The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein–coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human β2AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2-yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide], exhibiting a unique chemotype and low micromolar affinity for the β2AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the β2AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the β2AR. In cell-signaling studies, 15 inhibits cAMP production through the β2AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits β-arrestin recruitment to the activated β2AR. This study presents an allosteric small-molecule ligand for the β2AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.

•Garcinol had a chemopreventive effect on DMBA-induced oral squamous cell carcinoma.•Garcinol inhibits oral cancer cells proliferation, cell cycle and colony formation.•Garcinol induces oral cancer cells apoptosis.•Changing the C8 side chain of Garcinol will affect the inhibitory efficacy.Garcinol from the fruit rind of Garcinia indica shows anti-carcinogenic and anti-inflammatory properties, but its mechanism and key functional groups were still need to be identified. Our previous computer modeling suggested that the C8 side chain of Garcinol is so large that it may influence the bioactivity of the compound. 8-Me Garcinol, a derivative of Garcinol in which the bulky side chain at the C8 position of Garcinol is replaced with a much smaller methyl group, was synthesized through a 12-step procedure starting from 1,3-cyclohexanedione. The antitumor activity of Garcinol and 8-Me Garcinol was evaluated in vitro by MTT, cell cycle and cell apoptosis assays. The results showed that 8-Me Garcinol had weaker inhibitory activity on cells proliferation, and little effects on cell cycle and apoptosis in oral cancer cell line SCC15 cells when compared with Garcinol. All of the results indicated 8-Me Garcinol exerts weaker antitumor activity than Garcinol, and the C8 side chain might be an important active site in Garcinol. Changing the C8 side chain will affect the inhibitory effect of Garcinol.Download high-res image (37KB)Download full-size image

Four new POM-based hybrid compounds, namely, [Cu2(L1)3(H2O)2(P2W18O62)]·H2L1·4H2O (1), [Cu3(L2)6(P2W18O62)] (2), [Cu3(L3)5(H2O)(P2W18O62)]·4H2O (3) and [Cu3(L4)4(H2O)7(P2W18O62)]·26H2O (4) (L1 = 1,3-bis((1H-1,2,4-triazol-1-yl)methyl)benzene, L2 = 1,3-di(1H-1,2,4-triazol-1-yl)propane, L3 = 2-(1H-imidazol-2-yl)pyridine and L4 = 4-(1H-tetrazol-5-yl)pyridine), have been prepared under hydrothermal conditions. Compound 1 shows a three-dimensional (3D) framework with trinodal (4,4,6)-connected (3·42·5·66·72·83)(3·42·52·6)(3·42·62·7) topology. Compound 2 exhibits an unprecedented 3D framework with binodal (6,6)-connected SQC-888 topology. Compound 3 displays a two-dimensional (2D) structure with the existence of 2D → 3D interdigitation. In compound 4, {P2W18O62}6− is mono-supported by the linear tri-copper cluster {Cu3(H2O)L4}6+. In addition, the electrochemical properties and magnetic properties of 1–4 have also been studied.Graphical abstractFour POM-based hybrid compounds have been successfully prepared under hydrothermal conditions. Electrochemical analysis shows that 1–4-CPE display reversible redox properties and exhibit good electrocatalytic activity toward the reduction of nitrite. Magnetic study indicates an overall ferromagnetic interaction between the copper ions in 4.

Five new coordination polymers, namely, [Zn(HBTC)(L1)]·4H2O (1), [Zn3(BTC)2(L2)2(H2O)2]·2H2O (2), [Zn(HBTC)(L3)] (3), [Cd(HBTC)(L1)(H2O)]·H2O (4) and [Cd(H2BTC)2(L3)2]·2H3BTC (5) (H3BTC = 1,3,5-benzenetricarboxylic acid, L1 = 1,6-di(1,2,4-triazol-1-yl)hexane, L2 = 1,3-di(1,2,4-triazol-1-yl)propane and L3 = 1,3-bis((1,2,4-triazol-1-yl)methyl)benzene) have been successfully isolated under hydrothermal conditions. Compound 1 exhibits a rare 2D → 3D entangled structure with the coexistence of polycatenation and interdigitation. Compound 2 contains new trinodal (5.62)(52.6)(54.82) layers and features a 2D → 2D entangled network with the coexistence of polycatenation and polythreading motifs. Compound 3 shows a 2D → 2D polythreaded framework. When O–H⋯O hydrogen-bonding interactions are taken into consideration, the framework of 3 can be regarded as a 2-fold interpenetrating hms network. Compound 4 displays an unusual 2D → 3D interdigitated framework. Compound 5 displays a 1D chain structure. The thermal stabilities and fluorescence properties of compounds 1–5 have been investigated.

