Michel Chanon

Photodynamic activities of silicon phthalocyanines against achromic M6 melanoma cells and healthy human melanocytes and keratinocytes

Dichlorosilicon phthalocyanine (Cl2SiPc) and bis(tri-n-hexylsiloxy) silicon phthalocyanine (HexSiPc) have been evaluated in vitro as potential photosensitizers for photodynamic therapy (PDT) against the human amelanotic melanoma cell line M6. Each photosensitizer is dissolved in a solvent-PBS mixture, or entrapped in egg-yolk lecithin liposomes or in Cremophor EL micelles. The cells are incubated for 1 h with the sensitizer and then irradiated for 20 min, 1 h or 2 h (lambda > 480 nm, 10 mW cm-2). The photocytotoxic effect is dependent on the photosensitizer concentration and the light dose. Higher phototoxicity is observed after an irradiation of 2 h: treatment with a solution of photosensitizer (2 x 10(-9) M) leads to 10% (HexSiPc in egg-yolk lecithin liposomes) or 20% (Cl2SiPc in DMF-PBS solution) cell viability. After 1 h incubation and 20 min of light exposure, the photodynamic effect is connected with the type of delivery system used. For HexSiPc, lower cell viability is found when this photosensitizer is entrapped in egg-yolk lecithin instead of solvent-PBS or for Cremophor EL micelles with Cl2SiPc. Liposome-delivered HexSiPc leads to lipid damage in M6 cells, illustrated by an increase of thiobarbituric acid-reacting substances (TBARs), but the change is not significant with Cremophor EL. The same is observed for the antioxidative defences after photodynamic stress. The cells irradiated with HexSiPc entrapped in liposomes display an increase of superoxide dismutase (SOD) activity and a decrease of glutathione (GSH) level, glutathione peroxidase (GSHPx) and catalase (Cat) activities.

A new and simple approach to chemical complexity. Application to the synthesis of natural products.

A new approach to describe the complexity of chemical structures is proposed. This index is simple and can be easily programmed. It derives from Whitlocks index and, despite its empirical character, provides results paralleling those obtained with the mathematical Bertz index. It has been applied to follow the strategic progress of some natural product syntheses.

Photophysical and Redox Properties of a Series of Phthalocyanines: Relation with Their Photodynamic Activities on TF‐1 and Daudi Leukemic Cells

Abstract— The photodynamic therapy (PDT) efficiency of five phthalocyanines, chloroaluminum phthalocyanine (AlPc), dichlorosilicon phthalocyanine (SiPc), bis(tri‐n‐hexylsi‐loxy)silicon phthalocyanine (PcHEX), bis(triphenyl‐siloxy)silicon phthalocyanine (PcPHE) and nickel phthalocyanine (NiPc), was assessed on two leukemic cell lines TF‐1 and erythroieukemic and B lymphoblastic cell lines, Daudi, respectively. AlPc showed the best photocytotox‐icity leading to 0.008 surviving fraction at 2 × 10−9M for TF‐1 and 4 × 10−9M for Daudi. At 5 × 10−7M, SiPc and PcHEX induced a significant photokilling, whereas NiPc and PcPHE were inactive. Laser flash photolysis and photoredox properties of the phthalocyanines were investigated to try to relate these parameters with the biological effects. AlPc showed the longest triplet lifetime: 484 fis in dimethyl sulfoxide/H2O. This value was increased up to 820 u.s when AlPc was complexed with human serum albumin used as a membrane model. Such an enhancement was not observed with the silicon phthalocyanines. Upon irradiation, all the phthalocyanines generated singlet oxygen with 0.29–0.37 quantum yield values. The reduction potentials of the excited states obtained from measurement in the ground state and energy of the excited triplets show that AlPc is the best electron acceptor. The in vitro photocytotoxicity observed and the measured parameters are in agreement with a key role of electron transfer in PDT assays involving these phthalocyanines.

SYNTHESIS AND CHARACTERIZATION OF A SERIES OF HEXADECACHLORINATED PHTHALOCYANINES

Abstract Several methods known for the preparation of metallated (Al, Co, Li, Si, Zn) or unmetallated phthalocyanines were explored to synthesize the corresponding hexadecachlorophthalocyanines. The one pot condensation of tetrachlorophthalic anhydride or tetrachlorophthalonitrile in molten urea in the presence or not of a metal salt, led to chlorinated phthalocyanines in 5–36% yield depending on the metal. Al and Zn atoms can be inserted in free hexadecachlorophthalocyanine in 46–80% yield. The substitution of the two lithium atoms of the dilithium phthalocyanine by Al salt get to 68% aluminum phthalocyanine. All phthalocyanines synthesized were purified and fully characterized. 1 H, 13 C and 27 Al NMR data were obtained. As a rule, the Q band of the UV–Vis spectrum displayed a 30 nm bathochromic shift relative to the band of unchlorinated compounds.

