Novel Synthesis of Substituted 2-Trifluoromethyl and 2-Perfluoroalkyl N-Arylpyridinium Compounds-Mechanistic Insights.

We report a new one-pot synthesis of 2-trifluoromethylated/2-perfluoroalkylated N-aryl-substituted pyridiniums, 5,6,7,8-tetrahydroquinoliniums and 6,7,8,9-tetrahydro-5H-cyclohepta[b]-pyridinium compounds starting from an activated ß-dicarbonyl analogue (here a perfluoro-alkylated gem-iodoacetoxy derivative), an aromatic amine and a (cyclic or acyclic) ketone. The key step of this multicomponent reaction, involves the formation of a 3-perfluoroalkyl-N,N'-diaryl-1,5-diazapentadiene intermediate, various examples of which were isolated and characterized for the first time, together with investigation of their reactivity. We propose a mechanism involving a concurrent inverse electron demand Diels-Alder or Aza-Robinson cascade cyclisation, followed by a bis-de-anilino-elimination. Noteworthy, a meta-methoxy substituent on the aniline directs the reaction towards a 2-perfluoroalkyl-7-methoxyquinoline, resulting from the direct cyclization of the diazapentadiene intermediate, instead of pyridinium formation. This is the first evidence of synthesis of pyridinium derivatives from activated ß-dicarbonyls, ketones, and an aromatic amine, the structures of which (both reactants and products) being analogous to species involved in biological systems, especially upon neurodegenerative diseases such as Parkinson's. Beyond suggesting chemical/biochemical analogies, we thus hope to outline new research directions for understanding the mechanism of in vivo formation of pyridiniums, hence possible pharmaceutical strategies to better monitor, control or prevent it.

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 3alpha/beta, the latter on being consistent with a decrease in beta-catenin activity and mRNA levels of various beta-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.

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.

Novel synthesis of 2-(trifluoromethyl)- and 2-(perfluoroalkyl)-2-hydroxy-2H-chromenes and their regiospecific reaction with silyl enol ethers.

The synthesis of substituted 2-(trifluoromethyl)- and 2-(perfluoroalkyl)-2-hydroxy-2H-chromenes 2a-o was achieved in good yields by intramolecular cyclization of 3-(perfluoroalkyl)-3-phenoxypropenals 1 in the presence of aluminum chloride. Then a Lewis acid mediated nucleophilic reaction with silyl enol ethers 3 proceeded with complete regiospecificity to afford 4-functional 2-(trifluoromethyl)- and 2-(perfluoroalkyl)-4H-chromenes 4a-p with high yields.

Novel synthesis, reactivity, and stereochemistry of substituted 3-trifluoromethyl- and 3-perfluoroalkyl-3-phenoxyprop-2-enal.

Substituted 3-phenoxy-3-perfluoroalkylprop-2-enals 3a-s are synthesized in high yields starting from a gem-iodoacetoxy derivative 1 and phenoxides 2. Then efficient syntheses of push-pull derivatives 4, 5,8a,b, and nonconjugated analogues 6 and 7 illustrate the synthetic potentialities of 3. Stereochemical studies of these perfluoroalkyl-containing trisubstituted olefinic derivatives 3-8b revealed that the (4)J(CF) coupling constant observed in the (13)C NMR spectra was crucial in the determination of their configurations and conformations in solution. The solvent polarity effect on the stereochemistry of push-pull compounds 3-5 and 8a,b was studied. Unusual significant medium polarity effect on the stereochemistry of imino enol ether derivative 4 was observed.

New regiospecific synthesis of 2-trifluoromethyl-1,5 diazapentadiene compounds and of 2-trifluoromethylquinolines, their cyclization products.

2-trifluoromethylquinolines 5 are synthesized in high yields using a perfluoroalkylated gem-iodoacetoxy derivative 3 and arylamines 4. The intermediate of this reaction, 2-trifluoromethyl-1,5-diazapentadiene compound 6, was isolated. The procedures are easy, and yields are in general high. This sequence represents a valuable new synthesis of substituted 2-trifluoromethylquinolines and of 2-trifluoromethyl-diazapentadienes (vinamidine compounds).