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International audience; The most prevalent form of Charcot-Marie-Tooth disease (CMT type 1A) is characterized by duplication of the PMP22 gene, peripheral dysmyelination and decreased nerve conduction velocities leading to muscle weakness. Recently, oxidative stress was reported as a feature in CMT1A patients. Curcumin exhibits antioxidant activities and has shown beneficial properties on peripheral nerves. However, curcumin presents unfavorable pharmacokinetics. We developed curcumin-cyclodextrin/cellulose nanocrystals (Nano-Cur) to bypass this limitation. The present study investigated the therapeutic potential of Nano-Cur in vitro in Schwann cells (SCs) and in vivo in the transgenic CMT1A rat model. In vitro, Nano-Cur treatment (0.01 μM for 8 h) reduced reactive oxygen species and improved mitochondrial membrane potential in CMT1A SCs. Moreover, Nano-Cur treatment (0.01 μM for 1 week) increased the expression of myelin basic protein in SC/neuron co-cultures. Preliminary in vivo experiments carried out in WT rats showed that intraperitoneal (i.p.) injection of Nano-Cur treatment containing 0.2 mg/kg of curcumin strongly enhanced the bioavailability of curcumin. Afterwards, in 1-month-old male CMT1A rats, Nano-Cur treatment (0.2 mg/kg/day, i.p. for 8 weeks) significantly improved sensori-motor functions (grip strength, balance performance, and mechanical and thermal sensitivities). Importantly, sensory and motor nerve conduction velocities were improved. Further histological and biochemical analyses indicated that myelin sheath thickness and myelin protein expression (myelin protein zero and PMP22) were increased. In addition, oxidative stress markers were decreased in the sciatic nerve and gastrocnemius muscle. Finally, Nrf2 expression and some major antioxidant enzymes were increased in sciatic nerve. Therefore, Nano-Cur significantly improved cellular, electrophysiological, and functional features of CMT1A rats.

International audience; This paper describes the preparation of two chalcone/β-cyclodextrin/cellulose-nanocrystals complexes and thestudy of their antiproliferative activities against two colorectal and two prostatic cancer cell lines. The aim of thiswork was to enhance hydrosolubility of chalcones thanks to the hydrophilic character of cellulose nanocrystals.These latter were linked, through ionic interactions, to a cationic derivative of β-cyclodextrins whose lipophiliccavity allowed the encapsulation of hydrophobic chalcones: 3-hydroxy-3′,4,4′,5′-tetramethoxychalcone (1) and3′,4,4′,5′-tetramethoxychalcone (2). First, we showed that encapsulation allowed hydrosolubilization of chalcones.Then, chalcone/β-cyclodextrin/cellulose-nanocrystals complexes demonstrated enhanced in vitro antiproliferativeactivities, compared to the corresponding free-chalcones.

A new gold nanoparticle-based construct has been designed to hydrophobic drugs delivery into cancer cells. Cyclodextrin scaffolds adsorbed on polyethyleneimine-coated gold nanoparticles (AuNP@PEI@CD) have been used to encapsulate hydrophobic tetrapyrrolic compounds consisting of gold complexes of 5,10,15,20-tetraphenyl porphyrin (AuTPPCl) and 5-(4-acetoxyphenyl)-10,15,20-triphenyl porphyrin (AuTPPOAcCl). These two nanoparticles have been tested for their cytotoxic activities against the two colorectal cancer cell lines HT-29 and HCT-116 and have shown significant increases in toxicity when compared to the corresponding non-vectorized tetrapyrrolic macrocycles.

Two protoporphyrin IX (PpIX) adamantane derivatives were synthesized and then metallated with zinc. The Zn-PpIX derivatives, exhibiting a high singlet oxygen quantum yield, were tested for their photodynamic activity against the HT-29 cell line. In order to enhance their water-solubility and their cellular bioavailability, these photosensitizers were encapsulated into the hydrophobic cavity of cyclodextrins (CD) previously attached to cellulose nanocrystals (CNCs) via electrostatic interactions. Under illumination, the encapsulated adamantanyl-porphyrins exerted an enhanced in vitro cytotoxicity, as compared with the corresponding free photosensitizers.

