Zohra Benfodda

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.

Metabolic intervention on lipid synthesis converging pathways abrogates prostate cancer growth

One of the most conserved features of all cancers is a profound reprogramming of cellular metabolism, favoring biosynthetic processes and limiting catalytic processes. With the acquired knowledge of some of these important changes, we have designed a combination therapy in order to force cancer cells to use a particular metabolic pathway that ultimately results in the accumulation of toxic products. This innovative approach consists of blocking lipid synthesis, at the same time that we force the cell, through the inhibition of AMP-activated kinase, to accumulate toxic intermediates, such as malonyl-coenzyme A (malonyl-CoA) or nicotinamide adenine dinucleotide phosphate. This results in excess of oxidative stress and cancer cell death. Our new therapeutic strategy, based on the manipulation of metabolic pathways, will certainly set up the basis for new upcoming studies defining a new paradigm of cancer treatment.

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.

Advances in the synthesis of α-quaternary α-ethynyl α-amino acids

Abstractα-Quaternary α-ethynyl α-amino acids are an important class of non-proteinogenic amino acids that play an important role in the development of peptides and peptidomimetics as therapeutic agents and in the inhibition of enzyme activities. This review provides an overview of the literature concerning synthesis and applications of α-quaternary α-ethynyl α-amino acids covering the period from 1977 to 2015.

Synthesis of 1,4-disubstituted 1,2,3-triazole Derivatives Using Click Chemistry and their Src Kinase Activities.

BACKGROUND Tyrosine kinases (TK) are enzymes that catalyze the phosphorylation of tyrosine residues on proteins by the transfer of phosphate moiety of ATP. TK are key regulators of various cell functions, such as cellular growth, proliferation, migration, differentiation, and apoptosis. Src mutations and/or overexpression has been correlated with tumor growth, metastasis, and angiogenesis [4,5]. Thus, the design and the discovery of novel Src kinase inhibitors remains critically important. METHODS A series of 1,4-disubstituted 1,2,3-triazoles derivatives were designed and prepared as potential inhibitors for Src kinase. In this manuscript, all of the designed compounds were screened via molecular docking using PLANTS as virtual screening software to identify new inhibitors of Src kinase. Subsequently, all of the screened compounds were synthesized via Huisgens 1,3-dipolar cycloaddition between terminal alkynes (1) and methyl 2-azidoacetate (2) with Cu(I) in excellent yields at room temperature. RESULTS In the present study, we report the design and the synthesis of a series of 1,4-disubstituted 1,2,3-triazoles involving one pot condensation of methyl 2-azidoacetate and different terminal alkynes. All the synthesized triazoles were characterized by IR, 1 H, 13 C, 19 F NMR, and HRMS. They were investigated as inhibitors of Src kinase. CONCLUSION A series of 1,4-disubstituted 1,2,3-triazole compounds were synthesized through an easy, convenient Cu(I) catalyzed click reaction and evaluated for their Src kinase activity. Compound 3m exhibited significant inhibitory activity against Src Kinase. These results, along with molecular design docking observations, are significant evidence to demonstrate the compound 3m could be optimized as a potential Src kinase inhibitor in further studies.

A Convenient Synthesis of N-Functionalized Perfluoroalkanesulfonamides

This article describes the synthesis of new N-functionalized perfluoroalkanesulfonamides (5) with two sulfonamides functionalities. Perfluoroalkanesulfonyl fluoride underwent a reaction with 2-chloroethylamine hydrochloride or 3-bromopropylamine hydrobromide to give N-(2-chloroethyl or 3-bromopropyl) perfluoroalkanesulfonamides (1). Reaction of (1) with potassium thiocyanate gave N-(2-thiocyanatoethyl or 3-thiocyanatopropyl) perfluoroalkanesulfonamides (3). The sulfonyl chloride derivatives (4) were prepared by reaction of 3 with sulfuryl chloride. In the last step, 4 reacted with ammonia to give the bis sulfonamides derivatives (5). The structures of all new compounds prepared were determined by 1H, 19F, and 13C NMR spectroscopies and by HR-MS.

Synthesis, Anticancer Activity and Computational SAR Analysis ofAcylsulfonylpiperazines Derivatives

A series of 1-acyl-4-sulfonylpiperazine derivatives has been prepared. The antiproliferative effect of these compounds was evaluated in vitro against human prostate cancer cell line C4-2, several among them exhibited interesting growth inhibitory against this particular cell line. Finally, a molecular modeling study was employed to analyze the structure/activity relationships (SAR) of these novel compounds..