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To exploit the S3′ subsite of renin active site for renin inhibitor design, 42 aliskiren derivatives with modified P2′ portion were designed, synthesized and biologically evaluated. Some highly potent renin inhibitors (IC 50 < 3 nM) were identified, among which compounds 38 (IC 50 = 0.9 nM) and 39 (IC 50 = 0.7 nM) were over 2.5-fold more potent than aliskiren (IC 50 = 2.3 nM). SAR analysis indicated that incorporation of polar hydrophilic moieties into the P2′ portion of renin inhibitors generally enhanced the potency. Consistently with this, molecular modeling study revealed that the triazole part of 39 could provide additional interactions to the S3′ subsite of renin active site. Moreover, in vivo evaluation in the double transgenic mouse hypertension model demonstrated that 39 produced greater reduction of the mean arterial blood pressure than ariskiren at the doses of 17.0 and 34.0 μmol/kg, respectively. Taken together, the S3′ subsite of renin active site merits further consideration for renin inhibitor design. [ABSTRACT FROM AUTHOR]

A practical asymmetric synthesis of 3,4-disubstituted proline derivatives has been realized with high stereoselectivity and moderate yield. The key steps involved are desymmetric ring-opening reaction of commercially available anhydrides, intramolecular Strecker reaction and thermodynamically controlled cyanide hydrolysis. Based on this methodology, the synthesis of HCV protease inhibitor Telaprevir was achieved. [ABSTRACT FROM AUTHOR]

1-[18F]Fluoro-1-deoxy-2,5-anhydro- D-mannitol ( 3, 18F-FDAM) has been synthesized in 6 steps starting from 2,5-anhydro- D-mannitol (2,5-AM) and evaluated as a new radiotracer for PET imaging of MCF-7 breast tumor. The result of PET imaging study showed that 3 displayed a slightly higher uptake by breast tumor in comparison with the normal breast tissue, implying the possibility of development of PET radiotracers based on targeting fructose transporters. [ABSTRACT FROM AUTHOR]

Abstract: Propylphosphonic anhydride (®T3P) promotes cyclization of o-aminobenzenethiol, o-aminophenol, and o-phenylenediamine with carboxylic acids under microwave irradiation. The one-pot procedure is efficient and allows short reaction times, easy workup, and good yields. Thus, we describe here a method for quick preparation of benzothiazoles, benzoxazoles and benzimidazoles. [Copyright &y& Elsevier]

Abstract: The synthesis and biological evaluation of corosolic acid derivatives and related compounds as inhibitors of rabbit muscle glycogen phosphorylase a is described. Within this series of compounds, 8 (IC50 =7.31μM), 12d (IC50 =3.26μM), and 12e (IC50 =5.1μM) exhibited more potent activities than the parent compound 1 (IC50 =20μM). SAR of these compounds is also discussed. [Copyright &y& Elsevier]

Abstract: The synthesis of a series of maslinic acid derivatives is described and their effect on rabbit muscle glycogen phosphorylase a evaluated. Within this series of compounds, 15 (IC50 =7μM) is the most potent GPa inhibitor. SAR of the maslinic acid derivatives are discussed. [Copyright &y& Elsevier]

Abstract: The semi-synthesis, in vitro and in vivo biological evaluation of corosolic acid (1) and maslinic acid (2) are described. Compounds 1 and 2 represent a new class of inhibitors of glycogen phosphorylases. Both 1 and 2 inhibit the increase of fasted plasma glucose of diabetic mice induced by adrenaline. It is therefore proposed that naturally occurring pentacyclic triterpenes 1 and 2 might reduce blood glucose, at least in part, through inhibiting hepatic glycogen degradation. [Copyright &y& Elsevier]

Abstract An efficient approach to chiral α-hydroxy acid esters by Lewis acid-mediated asymmetric [1,5]-hydride shift and isomerization of 2-(3-pyrroline-1-yl)arylketone acid ester has been achieved in up to 96% yield and 94% ee. This protocol would be applied in the synthesis of chiral α-hydroxy acid derivatives with simplicity and high enantioselectivity. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

A quick preparation of the title compounds is developed via T3P-promoted reaction of appropriately ortho-functionalized anilines with carboxylic acids under microwave conditions. [ABSTRACT FROM AUTHOR]