International audience; This Letter reports the synthesis and the characterization of two new water-stable and soluble photosensitizer-conjugated magnetic nanoparticles (PS-MNPs) composed of an iron oxide magnetic core coated with a biocompatible dextran shell bearing polyaminated chlorin p6. Designed to improve cancer cell targeting, these photosensitizers were assayed for their antitumour activity against two variants of B16 mouse melanoma cell line (B16F10 and B16G4F, with or without melanin, respectively). Cell viability measurements demonstrated that PS-MNPs were more phototoxic than PEI-chlorin p6 making these photosensitizers promising for further in vitro and in vivo investigations.

Background Photodynamic therapy, using porphyrins as photosensitizers (PS), has been approved in treatment of several solid tumors. However, commonly used PS induce death but also resistance pathways in cancer cells and an alteration of surrounding normal tissues. Because polyamines (PA) are actively accumulated in cancer cells by the Polyamine Transport System (PTS), they may enable PS to specifically target cancer cells. Here, we investigated whether new protoporphyrin IX-polyamine derivatives were effective PS against prostate cancer and whether PA increased PDT specificity after 630 nm irradiation. Methods CHO and CHO-MG cells (differing in their PTS activity) were used to assess efficacy of polyamine vectorization. MTT assays were performed on human prostate non-malignant (RWPE-1) and malignant (PC-3, DU 145 and LNCaP) cell lines to test PS phototoxicity. ROS generation, DNA fragmentation and cell signalling were assessed by ELISA/EIA, western-blots and gel shift assays. Finally, PS effects were studied on tumor growth in nude mice. Results Our PS were more effective on cancer cells compared to non-malignant cells and more effective than PpIX alone. PpIX-PA generated ROS production involved in induction of apoptotic intrinsic pathways. Different pathways involved in apoptosis resistance were studied: PS inhibited Bcl-2, Akt, and NF-κB but activated p38/COX-2/PGE2 pathways which were not implicated in apoptosis resistance in our model. In vivo experiments showed PpIX-PA efficacy was greater than results obtained with PpIX. Conclusions All together, our results showed that PpIX-PA exerted its maximum effects without activating resistance pathways and appears to be a good candidate for prostate cancer PDT treatment.

International audience; Porphyrin-polyamine conjugates bearing two (cis or trans position) or four spermidine or spermine units were synthesized. We studied the photostability, the hydrophilic/lipophilic balance of porphyrin-polyamine derivatives and the production of singlet oxygen. All these compounds possess physicochemical features required for their use in PDT. Then, we investigated the photocytotoxic efficacy of these porphyrin-polyamine derivatives and the cell death pathway implicated. All compounds appear to be more efficient than Photofrin® to induce HaCat and MCF7 cell death, essentially by apoptosis. Collectively, these data show that porphyrin-polyamine conjugates could be promising phototherapeutic agents.

International audience; We report an efficient synthesis of tetra‐ and hexa‐substituted carbohydrate‐coated compounds, which we have named "star‐like" surfactants, starting from either α‐methylglucose or myo‐inositol as a central core. The synthesis explores a new approach to such multipolar compounds using [3+2] copper (I)‐catalyzed cycloadditions to attach the respective building blocks.

International audience; Synthesis of a triazole-linked 3'-5' thymidine dimer making use of 1,3-dipolar cycloaddition is described. The azido-precursor was obtained by regioselective chlorination of thymidine, followed by azidation. The second precursor, a propargyl derivative, was obtained by selective 3'-O-alkylation of thymidine. Two 'click systems' were compared to obtain the desired dimer. These reactions were performed by microwave irradiation.

