Hubert Blancou

Abrogation of De novo Lipogenesis by Stearoyl-CoA Desaturase 1 Inhibition Interferes with Oncogenic Signaling and Blocks Prostate Cancer Progression in Mice

Increased de novo fatty acid (FA) synthesis is one hallmark of tumor cells, including prostate cancer. We present here our most recent results showing that lipid composition in human prostate cancer is characterized by an increased ratio of monounsaturated FA to saturated FA, compared with normal prostate, and evidence the overexpression of the lipogenic enzyme stearoyl-CoA desaturase 1 (SCD1) in human prostate cancer. As a new therapeutic strategy, we show that pharmacologic inhibition of SCD1 activity impairs lipid synthesis and results in decreased proliferation of both androgen-sensitive and androgen-resistant prostate cancer cells, abrogates the growth of prostate tumor xenografts in nude mice, and confers therapeutic benefit on animal survival. We show that these changes in lipid synthesis are translated into the inhibition of the AKT pathway and that the decrease in concentration of phosphatidylinositol-3,4,5-trisphosphate might at least partially mediate this effect. Inhibition of SCD1 also promotes the activation of AMP-activated kinase and glycogen synthase kinase 3α/β, the latter on being consistent with a decrease in β-catenin activity and mRNA levels of various β-catenin growth-promoting transcriptional targets. Furthermore, we show that SCD1 activity is required for cell transformation by Ras oncogene. Together, our data support for the first time the concept of targeting the lipogenic enzyme SCD1 as a new promising therapeutic approach to block oncogenesis and prostate cancer progression. Mol Cancer Ther; 9(6); 1740–54. ©2010 AACR.

Synthesis of terminally perfluorinated long-chain alkanethiols, sulfides and disulfides from the corresponding halides

Abstract Semifluorinated n -alkanethiols, symmetrical sulfides and disulfides bearing the chain(s) F(CF 2 ) n (CH 2 ) m with n =4, 6, 8, 10, and m =2, 11 have been prepared by various synthetic methods, starting from the corresponding iodides or bromides. Methods based on sodium hydrogen sulfide, commonly used to accomplish this conversion, treatment of the Bunte salt obtained from sodium thiosulfate, the basic hydrolysis of isothiouronium salts, the hydrolysis under mild conditions of thiophosphorates formed from sodium thiophosphate and the basic hydrolysis of thiol acetic acid derivatives, have been investigated and compared relatively to the selective synthesis of the title compounds. The thiolacetic route yields essentially the thiols with some amounts of disulfides. Results from thiourea appears similar. Sodium thiophosphate constitutes an excellent route for the synthesis of thioethers, particularly when starting from the bromides. The two classical methods based on sodium hydrogen sulfide and sodium thiosulfate exhibit poor selectivity. It has been possible to obtain all the sulfur compounds reported in the pure state.

Reactivite comparee des perfluoroiodoalcanes (RFI) et des perfluoroalcoyl-2 iodo-1 ethanes (RFC2H4I) en presence de couple metallique zinc-cuivre dans les solvants phosphates d'alcoyles

Abstract Reactivity of perfluoroalkyl iodides R F I and 1-perfluoroalkyl-2-iodoethanes R F C 2 H 4 I, in presence of a zinc-copper couple in alkyl phosphates solvents, is described. R F I and R F C 2 H 4 I react via an organometalllc route to give per- and poly-fluoroorganozinc (R F ZnI and R F C 2 H 4 ZnI) compounds. Then, in particular conditions, they react with alkyl to give phosphoro-fluorinated molecules (phosphinates, phosphine oxides, phosphines). The compoundss stabilities are studied.

Synthesis and investigation of inhibition effect of fluorinated sulfonamide derivatives on carbonic anhydrase.

