Synthesis of enantiopure α-Tfm-proline and α-Tfm-pipecolic acid from oxazolo-pyrrolidines and -piperidines.

Enantiopure α-Tfm-proline and α-Tfm-pipecolic acid were synthesized starting from commercially available diesters and ethyl trifluoroacetate. A Strecker type reaction on intermediate chiral Tfm-oxazolo-pyrrolidine and -piperidine provided the corresponding nitrile precursor of enantiopure (R) and (S) α-Tfm-proline and α-Tfm-pipecolic acid. The C-terminal peptide coupling reaction of α-Tfm-pipecolic acid has been successfully achieved.

"CO" as a Carbon Bridge to Build Complex C2-Branched Glycosides Using a Palladium-Catalyzed Carbonylative Suzuki-Miyaura Reaction from 2-Iodoglycals.

Development of a palladium-catalyzed carbonylative Suzuki-Miyaura coupling reaction between 2-iodoglycal partners and diverse aryl- and alkenyl-boronic acids is presented, leading to original 2-ketoglycals. The newly formed carbonyl link could be exploited to access 2-aryl/alkenyl-methylene-α-glucopyranoside scaffolds via a three-step sequence including an indium-mediated Ferrier-type reaction.

Orthogonal 19 F-Labeling for Solid-State NMR Spectroscopy Reveals the Conformation and Orientation of Short Peptaibols in Membranes.

Peptaibols are promising drug candidates in view of their interference with cellular membranes. Knowledge of their lipid interactions and membrane-bound structure is needed to understand their activity and should be, in principle, accessible by solid-state NMR spectroscopy. However, their unusual amino acid composition and noncanonical conformations make it very challenging to find suitable labels for NMR spectroscopy. Particularly in the case of short sequences, new strategies are required to maximize the structural information that can be obtained from each label. Herein, l-3-(trifluoromethyl)bicyclopent[1.1.1]-1-ylglycine, (R)- and (S)-trifluoromethylalanine, and 15 N-backbone labels, each probing a different direction in the molecule, have been combined to elucidate the conformation and membrane alignment of harzianin HK-VI. For the short sequence of 11 amino acids, 12 orientational constraints have been obtained by using 19 F and 15 N NMR spectroscopy. This strategy revealed a ß-bend ribbon structure, which becomes realigned in the membrane from a surface-parallel state towards a membrane-spanning state, with increasing positive spontaneous curvature of the lipids.

Structural Behavior of the Peptaibol Harzianin HK VI in a DMPC Bilayer: Insights from MD Simulations.

Microsecond molecular dynamics simulations of harzianin HK VI (HZ) interacting with a dimyristoylphosphatidylcholine bilayer were performed at the condition of low peptide-to-lipid ratio. Two orientations of HZ molecule in the bilayer were found and characterized. In the orientation perpendicular to the bilayer surface, HZ induces a local thinning of the bilayer. When inserted into the bilayer parallel to its surface, HZ is located nearly completely within the hydrophobic region of the bilayer. A combination of solid-state NMR and circular dichroism experiments found the latter orientation to be dominant. An extended sampling simulation provided qualitative results and showed the same orientation to be a global minimum of free energy. The secondary structure of HZ was characterized, and it was found to be located in the 310-helical family. The specific challenges of computer simulation of nonpolar peptides are discussed briefly.

Access to Complex C2-Branched Glycoconjugates via Palladium-Catalyzed Aminocarbonylation Reaction of 2-Iodoglycals.

A convenient and straightforward synthesis of 2-amidoglycals through a palladium-catalyzed aminocarbonylation reaction between 2-iodoglycal partners and diverse amines in the presence of a "CO" source has been developed. Several amines such as aliphatics, benzylics, or aromatics are compatible with our reaction conditions as well as sulfonamides. Further deprotection steps have been successfully applied, leading to glycoside mimics. This method constitutes a new route to access original glycopeptide- and glycolipid-type analogues possessing a C-C bond at the C2-position.

