Discovery of Orally Bioavailable -Benzylpiperidinol Derivatives as Potent and Selective USP7 Inhibitors with In Vivo Antitumor Immunity Activity against Colon Cancer.

USP7 emerges as a potential therapeutic target for cancers, as it plays an important role in the development of tumorigenesis by stabilizing multiple cancer-relevant proteins. Nevertheless, the discovery of drug-like USP7 inhibitors remains challenging. Herein, we report a series of -benzylpiperidinol derivatives as potent and selective USP7 inhibitors (e.

Structural evolution from preorganized mononuclear triazamacrocyclic metalloligands to polynuclear metallocages and heterometallic 2D layers: modular architectures, assembly tracking and magnetic properties.

The reaction of a macrocyclic ligand 1,4,7-triazacyclononane-1,4,7-tripropionic acid (tacntpH3) with Ni(II)/Co(II) sources in the presence or absence of lanthanide cations yielded a series of doubly mononuclear ionic complexes (HO)[Ln(HO)][Ni()] (1-NiLn, Ln = La, Ce, Yb) and a mononuclear Co(III) complex [Co()]·4HO (2-Co) incorporating transition metal centers enveloped by both an azamacrocycle ring and pendant carboxylate groups. Either of the two preorganized mononuclear species [M()] was taken as a tripodal 3d metalloligand for the further assembly of modular architectures. Two pentanuclear metallocage-[Ln(NO)] complexes [NiII5()(HO)][Ln(NO)]Cl·2HO (3-NiLn, Ln = La, Ce), one nonanuclear metallocage [NiII9()(HO)](ClO)·10HO (4-Ni), and two types of 2D layered heterometallic 3d-4f coordination networks ((HO)[NiII2Yb()](ClO)·3HO (5-NiYb) and [CoIII2Tb()(HO)](ClO)·Cl·5HO (6-CoLn, Ln = La, Eu, Tb, Dy)) differing largely in their weaving architecture were controllably prepared the precise regulation of multiple reaction parameters.

The strong and cytotoxicity of three new cobalt(II) complexes with 8-methoxyquinoline.

Three new cobalt(II) complexes, [Co(MQL)Cl] (CoCl), [Co(MQL)Br] (CoBr), and [Co(MQL)I] (CoI), bearing 8-methoxyquinoline (MQL) have been designed for the first time. MTT assays showed that CoCl, CoBr, and CoI exhibit much better antiproliferative activities than cisplatin toward cisplatin-resistant SK-OV-3/DDP and SK-OV-3 ovarian cancer cells, with IC values of as low as 0.32-5.

Smart Tetraphenylethene-Based Luminescent Metal-Organic Frameworks with Amide-Assisted Thermofluorochromics and Piezofluorochromics.

Luminescent metal-organic frameworks (MOFs) are appealing for the design of smart responsive materials, whereas aggregation-induced emission (AIE) fluorophores with twisted molecular rotor structure provide exciting opportunities to construct MOFs with new topology and responsiveness. Herein, it is reported that elongating AIE rotor ligands can render the newly formed AIE MOF (ZnETTB) (ETTB = 4',4''',4''''',4'''''''-(ethene-1,1,2,2-tetrayl)tetrakis(([1,1'-biphenyl]-3,5-dicarboxylic acid))) with more elasticity, more control for intramolecular motion, and specific amide-sensing capability. ZnETTB shows specific host-guest interaction with amide, where N,N-diethylformamide (DEF), as an example, is anchored through CH···O and CH···π bonds with Zn cluster and ETTB ligand, respectively.

Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.

Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity.

Two Organic Hybrid Manganese Selenoarsenates: The Discovery of One-Dimensional Low-Valent Selenoarsenate(II).

Two organic hybrid manganese selenoarsenates, [Mn(en)][MnAsSe] (; en = ethanediamine) and {[Mn(atep)][Mn(tepa)](AsSe)} [; atep = 4-(2-aminoethyl)triethylenetetramine], were made under mild solvothermal conditions. is a new type of one-dimensional low-valent selenoarsenate(II) constructed by the linkages of tetrahedral [MnSe] units and two manners of bridging of [AsSe] anions. comprises a neutral {[Mn(atep)][Mn(tepa)](AsSe)} molecule with a rare seven-coordinated manganese center, which represents the sole example of an organic hybrid selenoarsenate with the [Mn(tepa)] complex as the bridging group.