A Brønsted acid catalyzed redox-annulated cascade reaction between 2-arylpyrroles and 2-(pyrrolidin-1-yl)-, 2-(piperidin-1-yl), or 2-morpholinobenzaldehydes has been developed. This dehydration/1,5-hydride shift/cyclization sequence results in the construction of two new C(sp2)-C(sp3) bonds, providing structurally diverse 1,2-pyrrole-annulated benzazepines in yields of 25-65 %. [ABSTRACT FROM AUTHOR]

Insulin degrading enzyme (IDE) is a zinc metalloprotease that cleaves numerous substrates among which amyloid-β and insulin. It has been linked through genetic studies to the risk of type-2 diabetes (T2D) or Alzheimer's disease (AD). Pharmacological activation of IDE is an attractive therapeutic strategy in AD. While IDE inhibition gave paradoxal activity in glucose homeostasis, recent studies, in particular in the liver suggest that IDE activators could be also of interest in diabetes. Here we describe the discovery of an original series of IDE activators by screening and structure-activity relationships. Early cellular studies show that hit 1 decreases glucose-stimulating insulin secretion. Docking studies revealed it has an unprecedented extended binding to the polyanion-binding site of IDE. These indole-based pharmacological tools are activators of both Aβ and insulin hydrolysis by IDE and could be helpful to explore the multiple roles of IDE. [Display omitted] • Screening of an unbiased library provided an original series of IDE activators. • Structure-activity relationships showed key role of sulfonamide and imidazole. • Docking revealed original binding in the polyanion binding site. [ABSTRACT FROM AUTHOR]

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. Experimental Approach We analysed the gene expression profile of STING and related downstream targets in the skin samples of healthy people and psoriasis patients from the GEO database. Cellular inhibitory activity of H‐151 on STING pathway was confirmed via qPCR and western blotting. The preventive effect of topical application of H‐151 on imiquimod‐induced psoriatic mice was examined through histological, immunohistochemical, immunofluorescent, flow cytometric analysis, ELISA Kits and other approaches. Preliminary mechanistic studies were also performed. Key Results: Gene expressions of STING and its downstream target were up‐regulated in lesional skin samples from psoriasis patients. Topical administration of H‐151 attenuated the skin lesions in imiquimod‐induced psoriatic mouse model, while the secretion of pro‐inflammatory cytokines (IL‐17, IL‐23 and IL‐6), infiltration of M1 macrophages and differentiation of Th17 cells were significantly suppressed by H‐151 treatment. Mechanistically, H‐151 inhibited STING/NF‐κB signalling in both keratinocytes and immune cells. Conclusion and Implications: H‐151 displayed anti‐inflammatory activity in both keratinocytes and immune cells, and decreased the severity of psoriatic response in vivo. Inhibition of STING signalling pathway may represent a novel therapeutic approach to psoriasis and related complications. [ABSTRACT FROM AUTHOR]

Abstract: Twelve derivatives of oleanolic acid (1) have been synthesized and evaluated for their inhibitory activities against the growth of prostate PC3, breast MCF-7, lung A549, and gastric BGC-823 cancer cells by MTT assays. Within these series of derivatives, compound 17 exhibited the most potent cytotoxicity against PC3 cell line (IC50 =0.39μM) and compound 28 displayed the best activity against A549 cell line (IC50 =0.22μM). SAR analysis indicates that H-donor substitution at C-3 position of oleanolic acid may be advantageous for improvement of cytotoxicity against PC3, A549 and MCF-7 cell lines. [Copyright &y& Elsevier]

Oxazolidin-2-one served as a class of highly important nitrogen-containing five-membered heterocycles has been found in a wide range of biologically active molecules and chiral ligands. Consequently, its synthesis has attracted significant attention from chemists, leading to extensive investigations in this area. In this study, we developed a novel and more sustainable synthetic approach, using BF 3 ·Et 2 O as the catalyst to facilitate intramolecular oxo-Michael addition reactions of Boc-protected p -quinoamines. This approach allowed for the efficient construction of diverse polycyclic fused oxazolidin-2-one compounds and yields up to 98 %. Furthermore, the anti-tumor activity of these structurally unique oxazolidin-2-one derivatives was reported. [Display omitted] [ABSTRACT FROM AUTHOR]