Two new coordination polymers, {[Zn3L2.5(μ3-OH)(H2O)3]·4H2O}n (1) and [Zn2L1.5(μ3-OH)(4,4′-bpy)0.5]n (2) (H2L = 2,5-bis(4-methylbenzoyl)terephthalic acid, 4,4′-bpy = 4,4′-bipyridine), have been hydrothermally synthesized and characterized by elemental analysis, IR spectroscopy, TG, PXRD and single crystal X-ray diffraction. Complex 1 possesses a 2D double-layer configuration with 48·62 network constructed with trinuclear zinc(II) clusters and L2− ligands, which extends into a 3D architecture via O–H···O interactions between coordinated water molecules and lattice water molecules. Complex 2 is a uninodal 8-connected 3D framework with a 424·64 network based on tetranuclear zinc(II) clusters as nodes. Moreover, the luminescent properties of complexes 1 and 2 were also investigated.Two zinc(II) coordination polymers were synthesized through hydrothermal reaction. Complex 1 possesses a 2D double-layer configuration with 48·62 network based on trinuclear zinc(II) clusters. When the 4,4′-bpy was added into the reaction system, we obtained complex 2 which is a uninodal 8-connected 3D framework with a 424·64 network based on tetranuclear zinc(II) clusters as nodes.Highlights► Two original coordination polymers have been synthesized. ► Complex 1 possesses a 2D double-layer based on trinuclear zinc(II) clusters. ► Complex 2 is a novel 3D framework based on tetranuclear zinc(II) clusters. ► The luminescent properties of complexes 1 and 2 were investigated.

A series of new 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives were designed and synthesized. Their cytotoxicity in vitro against six tumor cell lines (DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa) were evaluated by standard MTT assay. The pharmacological results showed that most of the newly synthesized podophyllotoxin derivatives displayed potent cytotoxicity against at least one of the tested tumor cells; and among the new derivatives, 11b was more potent than podophyllotoxin against HepG2 and Hela cell lines. Furthermore, 11b exhibited much better selectivity toward the normal cell lines L929 and Vero than etoposide, 5-Fu and podophyllotoxin. The possible antitumor mechanism of 11b is to inhibit the activity of DNA topoisomerase II, result in the S-phase arrest, and then cause apoptotic cell death.The synthesis and biological evaluation of antitumor activity for novel 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives are described.

Two serious three-dimensional (3D) lanthanide organic frameworks, {[Ln(Hbidc)(ox)1/2(H2O)]·H2O}n [Ln = Pr (1), Nb (2) and Sm (3)] (H3bidc = Benzimidazole-5,6-dicarboxylic acid, H2ox = oxalic acid) and [Ln(Hbidc)(ox)1/2]n [Ln = Eu (4) and Gd (5)], have been synthesized solvothermally under different temperature conditions. Their structures have been characterized by single-crystal X-ray diffraction, elemental analysis, IR spectra and thermogravimetric analysis. Structure analyses reveal that the five compounds exhibit similar 3D network structures that ox2− and Hbidc2− ligands showing the same coordination mode to link metal centers. The difference between the two kinds of compounds is that the coordination and lattice water molecules are absent in 4–5 due to the higher reaction temperature. Additionally, the luminescence properties of compounds 3 and 4 have been investigated in detail.Two series of 3D lanthanide organic frameworks have been synthesized solvothermally under different temperature conditions. Furthermore, the luminescence properties of compounds 3 and 4 have been investigated as well.Highlights► Two series of 3D lanthanide-organic frameworks have been synthesized solvothermally. ► The lattice and coordinated water molecules are absent under a higher temperature. ► They are constructed firstly by benzimidazole-5,6-dicarboxylic acid and oxalic acid.