A new anti-cancer drug delivery system, based on gold nanoparticles, has been designed for hydrophobic active compounds. The system is a conjugate of gold/polyethyleneimine (AuNPs/PEI) nanoparticles and sulphated β-cyclodextrin (CD). Anionic cyclodextrin was attached to the positively charged AuNPs/PEI nanoparticles by ionic bonds. Tanshinone IIA and α-mangostin were extracted, purified and encapsulated into the AuNPs/PEI/CD nanoparticles. In vitro preliminary cell viability assays against prostate cancer cell lines PC-3 and DU145 showed that encapsulation resulted in increased cytotoxicity.

International audience; The synthesis of curcumin-cyclodextrin/cellulose nanocrystals (CNCx) nano complexes was performed. CNCx were functionalized by ionic association with cationic β-cyclodextrin (CD) and CD/CNCx complexes were used to encapsulate curcumin. Preliminary in vitro results showed that the resulting curcumin-CD/CNCx complexes exerted antiproliferative effect on colorectal and prostatic cancer cell lines, with IC50s lower than that of curcumin alone.

This paper reports the synthesis of new chlorin–polyamine conjugates designed to improve the targeting of cancer cells. Photocytotoxic activity of these photosensitizers was tested against human chronic myelogenous leukemia cells (K562) and compared to the effects of Photofrin II ® and chlorin e 6 .

New crosslinked microcrystalline cellulose plastic films were made by olefin metathesis. Cellulose was first acylated under microwave irradiation by 10‐undecenoyl chloride in lithium chloride/N,N‐d...

The aim of this work is the synthesis of a new family of glycosylated porphyrins in which the sugar moieties are linked to the tetrapyrrole ring by a thioglycosidic bond. Two series have been designed. The first one corresponds to meso-aryl porphyrin derivatives. The second one has been obtained from protoporphyrin IX derivatization. Aryl-porphyrins were prepared from tristolyl o- and p-hydroxyporphyrins followed by bromoallylation and thioglycosylation with peracetylated S-glucose, mannose and galactose and deprotection. The other series has been synthesized from protoporphyrin IX dimethylester with a regioselective glycosylation of terminal alkenyl carbon. The UV-visible, NMR and MALDI mass spectra are presented. Photocytotoxicities of the synthesized compounds against K562 chronic leukaemia cell line has been evaluated.

In this paper, we present the synthesis of two glycosylated strapped porphyrins. Structural elucidation is described ( 1 H NMR, MS Maldi and UV visible). The photocytotoxicity of these glycosyl strapped porphyrins against carcinogenic K562 cells is compared to hematoporphyrin as reference.

— Photodynamic treatment of promyelocytic K562 cells in the presence of a monoglucosylporphyrin or hematoporphyrin leads to a sequence of events recognized as hallmarks of apoptosis: a drop in mitochondrial potential, concurrent with a drop in ATP level and a decrease in cell respiration, translocation of phosphatidylserine of the plasma membrane, DNA fragmentation, appearance of apoptotic bodies and eventually loss of plasma membrane integrity. The chronology of these events is in accordance with sequential events induced by other known proapoptotic agents; in contrast to these agents that induce apoptosis in a restricted part of the cell population, we observed that the entire cell population (apart from a small percentage of cells that endured rapid necrosis during phototreatment) underwent apoptosis after irradiation in the presence of porphyrins. It appears that photodynamic treatment allows the bypass of early apoptotic signals in K562 cells that are otherwise renowned for their resistance to drug-induced apoptosis (A. McGahon, R. Bissonnette, M. Schmitt, K. M. Cotter, D. R. Green and T. G. Cotter, Blood 83, 1179–1187, 1994). Singlet oxygen is believed to be the proximate reactive species generated by porphyrin illumination. Because this molecule reacts with almost every cellular constituent, the way that singlet oxygen or its reactive oxygen species byproducts trigger apoptosis remains to be elucidated.

A series of neutral meso-arylglycosylporphyrins has been tested in order to evaluate their potency as antifungal agents against the yeast Saccharomyces cerevisiae. Photodynamic activity of these molecules results in intracellular damage as evidenced by the loss of clonogenicity and DNA fragmentation. The ability of these photosensitizers to permeate yeast cells is determined by microspectrofluorimetry and is correlated with their antifungal potency. Amphiphilic porphyrin derivatives are shown to exhibit the more pronounced photoactivity.