Preferential photoinactivation of leukemia cells by aluminum phthalocyanine

The efficacy of chloroaluminum phthalocyanine (AlPc) for photodynamic therapy (PDT) has been evaluated in vitro on acute myeloid leukemia (AML) cells, normal peripheral blood leukocytes (PBL) and mobilized peripheral blood stem cells (mPBSC). The selectivity of the treatment has been evaluated by mixing PBL and TF-1, an erythroleukemic cell line. Upon photoradiation, this photosensitizer leads to a significant and preferential photokilling of leukemia cells in comparison to normal cells. The use of stimulated lymphocytes in PBL/TF-1 mixtures instead of resting cells also leads to a preferential killing towards TF-1 although activated PBL are more affected than resting PBL. The analysis of AlPc intracellular emission by flow cytometry shows that the uptake of the dye by leukemia cells is faster. This good efficacy towards AML and the observed lower phototoxicity towards normal cells (PBL, normal progenitors) suggest that this phthalocyanine is a potential bone marrow purging agent.

Gear effect—10: Conformational aspects of the positive or negative buttressing effects of methyl groups: polymethylpyridines

Abstract The effect of the shape of a methyl group on reactivity, which cannot be accounted for by considering a methyl group as a spherical substituent with the appropriate van der Waals radius, was considered in kinetics of alkylalion of substituted pyridines and barriers to rotation and ground state conformations of an isopropyl group attached to a planar framework. The perturbation of a methyl group by an o-methyl group is accounted for by a unique conformational explanation which involves the polyhedral shape of the methyl group.

EFFICIENT PHOTODYNAMIC ACTION OF VICTORIA BLUE BO AGAINST THE HUMAN LEUKEMIC CELL LINES K‐562 AND TF‐1

Abstract— Photodynamic induced cytotoxicity by Victoria blue BO (VB‐BO), merocyanine 540 (MC540), Nile blue A (NB) and 4‐tetrasulfonatophenyl‐porphyrin (4‐TSPP) has been studied on two human leukemic cell lines: K‐562 and TF‐1. Cells were incubated with dyes and irradiated with different doses of white light. Cell survival was assessed by propidium iodide (PI) staining using flow cytometry analysis. Concentrations of 5 x 10 8M VB‐BO were found to kill 75% of cells, and a concentration of 1 × 10−7M induced more than 99% of cell killing. To obtain the same cytotoxic level, the presence of 2.6 × 10−5M of MCS40 during irradiation was needed. Under the conditions used, NB was ineflective as a photosensitizer, although uptake studies showed that this dye was taken by the cells in much greater amounts than any other studied dye. Cell cycle distribution of TF‐1 cells, surviving MC540 or VB‐BO photoscnsitization has bccn studied by flow cytometry analysis after staining with Hoechst 33342 and PI. It was found that cells in G1 phase were slightly more resistant toward MCS40– and VB‐BO‐mediated photosensitization than cells in other phascs of the ccll cycle

Supported redox photosensitizers for the activation of alkylaromatics towards oxygen

Abstract Several 2,4,6-trinitrobenzene derivatives and 2,4,7-trinitrofluorenone were grafted on silica and used as supported electron-acceptor photosensitizers. The grafting was effected by two methods: reaction of a halogenated derivative with aminopropyl silica or condensation on silica of the electron acceptor previously transformed into monochlorosilane. The oxidation of 4-methyl anisole by redox photosensitization was used as a test reaction to compare the efficiencies of these heterogeneous photosensitizers. Silica grafted 2,4,6-trinitrobenzene was then used to oxidize 4-substituted methyl aromatic compounds into the corresponding aromatic aldehydes with 76%–90% yields and 100% selectivity.

5-(ENDO)-isopropylsulfonyl- 5-(EXO)-phenyl -2-norbornene : X-ray and molecular mechanics assessment of the high efficiency of this new radical clock

Abstract The synthesis of 5-(endo)-(1′-chloro-1′-methylethyl)sulfonyl-5-(exo)-phenyl- 2-norbornene a new highly efficient radical clock is described. The rate of the intramolecular radical cyclization (addition of a C-centered α-sulfonyl radical on a double bond) is presently one of the fastest (109s−1-1). In order to explain this interesting value, force field calculations (MM2 method) and X ray analysis were performed for the title compound and for the corresponding 5-(exo)-cyano compound. The enhancement of the efficiency in the case of the former is mainly due to the effect of the (exo)-phenyl which pushes the wholeendo substituent toward the double bond of the norbornenyl group.

A highly efficient radical clock as a probe of the mechanism of sulfone halogenation by perhaloalkanes

Abstract Halogenation of (endo)-5-(2-i-propylsulfonyl)-2-norbornene 5, a new highly efficient radical probe, shows that if an SET mechanism was occurring in the -α-halogenation of sulfones by perhaloalkanes, it would have to involve a reaction step in which a C-centered radical reacts with CX4 . at a rate greater than 1010 s−1.