Homoleptic zincate-promoted room-temperature halogen-metal exchange of bromopyridines.

Homoleptic lithium tri- and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine-metal exchanges were realized at room temperature with a substoichiometric amount of nBu(4)ZnLi(2)·TMEDA reagent (1/3 equiv; TMEDA=N,N,N',N'-tetramethylethylenediamine). This reactivity contrasted with that of tBu(4)ZnLi(2)·TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N···Li stabilized polypyridyl zincates in the reaction. The one-pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C-Zn bonds in bromopyridines enabled us to perform efficient Negishi-type cross-couplings.

Synthesis and evaluation of new designed multiple ligands directed towards both peroxisome proliferator-activated receptor-γ and angiotensin II type 1 receptor.

Because of the complex biological networks, many pathologic disorders fail to be treated with a molecule directed towards a single target. Thus, combination therapies are often necessary, but they have many drawbacks. An alternative consists in building molecules intended to interact with multiple targets, called designed multiple ligands. We followed such a strategy in order to treat metabolic syndrome, by setting up molecules directed towards both type 1 angiotensin II (AT1) receptor and peroxisome proliferator-activated receptor-γ (PPAR-γ). For this purpose, many molecules were prepared by merging both pharmacophores following three different strategies. Their ability to activate PPAR-γ and to block AT1 receptors were evaluated in vitro. This strategy led to the preparation of many new PPAR-γ activating and AT1 blocking molecules. Among them, some exhibited both activities, highlighting the convenience of this approach.

Biotinylation enhances the anticancer effects of 15d­PGJ2 against breast cancer cells.

15-Deoxy-∆12,14-prostaglandin J2 (15d­PGJ2) is a natural agonist of peroxisome proliferator-activated receptor Î³ (PPARγ) that displays anticancer activity. Various studies have indicated that the effects of 15d­PGJ2 are due to both PPARγ-dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15d­PGJ2 (b­15d­PGJ2) on hormone-dependent MCF­7 and triple­negative MDA­MB­231 breast cancer cell lines. b­15d­PGJ2 inhibited cell proliferation more efficiently than 15d­PGJ2 or the synthetic PPARγ agonist, efatutazone. b­15d­PGJ2 was also more potent than its non-biotinylated counterpart in inducing apoptosis. We then analyzed the mechanisms underlying this improved efficiency. It was found not to be the result of biotin receptor-mediated increased incorporation, since free biotin in the culture medium did not decrease the anti-proliferative activity of b­15d­PGJ2 in competition assays. Of note, b­15d­PGJ2 displayed an improved PPARγ agonist activity, as measured by transactivation experiments. Molecular docking analyses revealed a similar insertion of b­15d­PGJ2 and 15d­PGJ2 into the ligand binding domain of PPARγ via a covalent bond with Cys285. Finally, PPARγ silencing markedly decreased the cleavage of the apoptotic markers, poly(ADP-ribose) polymerase 1 (PARP­1) and caspase­7, that usually occurs following b­15d­PGJ2 treatment. Taken together, our data indicate that biotinylation enhances the anti-proliferative and pro-apoptotic activity of 15d­PGJ2, and that this effect is partly mediated via a PPARγ-dependent pathway. These results may aid in the development of novel therapeutic strategies for breast cancer treatment.