A new class of porphyrins bearing thioglycosyl groups is presented in order to improve targeting of malignant cells and resistance to glycosidases. These compounds were synthesized in four steps. They produced 1 O 2 and their photocytotoxicity against the yeast Saccharomyces cerevisiae was compared with the effect of haematoporphyrin.

The synthesis of a series of pyrazine analogues of the anti-herpes compound, acyclovir is described. These syntheses were accomplished by various methods: in the presence of a Lewis acid or NaH for hydroxyethoxymethyl and hydroxybutyl groups or by sequential oxidation/reduction of l-β-D-ribofuranosyl)-2-pyrazinones for 2′,3′-acyclonucleosides. Antiviral (HSV-1, CMV, Cox B4, HIV-1) properties of these compounds were determined.

Two agricultural by-products, sugar-beet pulp and wheat bran, have been examined for their suitability to be transformed into bioplastics by esterification by lauroyl chloride. Influence of cellulose content was studied on eleven samples enriched in cellulose after chemical or enzymatic removal of pectins from sugar-beet pulp and heteroxylans from wheat bran. After a pretreatment by immersion in 0.5 mol/L sulfuric acid, esterification was carried out with lauroyl chloride. Neither the amount of cellulose nor the extraction treatment had a marked influence on the formation of plastic. A film could be obtained from all the wheat-bran samples, including samples with low cellulose content, but only from one sugar-beet pulp sample. The crystallinity of the cellulose in sugar-beet pulp and wheat bran were different. The nature of cellulose could be responsible for the failure of sugar-beet pulp residues to form plastic.

A moderate yield (55%) preparation of N-1 substituted thymine has been achieved by reacting an excess of 4-bromobutylacetate at 100 °C for 48 hrs. N-1, N-3 bisalkylated and O-alkylated compounds were also obtained as by-products. © 1997 Published by Elsevier Science Ltd.

Piperazinone nucleosides can be formed by N-glycosylation with 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose of either piperazin-2-ones or pyrazin-2-ones followed by reduction of the heterocycle with rhodium on alumina. All the prepared compounds were tested for their activity against the Visna virus, but did not show significant antiviral activity.

Various 5-alkyl-6-aza-5,6-dihydrouridines and 6-(β-D-ribopyranosyl)-5-alkyl-6-aza-5,6-dihydrouracils have been synthesized. A new regioselective method is described for coupling triazinic bases to the sugar unit. Different epimers were isolated. Antiretroviral activity against Visna virus was evaluated.

International audience; This Letter reports the synthesis and characterization of a new series of water-stable and soluble photosensitizers (PS-CNCs) composed of cellulose nanocrystals (CNCs) bearing polyaminated chlorin p6. With a view to improve cancer cell targeting, these photosensitizers were assayed for their antitumor activity against HaCat cell line. IC(50) values fell within the nanomolar-range, making these photosensitizers promising for further in vitro and in vivo investigations.

Glycosylation of 3-alkyl N 4 -(3-hydroxypropyl) 2-piperazinones by protected 1- O -acetyl ribofuranoses produces nucleoside analogs in which the base is separated from the sugar by a hydrocarbon spacer arm. The preliminary in vitro test results against retroviruses seem promising for compounds bearing a long alkyl chain.

Various 5-alkyl-6-aza-5,6-dihydrouridine were synthesized from the corresponding triazinic heterocycles and acetylated ribose. These nucleosides were tested for inhibitory activity on lentivirus Visna-Maedi.

The cross metathesis of 3′-allylic analogues of thymidine, 2′-deoxyuridine and 2′-deoxycytidine is used to obtain nucleoside dimers, in which an unsaturated hydrocarbon chain links the 3′ positions of the sugar moieties. The biological activity on HIV infected cells was also evaluated.