The STING antagonist H-151 ameliorates psoriasis via suppression of STING/NF-κB-mediated inflammation.

Background And Purpose: Psoriasis is a chronic inflammatory skin disease associated with both innate and adaptive immune responses. The stimulator of interferon genes (STING) protein engages in sensing of cytosolic DNA to initiate dsDNA-driven immune responses. In vitro and in vivo anti-psoriasis effects of STING antagonist H-151 were explored.

Synthesis and anti-inflammatory activity of saponin derivatives of δ-oleanolic acid.

Pentacyclic triterpenes (PTs) are the active ingredients of many medicinal herbs and pharmaceutical formulations, and are well-known for their anti-inflammatory activity. On the other hand, anti-inflammatory effects of AMP-activated protein kinase (AMPK) have recently drawn much attention. In this study, we found that a variety of naturally occurring PTs sapogenins and saponins could stimulate the phosphorylation of AMPK, and identified δ-oleanolic acid (10) as a potent AMPK activator.

Bisphosphine-Stabilized Gold Nanoclusters with the Crown/Birdcage-Shaped Au Cores: Structures and Optical Properties.

To estimate the effect of bisphosphine ligands on the formation of the isomeric core structures of gold nanoclusters, the different ligation of bisphosphine ligands is usually used to participate in the construction of gold nanoclusters. Here, the selection of the different bisphosphine ligands, DPEphos and Xantphos, is performed to construct two novel gold nanoclusters, [Au(DPEphos)Cl]Cl () and [Au(Xantphos)Cl]Cl(), which have been characterized by IR, H and P NMR, ESI-MS, XRD, SEM, XPS, TG, UV-vis, and X-ray crystal structure analysis. The structural analyses indicate that the ligation of bisphosphine ligands play a crucial role in the formation of the fascinating Au cores: gold nanocluster includes a birdcage-shaped Au core with eight electrons, while gold nanocluster contains a crown-shaped Au core with eight electrons.

Metal hydrogen-bonded organic frameworks: structure and performance.

Although great progress has been made in the design, synthesis, and performance expansion of porous materials, new porous materials with stable structures still need to be explored further. In recent years, porous molecular crystals formed by intermolecular interactions have attracted wide attention from chemists, especially metal hydrogen-bonded organic frameworks (M-HOFs) formed by connecting metal complexes through hydrogen bonds. Metal complexes with specific properties (e.

Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I.

Activation of AMPK emerges as a potential therapeutic approach to metabolic diseases. AdipoRon is claimed to be an adiponectin receptor agonist that activates AMPK through adiponectin receptor 1 (AdipoR1). However, AdipoRon also exhibits moderate inhibition of mitochondrial complex I, leading to increased risk of lactic acidosis.

N-benzylpiperidinol derivatives as novel USP7 inhibitors: Structure-activity relationships and X-ray crystallographic studies.

USP7 as a deubiquitinase plays important roles in regulating the stability of some oncoproteins including MDM2 and DNMT1, and thus represents a potential anticancer target. Through comparative analysis of USP7 co-crystal structures in complex with the reported piperidinol inhibitors, we noticed that the USP7 Phe409 sub-site might have good adaptability to the ligands. Based on this observation, 55 N-aromatic and N-benzyl piperidinol derivatives were designed, synthesized and biologically evaluated, among which compound L55 was identified as a highly selective and potent USP7 inhibitor (IC = 40.

Assembly of Dy and Dy cage-shaped nanoclusters.

Rapid kinetics, complex and diverse reaction intermediates, and difficult screening make the study of assembly mechanisms of high-nuclearity lanthanide clusters challenging. Here, we synthesize a double-cage dysprosium cluster [Dy(HL)(OAc)(O)(OH)(HO)]·6HO·6CHOH·7CHCN (Dy) by using a multidentate chelate-coordinated diacylhydrazone ligand. Two Dy cages are included in the Dy structure, which are connected via an OAc moiety.

