Diaryl ether and diaryl thioether syntheses on solid supports via copper (I)-mediated coupling.
An efficient method to synthesize diaryl ethers and thioethers on solid supports is described. Starting from immobilized phenols or arylhalides, coupling with an access of aryliodides/arylbromides or phenolic/thiophenolic substrates in solution was successful in the presence of CuCl and Cs(2)CO(3) as base. Coupling conditions known from solution-phase syntheses of diaryl ethers have been effectively modified and adapted to solid-phase synthesis. Optimized conditions enabled the coupling of sterically hindered and/or electronically deactivated aryl moieties. After coupling, a newly developed diversity-generating linker based on cinnamic acid allowed the diaryl ethers to be cleaved from the resin either via saponification/transesterification or via ozonolysis. Latter offers the possibility of generating several additional compounds by simple variation of the cleavage conditions. The target substances were generally isolated in good to excellent yields and high purities.
Discovery of potent and selective sirtuin 2 (SIRT2) inhibitors using a fragment-based approach.
Sirtuin 2 (SIRT2) is one of the sirtuins, a family of NAD(+)-dependent deacetylases that act on a variety of histone and non-histone substrates. Accumulating biological functions and potential therapeutic applications have drawn interest in the discovery and development of SIRT2 inhibitors. Herein we report our discovery of novel SIRT2 inhibitors using a fragment-based approach. Inspired by the purported close binding proximity of suramin and nicotinamide, we prepared two sets of fragments, namely, the naphthylamide sulfonic acids and the naphthalene-benzamides and -nicotinamides. Biochemical evaluation of these two series provided structure-activity relationship (SAR) information, which led to the design of (5-benzamidonaphthalen-1/2-yloxy)nicotinamide derivatives. Among these inhibitors, one compound exhibited high anti-SIRT2 activity (48 nM) and excellent selectivity for SIRT2 over SIRT1 and SIRT3. In vitro, it also increased the acetylation level of α-tubulin, a well-established SIRT2 substrate, in both concentration- and time-dependent manners. Further kinetic studies revealed that this compound behaves as a competitive inhibitor against the peptide substrate and most likely as a noncompetitive inhibitor against NAD(+). Taken together, these results indicate that we have discovered a potent and selective SIRT2 inhibitor whose novel structure merits further exploration.
Secoiridoids from Olea europaea
Abstract Three new secoiridoids have been isolated from the leaves of Olea europaea along with the previously reported. The compounds were identified by spectral means.