International audience; We develop herein the synthesis of a new class of monocatenary and bolaform surfactants from d-glucose, d-galactose and lactose. Two main pathways have been investigated: microwave-assisted glycosylation followed by olefin cross-metathesis, and the one-step click-chemistry methodology. Tensioactive properties of these new compounds have been studied in order to characterize the physicochemical behaviour of these new carbohydrate-based compounds in water.

International audience; This paper reports the synthesis and characterization of a new class of tetrabenzoporphyrins bearing glucosyl or polyamine units on meso positions to improve the targeting of cancer cells. Photocytotoxic activity of these photosensitizers was tested on cell lines HaCaT and MCF-7 and compared to Photofrin II.

International audience; Synthetic cyclopeptides, and particularly those derived from VEGF sequence, present considerable interest for the development of nanodevices devoted to tumour imaging or targeting. In order to provide selective peptide-targeted tetrapyrrolic structures, we designed two meso-porphyrin derivatives anchored to a 17-residue-long cyclopeptide, potent antagonist of VEGF receptors, via a flexible tetraethylene glycol chain. Anchoring was achieved by two different strategies: a classical secondary amide bond formation and microwave-assisted Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition ('click-chemistry'). These compounds appear to be promising candidates for applications in PDT.

International audience; A series of polyamine-porphyrin conjugates bearing two (cis or trans position) or four units of spermidine or spermine was synthesized. We studied the binding of these cationic porphyrins to calf thymus DNA by the means of UV-vis spectroscopy and we investigated their ability to cleave plasmid DNA in the presence of light. DNA binding and DNA photocleavage abilities were found to depend on structural characteristics as (a) the relative positions of the side chains on the porphyrin ring and (b) the nature of the attached side chains (spermidine or spermine). DNA cleavage was also studied in the presence of a singlet oxygen quencher (NaN(3)) and in the presence of a hydroxyl radical scavenger (mannitol). Singlet oxygen was the major species responsible for the cleavage of DNA previously observed. Collectively, these data show that polyamine-porphyrin conjugates could be promising phototherapeutic agents.

International audience; The synthesis and characterisation of pyridinium porphyrinic chloroacetyl cellulose ester chlorides, where photosensitizing agents are covalently bounded to the polymeric chain, is presented in this paper. First, cellulose was homogenously converted into chloroacetatecellulose ester in DMAc/LiCl solvent by using chloroacetyl chloride. The complete substitution of cellulose was achieved using 7 equiv of chloroacetyl chloride for a 2 h reaction at room temperature. The absence of base did not prove detrimental to reaction. The grafting of monopyridyltritolylporphyrin onto chloroacetatecellulose ester was then realised by alkylation of the photosensitizer in DMF. These new plasticfilms were found to be thermostable up to 55 °C; higher temperatures led to progressive deacetylation. First results of their photobactericidal activity against Staphylococcus aureus and Escherichia coli strains are very encouraging. Such materials could find applications in medical environments as an alternative to overcome the rampant bacterial multiresistance to classical antibiotics.

International audience; Starting from 5?-O-tosylthymidine, sequential azidation and Cu-catalyzed [3+2] azide?alkyne 1,3-dipolar cycloaddition led to the formation of a 3?,5?-pentathymidine in high yield. The whole process needed only work-up/precipitation steps and was completed within just 18min, thanks to microwave activation.

International audience; Syntheses of new glycosylated neutral and cationic porphyrin dimers linked at the meso-position via a flexible hydrocarbon chain are described. A detailed 1H and 13C NMR study allows their complete structural elucidation. The UV-visible, fluorescence and MALDI mass spectra are also presented. Photocytotoxicities of these compounds against K562 leukaemia cell line are compared to those of Photofrin II.

International audience; Porphyrinatedcellulose laurate esters have been prepared in homogeneous DMA/LiCl medium by 'one-pot, two-step' reactions starting from cellulose, protoporphyrin IX, and lauric acid and using a TsCl/Pyridine system. The plastic films obtained after casting were shown to display photobactericidal activity against Gram positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. This new photobactericidal polymer has potential for industrial, medical, or household applications.