A formal [3 + 3] cyclization reaction of 2-indolylmethanols with quinones was realized to furnish indole-fused scaffolds in moderate to excellent yields. This protocol was proceeded smoothly under acid condition, with high high yields and broad substrate scope. Image 1 • A formal [3 + 3] cyclization reaction of 2-indolylmethanols with quinone imines was realized to afford fused-indole scaffolds, employing C3-position of 2-indolylmethanols as nucleophilic site. [ABSTRACT FROM AUTHOR]

In this study, Complex I inhibitor R419 was firstly revealed to have significant anticancer activity against HepG2 cells (IC 50  = 5.2 ± 0.9 μM). Based on this finding, a series of R419 derivatives were synthesized and biologically evaluated. As results, 9 derivatives were found to have obvious anticancer activity. Among them, H20 exhibited the most potent activity (IC 50  = 2.8 ± 0.4 μM). Mechanism study revealed that H20 caused severe depletion of cellular ATP, dose-dependently activated AMPK, decreased Bcl-2/Bax ratio and induced necrotic cell death. Most importantly, H20 displayed definite inhibitory activity against Complex I. [ABSTRACT FROM AUTHOR]

GPR120 is an attractive target for the treatment of type 2 diabetes. In this study, a series of biphenyl derivatives were designed, synthesized by hybrid design. The selected compound 6a exhibited potent GPR120 agonist activity (EC 50  = 93 nM) and high selectivity over GPR40. The results of oral glucose tolerance test (OGTT) demonstrated that 6a exhibited significant glucose-lowering effect in glucose-loaded ICR male mice. Analysis of the structure–activity relationship is also presented. Compound 6a deserves further biological evaluation and structural modifications. [ABSTRACT FROM AUTHOR]

N-Substituted-3(10H)-acridones have been established as visible-light organic photocatalyst. These photosensitizers are efficient for oxidative coupling reaction of N-aryl tetrahydroisoquinolines with various nucleophiles. Notably, N-methyl-3(10H)-acridone ( Ia ) is stable and can be effectively prepared. It is a water-soluble and atom-economic catalyst, and thus holds promise for green chemical applications. Mechanistic studies confirm a single electron transfer (SET)-induced radical process and a rate-limiting step. Analysis of the photocatalytic reactivity−structure relationship reveals that the acridones are robust and tunable photosensitizers for photoredox catalysis. [ABSTRACT FROM AUTHOR]

A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC 50 s less than 10 μM. Among them, compound 20 (IC 50 = 2.3 μM) had the most potent biological activity, and effectively ameliorated plasma lipid levels of human adipose tissue specific CETP transgenic (ap2-CETPTg) mice and guinea pigs. Additional safety evaluation (no blood pressure elevation in guinea pigs) and pharmacokinetics studies indicated that the potential druggability for compound 20 which is a promising lead for development of a new class of CETP inhibitors for the treatment of dyslipidemia. [ABSTRACT FROM AUTHOR]

A high-yielding, copper-catalyzed dearomatization reaction of indole from 2-methylindole-derived oxime acetates was realized, providing access to structurally novel spiro[indoline-3,2′-pyrrolidine] derivatives in 67-98% yields. When the C-2 position of the indole was not substituted, azacarbazole derivatives were obtained in moderate yields. This transformation provides an efficient approach to access nitrogen-containing spiroindolenine and azacarbazole derivatives with wide substrate scope. [ABSTRACT FROM AUTHOR]

We disclosed a novel water-soluble photocatalyst that could promote aerobic oxidative hydroxylation of arylboronic acids to furnish phenols in excellent yields. This transformation uses visible-light irradiation under environmentally friendly conditions, that is, water-soluble catalyst, metal-free, green oxidant, room temperature. [ABSTRACT FROM AUTHOR]

Herpesvirus-associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with and stabilizes Mdm2, and represents one of the first examples that deubiquitinases oncogenic proteins. USP7 has been regarded as a potential drug target for cancer therapy. Inhibitors of USP7 have been recently shown to suppress tumor cell growth in vitro and in vivo. Based on leading USP7 inhibitors P5091 and P22077, we designed and synthesized a series of thiazole derivatives. The results of in vitro assays showed that the thiazole compounds exhibited low micromolar inhibition activity against both USP7 enzyme and cancer cell lines. The compounds induced cell death in a p53-dependent and p53-independent manner. Taken together, this study may provide thiazole compounds as a new class of USP7 inhibitors. [ABSTRACT FROM AUTHOR]

