approaches, the iron depletion strategy based on metal chelation in the tumoral environment has been particularly studied in recent decades. After a short description of the importance of iron for cancer cell proliferation, we will review the different iron chelators developed as potential chemotherapeutics. Finally, the recent efforts to vectorize the chelating agents specifically in the microtumoral environment will be discussed in detai

Single-Electron-Transfer Oxidation of Trifluoroborates and Silicates with Organic Reagents: A Comparative Study

International audienceIn this report, the single-electron-transfer oxidation of alkyl trifluoroborates and silicates has been studied. Different types of oxidation reagents have been examined, focusing on organic oxidants and particularly the use of dyes in photocatalytic oxidations. Both trifluoroborates and silicates could provide C-centered radicals when using a tritylium salt or the Ledwith–Weitz aminium salt. Photocatalysis with the Fukuzumi reagent suggested that trifluoroborates are more easily oxidized than biscatecholato silicates under these conditions

pH‐Sensitive Poly(ethylene glycol)/Poly(ethoxyethyl glycidyl ether) Block Copolymers: Synthesis, Characterization, Encapsulation, and Delivery of a Hydrophobic Drug

International audienceCurcumin is a natural polyphenolic compound known for its numerous pharmacological properties. However, its low water solubility and instability at neutral pH are serious drawbacks preventing its use as an oral drug. Well‐defined amphiphilic poly(ethylene glycol)‐block‐poly(ethoxyethyl glycidyl ether) (PEG‐b‐PEEGE) block copolymers carrying acid‐labile acetal groups are synthesized by anionic ring‐opening polymerization and investigated as potential pH‐sensitive nano‐carriers for delivery of curcumin to cancer cells. The nanoparticles, resulting from copolymer self‐assembly in aqueous media, are characterized by dynamic light scattering and cryo‐transmission electron microscopy. The nanoparticles’ stabilities are evaluated in three different phosphate buffers (pH = 7.2, 6.4, and 5.3). The stability decreases at lower pH and a complete disappearance of the nanoparticles is noticed after 4 days at pH 5.3. Curcumin is encapsulated in hydrophobic core of mPEG40‐b‐PEEGE25 nanoparticles allowing significant enhancements of curcumin solubility in water and lifetime at neutral pH. In vitro curcumin release is studied at different pH by UV‐spectroscopy and high‐performance liquid chromatography (HPLC). The cytotoxicity of curcumin and curcumin encapsulated in micelles is evaluated by cell viability 3‐(4,5‐Dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) assay on MDA‐MB‐231 human breast cancer cell

Novel luminescent benzopyranothiophene- and BODIPY-derived aroylhydrazonic ligands and their dicopper(II) complexes: syntheses, antiproliferative activity and cellular uptake studies

International audienceTwo novel unsymmetrical binucleating aroylhydrazonic ligands and four dicopper(II) complexes carrying fluorescent benzopyranothiophene (BPT) or boron dipyrromethene (BODIPY) entities were synthesized and fully characterized. Complex 1, derived from the BPT-containing ligand H3L1, had its crystal structure elucidated through X-ray diffraction measurements. The absorption and fluorescence profiles of all the compounds obtained were discussed. Additionally, the stability of the ligands and complexes was monitored by UV–vis spectroscopy in DMSO and biologically relevant media. All the compounds showed moderate to high cytotoxicity towards the triple negative human breast cancer cell line MDA-MB-231. BPT derivatives were the most cytotoxic, specially H3L1, reaching an IC50 value up to the nanomolar range. Finally, fluorescence microscopy imaging studies employing mitochondria- and nucleus-staining dyes showed that the BODIPY-carrying ligand H3L2 was highly cell permeant and suggested that the compound preferentially accumulates in the mitochondria

Cross coupling of alkylsilicates with acyl chlorides via photoredox/nickel dual catalysis: a new synthesis method for ketones

International audiencePhotoredox/Nickel dual catalysis using easy oxydized bis-catecholato hypercoordinated silicon derivatives as radical sources and acylchlorides as electrophile allows a new method of formation of dialkyl and alkyl-aryl ketones as well as dibenzyl ketones which are less easily accessed. Flow chemistry can be use

Versatile Access to Martin's Spirosilanes and Their Hypervalent Derivatives

International audienceA new route to Martins spirosilanes has been devised. The original synthesis does not allow diversely substituted spirosilane derivatives to be synthesized, and thus their corresponding silicates. In this report, Martins spirosilanes bearing alkyl, aryl, halogen, alkoxy, and trifluoromethyl substituents on the aryl ring have been prepared through a versatile four-step route. Addition of fluoride onto these Lewis acids as a prototypical reaction with a nucleophile yielded a library of stable fluorosilicates. Both sets of compounds have been characterized by X-ray crystallograp

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis, Structural Studies and Reactivity

International audienceWhile the generation of aryl radicals by photoredox catalysis is well-documented under reductive conditions, it has remained challenging under an oxidative pathway. Because of the easy photooxidation of alkyl bis-catecholato silicates, a general study on phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized and their reactivity has been explored. It was found that thanks to the substitution of the catecholate moiety and notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings

Polyaminoquinoline iron chelators for vectorization of antiproliferative agents: design, synthesis, and validation.

International audienceIron chelation in tumoral cells has been reported as potentially useful during antitumoral treatment. Our aim was to develop new polyaminoquinoline iron chelators targeting tumoral cells. For this purpose, we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, which we named Quilamines, based on an 8-hydroxyquinoline (8-HQ) scaffold linked to linear polyamine vectors. These were designed to target tumor cells expressing an overactive polyamine transport system (PTS). A set of Quilamines bearing variable polyamine chains was designed and assessed for their ability to interact with iron. Quilamines were also screened for their cytostatic/cytotoxic effects and their selective uptake by the PTS in the CHO cell line. Our results show that both the 8-HQ moiety and the polyamine part participate in the iron coordination. HQ1-44, the most promising Quilamine identified, presents a homospermidine moiety and was shown to be highly taken up by the PTS and to display an efficient antiproliferative activity that occurred in the micromolar range. In addition, cytotoxicity was only observed at concentrations higher than 100 μM. We also demonstrated the high complexation capacity of HQ1-44 with iron while much weaker complexes were formed with other cations, indicative of a high selectivity. We applied the density functional theory to study the binding energy and the electronic structure of prototypical iron(III)-Quilamine complexes. On the basis of these calculations, Quilamine HQ1-44 is a strong tridentate ligand for iron(III) especially in the form of a 1:2 complex

Reactant-Induced Photoactivation of a Gold-Catalyzed Csp2-Csp Cross-Coupling Leading to Indoles

A novel access to 2,3-disubstituted indoles from o-alkynyl aniline and iodoalkyne derivatives via a gold-catalyzed sequence under visible-light irradiation and in the absence of an exogenous photocatalyst was uncovered. A wide scope of the process was observed. Of note, 2-iodo-ynamides that have never been used in any organometallic cross-coupling reaction could be used as electrophiles. The resulting N-alkynyl indoles lend themselves to post-functionalization affording valuable scaffolds, notably benzo[a]carbazoles. Mechanistic studies converged on the fact that a potassium sulfonyl amide generates emissive aggregates in the reaction medium. Static quenching of these aggregates by a vinylgold(I) intermediate yields to an excited state of the latter, which can react with an electrophile via oxidative addition and reductive elimination to forge the key C-C bond. This reactant-induced photoactivation of an organogold intermediate opens rich perspectives in the field of cross-coupling reactions