International audience; An efficient five-step synthesis method was developed to obtain tritolylporphyrin and protoporphyrin IX polyamine conjugates. These compounds were composed of either one polyamine unit (spermidine or spermine) covalently tethered to monocarboxyphenyl tritolylporphyrin or two molecules of polyamines borne by protoporphyrin IX. In each compound, an aliphatic spacer arm is linked to the N(4) polyamine position. Photocytotoxicity of these new compounds was evaluated against K562 human chronic myelogenous leukemia cells and compared to Photofrin II; protoporphyrin IX polyamine conjugates exhibited much stronger photocytocicity than Photofrin II and were shown to readily induce necrosis in treated cells.

Under mild conditions (Lewis acid/solvent/room temperature), the reaction of unprotected glucose, deoxyribose or xylose with hydroxylalkylthymine gives selectively nucleoside analogs with a spacer arm between sugar and base moiety. Experimental conditions (Lewis acid, solvent) for this new strategy leading to nucleoside analogs synthesis are discussed.

We report the efficient solid-phase synthesis of a new family of peptidic porphyrins containing a constrained RGD moiety obtained by ring-closing metathesis.

A series of galactose-based surfactants with various structures likely to display new interesting properties were synthesized. Four monocatenary surfactants were elaborated by microwave-assisted galactosylation of undecanol or 10-undecenol. These compounds were slightly soluble in water. Their tensioactive properties were determined at 45 degrees C. Olefin metathesis was used to synthesize the two single-chain bolaforms from undec-10-enyl galactopyranosides; two pseudomacrocyclic bolaforms were prepared by grafting two carbamates at O-4 and O-4' sugar positions of the single-chain bolaforms. These four surfactants are insoluble in water and undergo monolayer compression. Cyclization of these bolaforms by olefin metathesis led to macrocyclic surfactant analogues of archaeobacterial membrane components.

The synthesis and characterisation of symmetrical glycosylated neutral and cationic porphyrin dimers linked at the meso -position via a flexible hydrocarbon chain to improve targeting on malignant cells is reported. Photocytotoxicity of these compounds against the K562 leukemia cell line compared to the effect of hematoporphyrin is also presented.

Novel porphyrins bearing nitro groups and glucosyl moieties were synthesized. The antibacterial activity of these compounds on Escherichia coli and Staphylococcus aureus is described. Results reveal that their photocytotoxicity is markedly dependent on the nature, the number and the linking position of the glycosyl moieties and nitro groups controlling their amphiphilic characters.

The synthesis of a series of 4′-substituted hydroxybutyl pyrazine analogues of the anti-herpes compound, acyclovir, is described. The compounds were characterized with 1H and 13C nmr, mass and IR spectroscopy. Antiviral (HSV-1, CMV, Cox B4, HIV-1) properties of these compounds were examined. None of these compounds were active against these viruses.

New porphyrins bearing glycosyl groups and alanine moieties to improve targeting on malignant cells were synthesised in four steps. Fluorescence properties were extensively determined and indicated aggregated formation in water. These compounds produced 1O2. Photocytotoxicity of these molecules against K562 Leukemia cell line was compared to the effect of hematoporphyrin. © 1997 Published by Elsevier Science Ltd.

Cinq nouveaux alkyl sulfonates de sodium R(R)CH—SO3 Na a deux chaines egales variant de 7 a 11 atomes de carbones ont ete synthetises et purifies.La solubilite en fonction de la temperature a ete etudiee dans l'eau pure.A partir des mesures de tension superficielle en fonction de la concentration, la courbe γ = f (log C) a permis la determination des CMC et de l'exces de surface. Dans la serie homologue, on observe une relation lineaire de la forme log CMC = A + Bn, n etant le nombre total de carbones. L'aire occupee par molecule est la meme pour tous les termes de la serie.La tension superficielle, au-dela de la CMC, diminue lorsque n augmente.En presence de NaCI, l'evolution de la CMC en fonction de la salinite permet de calculer le degre d'ionisation des micelles.