Regulation of the Metal Center and Coordinating Anion of Mononuclear Ln(III) Complexes to Promote an Efficient Luminescence Response to Various Organic Solvents.

A series of mononuclear lanthanide complexes [Ln()(NO)], (Ln = Dy(III), ; Tb(III), ; and Eu(III), ; = (,)-,-bis((1-methyl-1-benzo[]imidazol-2-yl)methylene)cyclohexane-1,2-diamine) is obtained by reacting -methylbenzimidazole-2-carbaldehyde () and 1,2-cyclohexanediamine () with Ln(NO)·6HO under solvothermal conditions. ligand is produced via an in situ Schiff base reaction of two molecules of and one molecule of . The metal center Ln(III) is in a NO environment formed by and NO.

Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers Through an Intrinsic Apoptosis Pathway.

In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.

Synthesis and antitumor activity of fluorouracil - oleanolic acid/ursolic acid/glycyrrhetinic acid conjugates.

Due to the obvious adverse effects of 5-fluorouracil that limit its clinical usefulness and considering the diverse biological activities of pentacyclic triterpenes, twelve pentacyclic triterpene-5-fluorouracil conjugates were synthesized and their antitumor activities were evaluated. The results indicated that all the single substitution targeted hybrids () possessed much better antiproliferative activities than the double substitution targeted hybrids (). Hybrid exhibited good antiproliferative activities against all the tested MDR cell lines.

Conjugation of Uridine with Oleanolic Acid Derivatives as Potential Antitumor Agents.

According to fused two bioactive moieties together by bonds covalently and available as a new single hybrid entity known as pharmacophore hybridization, a total of 10 targeted uridine-oleanolic acid hybrids were synthesized. Most of these hybrids showed excellent proliferation inhibition against tested Hep-G2, A549, BGC-823, MCF-7, and PC-3 tumor cell lines (IC50 < 8 μm), even with some IC50 values under 0.1 μm.

Isoquinoline derivatives Zn(II)/Ni(II) complexes: Crystal structures, cytotoxicity, and their action mechanism.

Three transition metal complexes with isoquinoline derivatives: [(MPDQ)2Zn(C2H5OH)ClO4]ClO4 (1) (MPDQ = 4,5-methylenedioxy-1-pyridinedihydroisoquinoline), [(PYP)2Zn(H2O)](ClO4)2 (2) (PYP = 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline) and [(MPDQ)2Ni(CH3OH)ClO4]ClO4 (3) were synthesized and fully characterized. All complexes exhibited strong proliferation inhibition activity against various tested cancer cells with high selectivity to tumour and normal cells. BEL-7404 cells were found most sensitive to complex 2 by inducing apoptosis.

Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity.

Five dimeric oleanolic acids linked at C-28 by 1,6-hexanediamine, or built around the carbon chains of varying lengths between two carboxyl groups were synthesized, to investigate the effect of internal spacer length and species upon the stereochemical features and anti-tumor activity of the resultant bis-oleanolic acids. The IC50 values of these dimeric compounds for cytotoxicity evaluation in vitro against Hep-G2, A549, BGC-823, MCF-7 and PC-3 tumor cell lines, were mainly under 10.0 μM.

Copper(II/I) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline: synthesis, crystal structure, antitumor activity and DNA interaction.

Three new copper(II) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline (PYP), i.e. [Cu₂(PYP)₂Cl₄] (1), [Cu₄(PYP)₄(ClO₄)₂(H₂O)₂](ClO₄)₂·2H₂O (2), and [Cu₂(PYP)2Cl4]n (3), were synthesized and fully characterized.

High antitumor activity of 5,7-dihalo-8-quinolinolato cerium complexes.

Three cerium complexes: [Ce(ClQ)4] (1) (H-ClQ=5,7-dichloro-8-hydroxylquinoline), [Ce(ClIQ)4]·CH2Cl2·0.5H2O (2) (H-ClIQ=5-chloro-7-iodo-8-hydroxylquinoline) and [Ce2(BrQ)4(H-BrQ)(H2O)3Cl2]·1.5H2O (3) (H-BrQ=5,7-dibromo-8-hydroxylquinoline) were synthesized.