Photoinduced CO-releasing molecule (photoCORM) as an in situ CO surrogate for palladium-catalysed aminocarbonylation.

Herein, we show that a photoCORM behaves as a highly substrate-tolerant, photoactivable in situ CO surrogate, allowing the synthesis of variously functionalised amides including the biologically active compound Moclobemide by Pd-catalysed aminocarbonylation between aryl iodides and amines under mild conditions. This work should bring about a useful input to the field of carbonylative transformations.

1H-1,2,3-triazolyl-1,6-naphthyridin-7(6H)-ones as Potential Fluorescent Nucleoside Analogues: Synthesis and Optical Properties.

In this article, we present the synthesis and the optical properties of three original molecules as potential fluorescent ribonucleoside analogues incorporating a 1,6-naphthyridin-7(6H)-one scaffold as a fluorescent nucleobase and a 1,2,3-triazole as a linkage. The nucleosides were prepared via a Cu alkyne-azide cycloaddition (CuAAC) reaction between a ribofuranosyl azide and a 4-ethynylpyridine partner. Construction of substituted 1,6-naphthyridin-7(6H)-ones was achieved through two additional steps. Optical property studies were investigated on nucleoside analogues. Powerful fluorescence properties have been evidenced with a remarkable change of emissivity depending on the polarity of the solvent, making these molecules suitable as a new class of artificial fluorescent nucleosides for investigating enzyme binding sites as well as probing nucleic acids. In addition, we are convinced that such analogues could be of great interest in the search for new antiviral or antitumoral drugs based on nucleosides.

1,6-Naphthyridin-7(6H)-ones: synthesis and optical properties.

Efficient synthesis of original 1,6-naphthyridin-7(6H)-ones and their optical properties are described. Their powerful fluorescence properties including dual fluorescence, solvatochromism, acidochromism, large Stokes shifts and high quantum yields, suitable for biological applications or as luminescent devices in materials science, are evidenced.

Reactant-induced photoactivation of in situ generated organogold intermediates leading to alkynylated indoles via Csp2-Csp cross-coupling.

Photosensitization of organogold intermediates is an emerging field in catalysis. In this context, an 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 is observed. Of note, 2-iodo-ynamides can be used as electrophiles in this cross-coupling reaction. The resulting N-alkynyl indoles lend themselves to post-functionalization affording valuable scaffolds, notably benzo[a]carbazoles. Mechanistic studies converge 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.

Boron, silicon, nitrogen and sulfur-based contemporary precursors for the generation of alkyl radicals by single electron transfer and their synthetic utilization.

Recent developments in the use of boron, silicon, nitrogen and sulfur derivatives in single-electron transfer reactions for the generation of alkyl radicals are described. Photoredox catalyzed, electrochemistry promoted or thermally-induced oxidative and reductive processes are discussed highlighting their synthetic scope and discussing their mechanistic pathways.

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

Two 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.

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

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of 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, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.

Isoxazole-Derived Aroylhydrazones and Their Dinuclear Copper(II) Complexes Show Antiproliferative Activity on Breast Cancer Cells with a Potentially Alternative Mechanism Of Action.

This paper reports the design, synthesis and cytotoxicity studies of two new isoxazole-derived aroylhydrazone ligands and their dinuclear copper(II) complexes. Compounds were fully characterized by various spectroscopic and analytical techniques. The molecular structures of four derivatives were confirmed by X-ray crystallography. The stability of the ligands and the complexes in aqueous medium was monitored spectroscopically. Both the ligands and the complexes were shown to interact with calf thymus DNA (ct-DNA). Additionally, structures containing a phenol pendant arm were significantly more cytotoxic than those carrying a pendant pyridine substituent, reaching sub-micromolar IC50 values on the triple-negative human breast cancer cell line MDA-MB-231. The metal chelation and transchelation ability of the compounds towards FeII , FeIII and ZnII ions was explored as a possible mechanism of action of these compounds.

Photosensitized oxidative addition to gold(I) enables alkynylative cyclization of o-alkylnylphenols with iodoalkynes.

The well-established oxidative addition-reductive elimination pathway is the most followed one in transition metal-catalysed cross-coupling reactions. While readily occurring with a series of transition metals, gold(I) complexes have shown some reluctance to undergo oxidative addition unless special sets of ligands on gold(I), reagents or reaction conditions are used. Here we show that under visible-light irradiation, an iridium photocatalyst triggers-via triplet sensitization-the oxidative addition of an alkynyl iodide onto a vinylgold(I) intermediate to deliver C(sp)2-C(sp) coupling products after reductive elimination. Mechanistic and modelling studies support that an energy-transfer event takes place, rather than a redox pathway. This particular mode of activation in gold homogenous catalysis was applied in several dual catalytic processes. Alkynylbenzofuran derivatives were obtained from o-alkynylphenols and iodoalkynes in the presence of catalytic gold(I) and iridium(III) complexes under blue light-emitting diode irradiation.

