ABSTRACT
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.
Subject(s)
Angiotensin II Type 1 Receptor Blockers/chemistry , Angiotensin II Type 1 Receptor Blockers/pharmacology , Drug Design , PPAR gamma/agonists , Angiotensin II Type 1 Receptor Blockers/chemical synthesis , Animals , Chromans/chemical synthesis , Chromans/chemistry , Chromans/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Ligands , MCF-7 Cells , Male , Molecular Docking Simulation , PPAR gamma/metabolism , Rats, Wistar , Receptor, Angiotensin, Type 1/metabolism , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
15-Deoxy-∆12,14-prostaglandin J2 (15dPGJ2) is a natural agonist of peroxisome proliferator-activated receptor γ (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.
Subject(s)
Breast Neoplasms/metabolism , PPAR gamma/chemistry , Prostaglandin D2/analogs & derivatives , Binding Sites/genetics , Biotinylation/methods , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Models, Molecular , Molecular Docking Simulation , PPAR gamma/agonists , PPAR gamma/genetics , Prostaglandin D2/chemistry , Prostaglandin D2/pharmacology , Thiazolidinediones/pharmacologyABSTRACT
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.
