Characterization of the SNAG and SLUG Domains of Snail2 in the Repression of E-Cadherin and EMT Induction: Modulation by Serine 4 Phosphorylation

Snail1 and Snail2, two highly related members of the Snail superfamily, are direct transcriptional repressors of E-cadherin and EMT inducers. Previous comparative gene profiling analyses have revealed important differences in the gene expression pattern regulated by Snail1 and Snail2, indicating functional differences between both factors. The molecular mechanism of Snail1-mediated repression has been elucidated to some extent, but very little is presently known on the repression mediated by Snail2. In the present work, we report on the characterization of Snail2 repression of E-cadherin and its regulation by phosphorylation. Both the N-terminal SNAG and the central SLUG domains of Snail2 are required for efficient repression of the E-cadherin promoter. The co-repressor NCoR interacts with Snail2 through the SNAG domain, while CtBP1 is recruited through the SLUG domain. Interestingly, the SNAG domain is absolutely required for EMT induction while the SLUG domain plays a negative modulation of Snail2 mediated EMT. Additionally, we identify here novel in vivo phosphorylation sites at serine 4 and serine 88 of Snail2 and demonstrate the functional implication of serine 4 in the regulation of Snail2-mediated repressor activity of E-cadherin and in Snail2 induction of EMT

Selective Anti-Markovnikov Cyclization and Hydrofluorination2 Reaction in Superacid HF/SbF5: A Tool in the Design of Nitrogen-Containing (Fluorinated) Polycyclic Systems

International audienc

Superacid synthesis of halogen containing N-substituted-4-aminobenzene sulfonamides: New selective tumor-associated carbonic anhydrase inhibitors

International audienceA series of new, halogen containing N-substituted 4-aminobenzenesulfonamides were synthesized by using superacid HF/SbF5 chemistry and investigated as inhibitors of several human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, that is, the cytosolic hCA I and II and, the tumor-associated transmembrane isoforms hCA IX and XII. Despite the substitution of the sulfonamide function, the presence of fluorine atom(s) in b position of the sulfonamide function strongly favors hCA inhibition. A similar effect of the b-fluorinated alkyl substitution on the amino function has been also observed. Among the tested compounds, several chlorinated derivatives have been identified as selective nanomolar, tumor-associated isoforms inhibitors. These non-primary sulfonamides probably bind in the coumarin-binding site, at the entrance of the cavity, and not to the metal ion as the primary sulfonamide inhibitors

Superacid synthesized tertiary benzenesulfonamides and benzofuzed sultams act as selective hCA IX inhibitors: toward understanding a new mode of inhibition by tertiary sulfonamides

International audienceA series of tertiary (fluorinated) benzenesulfonamides was synthesized in superacid HF-SbF5. To circumvent the problem of the in situ iminium ion formation, proved by low temperature NMR experiments, a tandem superacid catalysed cross-coupling reaction was employed to synthesize the benzofuzed sultams analogues. These tertiary benzenesulfonamides were tested as inhibitors of human carbonic anhydrases (hCAs, EC 4.21.1). These compounds did not inhibit the widespread off target hCA II isoform and showed strong selectivity toward tumor-associated carbonic anhydrase isoform IX. A dramatic effect of the electronic and structural shape of the inhibitors on selectivity was demonstrated, confirming the non-zinc-bonding mode of inhibition of this class of sulfonamides. This work allowed identifying a highly selective hCA IX inhibitor lead in this series

Carbonic Anhydrases inhibitory effects of new benzenesulfonamides synthesized by using superacid chemistry

International audienceA series of benzofused sultams and fluorinated benzenesulfonamides were synthesized in superacid HF/SbF5 from simple N-allylic derivatives. Almost all of these original compounds showed micromolar inhibitory activities against carbonic anhydrases I and II. The fluorinated derivatives inhibit better the tumor-associated isoforms IX and XII, and one of the tested compounds showed inhibition in the nanomolar range

Keteniminium Ion-Initiated Cascade Cationic Polycyclization

International audienceA novel and efficient keteniminium-initiated cationic polycyclization is reported. This reaction, which only requires triflic acid or bistriflimide as promoters, affords a straightforward entry to polycyclic nitrogen heterocycles possessing up to three contiguous stereocenters and seven fused cycles. These complex, polycyclic molecules can be obtained in a single operation from readily available ynamides which were shown to be remarkable building blocks for multiple, consecutive cationic transformations

Synthetic deoxynojirimycin derivatives bearing a thiolated, fluorinated or unsaturated N-alkyl chain: identification of potent α-glucosidase and trehalase inhibitors as well as F508del-CFTR correctors.

International audienc

Catching elusive glycosyl cations in a condensed phase with HF/SbF₅ superacid

International audienceGlycosyl cations are universally accepted key ionic intermediates in the mechanism of glycosylation, the reaction that covalently links carbohydrates to other molecules. These ions have remained hypothetical species so far because of their extremely short life in organic media as a consequence of their very high reactivity. Here, we report the use of liquid hydrofluoric acid-antimony pentafluoride (HF/SbF5) superacid to generate and stabilize the glycosyl cations derived from peracetylated 2-deoxy and 2-bromoglucopyranose in a condensed phase. Their persistence in this superacid medium allows their three-dimensional structure to be studied by NMR, aided by complementary computations. Their deuteration further confirms the impact of the structure of the glycosyl cation on the stereochemical outcome of its trapping