Cholesteryl Ester Transfer Protein (CETP) is an important therapeutic target for the treatment of atherosclerotic cardiovascular disease. Our molecular modeling study revealed that pentacyclic triterpenoid compounds could mimic the protein-ligand interactions of the endogenous ligand cholesteryl ester (CE) by occupying its binding site. Alignment of the docking conformations of oleanolic acid (OA), ursolic acid (UA) and the crystal conformations of known CETP inhibitor Torcetrapib in the active site proposed the applicability of fragment-based drug design (FBDD) approaches in this study. Accordingly, a series of pentacyclic triterpenoid derivatives have been designed and synthesized as novel CETP inhibitors. The most potent compound 12e (IC 50 :0.28 μM) validated our strategy for molecular design. Molecular dynamics simulations illustrated that the more stable hydrogen bond interaction of the UA derivative 12e with Ser191 and stronger hydrophobic interactions with Val198, Phe463 than those of OA derivative 12b mainly led to their significantly different CETP inhibitory activity. These novel potent CETP inhibitors based on ursane-type scaffold should deserve further investigation. [ABSTRACT FROM AUTHOR]

In order to discover more effective and less toxic drugs in the field of anti-tumor, the backbone structure of 17 β -estradiol was modified, and 11 target compounds were synthesized. Compounds 5 and 10 , which exhibited better anti-tumor activity and higher selectivity (more than 10-fold), were chosen for further biological investigation. Flow cytometry results indicated that 5 and 10 could arrest MCF-7 cells in the G2 phase and induce apoptosis. Immunohistochemical analysis revealed that 5 and 10 could bind to the estradiol receptor alpha in MCF-7 cells. Western blotting and real-time PCR assays were performed to detect the effects of compounds on apoptosis-related targets at the protein and gene levels. These results showed that both 5 and 10 could dosed-dependently increase the expression of Apaf-1, Bax, caspase-3,8,9 and reduce the expression levels of the anti-apoptotic factors Bcl-2 and Bcl-xL. Besides, the Human apoptosis array assay demonstrated the expression level of death receptor Trail R2/DR5 was upregulated obviously while the expression of TNF R1, IAPs and Hsp27/60/70 were downregulated. On the whole, 5 induced MCF-7 cell death through the endogenous pathway in mitochondria and the exogenous pathway with death receptor Trail R2/DR5. • Eleven 17 β -estradiol derivatives from modification were synthesized. • 5 and 10 possessed much better antiproliferative activities and higher selectivity than 17 β -estradiol. • 5 and 10 could arrest cell cycle at the G2 phase in MCF-7 cells and partly bind with the estradiol receptor alpha. • 5 induced MCF-7 cells death through both endogenous and exogenous pathways. [ABSTRACT FROM AUTHOR]

A novel class of (2E)-(2-oxo-1, 2-dihydro-3 H -indol-3-ylidene)acetate derivatives were designed and synthesized as potent anti-proliferative agents. Most of these compounds showed potent anti-proliferative activity against some tumor cell lines, including SK-BR-3, MDA-MB-231, HCT-116, SW480, Ovcar-3, HL-60, Saos-2 and HepG2. Compounds 8c and 11h were identified as the most potent ones, while HL-60, HCT116 and MDA-MB-231 were the most sensitive cell lines. Mechanistic study revealed that compound 8c enhanced reactive oxygen species level by inhibiting TrxR and then induced apoptosis by activating apoptosis proteins, bax and cleaved-caspase 3 in HCT116 cells. Preliminary SAR analysis indicated that modifications of the double bond and ester group made great effects on the anti-proliferative activity. Our findings suggested that it was worth further studies on the antitumor potency of (2E)-(2-oxo-1, 2-dihydro-3 H -indol-3-ylidene)acetates. [ABSTRACT FROM AUTHOR]