New desulfured troglitazone derivatives: Improved synthesis and biological evaluation.

Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer (TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.

Access to C-aryl/alkenylglycosides by directed Pd-catalyzed C-H functionalisation of the anomeric position in glycal-type substrates.

Directed palladium-catalyzed C-H functionalisation of C2-amido glycals onto the anomeric position is described as a novel route to C-aryl/alkenylglycosides. An aminoquinoline-type directing group was used to successfully introduce diverse (hetero)aryl and alkenyl groups at position 1 of the sugar (20 examples). Its application to the synthesis of a dapagliflozin analogue is presented.

Reprofiling of Troglitazone Towards More Active and Less Toxic Derivatives: A New Hope for Cancer Treatment?

The existence of unresponsive tumors and the appearance of resistant tumors during the course of treatments both justify that we increase urgently the panel of pharmacological molecules able to fight cancer. An interesting strategy is drug reprofiling (also known as drug repositioning, drug repurposing or drug retasking) that consists of identifying and developing new uses for existing drugs. This review illustrates drug reprofiling with troglitazone (TGZ), a synthetic PPARγ agonist initially used for the treatment of type II diabetes. The fact that TGZ also displays anticancer effects is known since the end of the nineties but its development as an anticancer agent was slowed down due to hepatotoxic side effects. Part of the knowledge available for TGZ, mainly the molecular basis for PPARγ activation, its metabolization pathways and the side effects on hepatocytes, were taken into account to elaborate new molecules. Key findings were that unsaturated TGZ derivatives, when compared to TGZ, do not activate PPARγ, exhibit a higher efficiency on cancer cells and a lower toxicity towards hepatocytes. However, a weakness is that the mechanisms involved in the anticancer effects are still not completely understood and that the efficiency of such derivatives has not yet been completely studied in vivo. Data about this point should become available very soon from animal models and this will be a prerequisite to initiate clinical trials with these potential new anticancer drugs developed from a drug repurposing strategy.

Optimization of troglitazone derivatives as potent anti-proliferative agents: towards more active and less toxic compounds.

Δ2-Troglitazone derivatives were shown to exhibit anti-proliferative activity in a PPARγ-independent manner. We prepared various compounds in order to increase their potency and decrease their toxicity towards non-malignant primary cultured hepatocytes. Many compounds induced viabilities less than 20% at 10 µM on various cancer cell lines. Furthermore, five of them showed hepatocyte viability of 80% or more at 200 µM. In addition, compounds 17 and 18 exhibited promising maximum tolerated doses on a murine model, enabling future investigations.

α- and ß-hydrazino acid-based pseudopeptides inhibit the chymotrypsin-like activity of the eukaryotic 20S proteasome.

We describe the synthesis of a library of new pseudopeptides and their inhibitory activity of the rabbit 20S proteasome chymotrypsin-like (ChT-L) activity. We replaced a natural α-amino acid by an α- or a ß-hydrazino acid and obtained inhibitors of proteasome up to a submicromolar range (0.7 µM for molecule 24b). Structural variations influenced the inhibition of the ChT-L activity. Models of inhibitor/20S proteasome complexes corroborated the inhibition efficacies obtained by kinetic studies.

Synthesis and conformational studies of peptidomimetics containing a new bifunctional diketopiperazine scaffold acting as a beta-hairpin inducer.

A practical synthesis of a new bifunctional diketopiperazine (DKP) scaffold 1, formally derived from the cyclization of L-aspartic acid and (S)-2,3-diaminopropionic acid, is reported. DKP-1 bears a carboxylic acid and an amino functionalities in a cis relationship, which have been used to grow peptide sequences. Tetra-, penta-, and hexapeptidomimetic sequences were prepared by solution-phase peptide synthesis (Boc strategy). Conformational analysis of these derivatives was carried out by a combination of 1H NMR spectroscopy, IR spectroscopy, CD spectroscopy, and computer modeling, and reveals the formation of beta-hairpin mimics involving 10-membered and 18-membered H-bonded rings and a reverse turn of the growing peptide chain.