Carbonylation of Alkyl Radicals Derived from Organosilicates through Visible-Light Photoredox Catalysis.

Primary, secondary, and tertiary alkyl radicals formed by the photocatalyzed oxidation of organosilicates underwent efficient carbonylation with carbon monoxide (CO) to give a variety of unsymmetrical ketones. This study introduces the possibility of radical carbonylation under a photooxidative regime.

Organic photoredox catalysis for the oxidation of silicates: applications in radical synthesis and dual catalysis.

Metal free photooxidation of alkyl bis(catecholato)silicates with the organic dye 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-benzene (4CzIPN) allows the smooth formation of alkyl radicals. The latter can be efficiently engaged either with radical acceptors to provide homolytic addition products or in photoredox/nickel dual catalysis reactions to obtain cross-coupling products.

Recent advances in cancer treatment by iron chelators.

The 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 detail.

Silicates as Latent Alkyl Radical Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent Bis-Catecholato Silicon Compounds.

This works introduces hypervalent bis-catecholato silicon compounds as versatile sources of alkyl radicals upon visible-light photocatalysis. Using Ir[(dF(CF3)ppy)2(bpy)](PF6) (dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine, bpy = bipyridine) as catalytic photooxidant, a series of alkyl radicals, including highly reactive primary ones can be generated and engaged in various intermolecular homolytic reactions. Based on cyclic voltammetry, Stern-Volmer studies, and supported by calculations, a mechanism involving a single-electron transfer from the silicate to the photoactivated iridium complex has been proposed. This oxidative photocatalyzed process can be efficiently merged with nickel-catalyzed Csp2-Csp3 cross-coupling reactions.

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

Tumor 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 cancer.

Intramolecular thiol-yne cyclisation as a novel strategy for thioglycal synthesis.

A novel intramolecular thiol-yne cyclisation strategy has been developed for the synthesis of thioglycals. Both ionic and radical mediated cyclisation pathways have been investigated for D- and L-sugars. The ionic cyclisation provides exclusive access to 5-exo products directly from the thioesters whereas the radical cyclisation provides access to both 5-exo and 6-endo products upon photochemical irradiation of the free thiols. These are the first examples of intramolecular thiol-yne cyclisation reactions applied to thiosugar synthesis.

Versatile access to Martin's spirosilanes and their hypervalent derivatives.

A new route to Martin's 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, Martin's 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 crystallography.

Synthetic applications of intramolecular thiol-ene "click" reactions.

The intermolecular thiol-ene reaction is emerging as a highly efficient; free-radical mediated "click" process with diverse applications in biofunctionalisation and materials science. The related intramolecular thiol-ene reactions offer significant potential for the preparation of a wide range of sulphur containing heterocycles including synthetic therapeutics such as cyclic peptides and thiosugars. Herein, we review recent advances in intramolecular thiyl-radical mediated reactions and their applications for synthetic and medicinal chemistry.

Synthesis and biological properties of Quilamines II, new iron chelators with antiproliferative activities.

To selectively target tumor cells expressing an overactive Polyamine Transport System (PTS), we designed, synthesized, and evaluated the biological activity of a new generation of iron chelators, derived from the lead compound HQ1-44, which we named Quilamines II. The structures of four new antiproliferative agents were developed. They differ in the size of the linker (HQ0-44 and HQ2-44) or in the nature of the linker (HQCO-44 and HQCS-44) between a hydroxyquinoline moiety (HQ) and a homospermidine (44) chain, the best polyamine vector. The Quilamines II were obtained after 6 to 9 steps by Michael addition, peptide linkage, and reductive amination or by using the Willgerodt-Kindler reaction. The biological evaluation of these second-generation Quilamines showed that modifying the size of the linker increased the selectivity of these compounds for the PTS. In addition, measurement of the toxicity of Quilamines HQ0-44 and HQ2-44 highlighted their marked antiproliferative nature on several cancerous cell lines as well as a differential activity on nontransformed cells (fibroblasts). In contrast, Quilamines HQCO-44 and HQCS-44 presented low selectivity for the PTS, probably due to a loss of electrostatic interaction. We also demonstrated that the HCT116 cell line, originating from a human colon adenocarcinoma, was the most responsive to the various Quilamines. As deduced from the calcein and HVA assays, the higher iron chelating capacity of HQ1-44 could explain its higher antiproliferative efficiency.

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

Iron 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.