Series of perfluoroalkanesulfonamides 1, sodium salt of perfluoroalkanesulfonamides 2 and polyfluoroalkanesulfonamides 3 derivatives were synthesized and characterized by (1)H NMR, (13)C NMR, (19)F NMR, IR and HRMS. Inhibition effects of these compounds on bovine carbonic anhydrase (bCA) and human carbonic anhydrase isoenzyme II (hCA) have been investigated. Comparing IC(50) values of the synthesized molecules 1, 2 and 3, it has been found that compound 2b is a more potent inhibitor than acetazolamide on hCA. Moreover 2b does not present cellular toxicity on sheep red globules.

Reactivite comparee des perfluoroiodoalcanes (RFI) et des perfluoroalcoyl-2 iodo-1 ethanes (RFCH2I) en presence de couple metalique zinc-cuivre dans un solvant dissociant particulier : le sulfolane (RF CnF2n+1, n pair)

Abstract Reactivity of perfluoroalkyl iodides (R F I) and perfluoroalkyl-2 iodide-1 ethanes (R F CH 2 CH 2 I), in the presence of a zinc-copper couple, in a particular dissociating solvent, “the sulfolane”, is described. R F I and R F CH 2 CH 2 I react via an organometallic route to give perfluoro-organozinc compounds. Then, R F CH 2 CH 2 I react with the sulfolane solvent. In this case, a diperfluoroalkyl-2 ethyl-1 sulfone (R F CH 2 CH 2 ) 2 SO 2 is obtained.

Synthèse d'acides ω perfluoroalkylalcanoı̈ques et d'ω perfluoroalkylalcanols

Resume Nous decrivons des syntheses adaptees des molecules de type C n F 2 n +1 (CH 2 ) m Y (Y=CO 2 H, CH 2 OH) lineaires pour lesquelles n =6,8 et m =4,5.

Synthèse de diamines à chaînes perfluoroalkylées

Abstract The addition of RFI to N-allyl phthalimide, in the presence of zinc, in different solvents(CH2Cl2/protic agent) has been studied. Under appropriate conditions this reactiongives 3-F-alkyl-2-iodopropane-l-N-phthalimides or 2,3-bis(F-alkyl methyl)butane-l,4-di-N-phthalimideswhich are hydrolysed to the corresponding diamines.

Synthese d'acides perfluoroalcane carboxylique et sulfinique par reduction electrochimique d'iodures de perfluoroalkyle sur cathode en fibres de carbone dans le solvant N,N dimethylformamide. Application a la synthese de perfluoro α,ω diacides.

Abstract The electrochemical reduction of C 6 F 13 I on a carbon fibre cathode in DMF as solvent and in the presence of SO 2 is studied. Depending on the water content of the solvent, perfluorohexyl sulfinic acid C 6 F 13 SO 2 H or perfluoropentyl carboxylic acid C 5 F 11 COOH are obtained. These reactions are applied to 1,4-diiodoperfluorobutane; by varying the composition of the solvent it has been possible to obtain the two diacidic compounds: HO 2 S(CF 2 ) 4 SO 2 H and HO 2 S(CF 2 ) 3 COOH.

Addition d'iodoperfluoroalcanes RFI (CnF2n + 1, n=4, 6, 8) au 2-méthyl-3-butyn-2-ol catalysée par le zinc dans différent solvants. Application à la synthèse de l'acétylénique à chaîne perfluorée

Abstract The addition of perfluoroalkyl iodides (R F I) to 2-methyl-3-butyn-2-ol activated by suspended zinc dust has been studied in different solvents and found to lead readily to perfluoroalkene iodides. The latter when treated with a base gave a perfluoroalkyne, R F CCH.

Addition of RFI (CnF2n+1I; n=4, 6, 8) to allyl alcohol catalyzed by zinc in different solvents: application to the synthesis of F-alkyl epoxypropanes

Abstract The addition of RFI to allyl alcohol catalyzed by zinc in different solvents has beenstudied. The adduct RFCH2CHICH2OH readily gives the corresponding F-alkyl epoxypropane.