The newly synthesized glycine- l -phenylalanine conjugates 11 and 16 have good anticancer activity. In vivo and in vitro experiments showed that both compounds inhibit the growth of solid tumors by inducing apoptosis of cancer cells. [Display omitted] • 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were synthesized. • Glycyrrhetinic acid (GA) derivatives 11 (IC 50 = 0.2 μM) and 16 (IC 50 = 0.7 μM) are much more potent than GA. • 11 and 16 showed significant tumor growth inhibition in A549 and T24 tumor xenograft model, respectively. • 16 showed low toxicity in vitro and in vivo experiments. • The mechanisms of action of compounds 11 and 16 were extensively investigated. Extensive research effort has been put in pentacyclic triterpenoids due to their numerous biological activities. However, their poor water solubility and low oral bioavailability limit their antitumor effects in vivo. To address these issues, 37 triterpenoid acid derivatives linked to l -phenylalanine or l -proline were designed and synthesized in this study. Structure-activity relationship (SAR) studies found two promising glycyrrhetinic acid (GA) derivatives 11 and 16. Compound 11 was obtained by C3-OH esterification and C30-COOH modification with l -phenylalanine while 16 was obtained by attaching C3-OH with l -phenylalanine. Compounds 11 and 16 exhibit up to 48- and 120-fold improvement respectively compared with the IC 50 values of naturally occurring GA in the cellular assay. Fluorescence microscope and flow cytometric analysis suggested that both compounds 11 and 16 increased the content of ROS and Ca2+ in cancer cells, decreased mitochondrial membrane potential (JC-1), and activated the regulator caspase-3/8/9 to trigger cell apoptosis. RNA-seq analysis and western blot analysis indicated that compounds 11 and 16 may promote apoptosis by upregulating the functions of pro-apoptotic factors while inhibiting the proteasome activity. [ABSTRACT FROM AUTHOR]

The reaction under conditions A) leads to the desired N-heterocyclic skeleton which is of pharmaceutical interest (reaction mechanism). [ABSTRACT FROM AUTHOR]

An intramolecular palladium(II)-catalyzed dearomative arylation reaction of indoles via CH bond functionalization was developed, providing access to structurally novel spiroindolenines with moderate to good yields. A one-pot process for the synthesis of spiroindoline derivatives was also realized. [ABSTRACT FROM AUTHOR]

The Rh(ii)-catalyzed sulfur ylide [1,2]-rearrangement of carbenoids generated from aryldiazoacetates has been realized via N–S bond insertion, generating tertiary sulfides in moderate to excellent yields. This demonstrates the first use of the sulfur ylide [1,2]-rearrangement undergoing N–S bond insertion. This protocol could proceed smoothly with high regioselectivity, low catalyst loading (0.1 mol% Rh2(OAc)4), gram-scale reaction and broad substrate scope. And the product could be converted into glycine derivatives through simple procedures. [ABSTRACT FROM AUTHOR]

2-Substituted dihydrobenzofurans are efficiently obtained by reaction of various sulfur ylides with o-quinone methides, which are generated under mild reaction conditions [ABSTRACT FROM AUTHOR]

Optimized conditions A) can be applied to various indoles and benzaldehydes bearing a pyrrolidine moiety in o-position. [ABSTRACT FROM AUTHOR]

A general method to synthesize N -aryl pyrrole derivatives was realized via the reactions of 2-(3-pyrroline-1-yl)arylaldehydes with indoles under acidic conditions, which underwent [1,5]-hydride shift/isomerization process. The desired products could be obtained in good to high yields with a wide substrate scope. [ABSTRACT FROM AUTHOR]

Visible-lightinduced isoindole formation triggered an intermolecularDiels–Alder reaction with dienophiles such as acetylenedicarboxylateand maleimides in the presence of air. The reaction resulted in excellentdiastereoselctivity and high yields under mild reaction conditions.This protocol provides an atom-economical, transition-metal-free (TM-free)and straightforward approach to structurally diverse bridged-ringheterocycles from easily accessible molecules. [ABSTRACT FROM AUTHOR]

A practical method to synthesize N -aryl pyrrole derivatives involving O -alkylated quinone methides as hydride acceptors has been developed via [1, 5]-hydride shift/isomerization cascade under acidic condition. The desired product could be obtained in moderate to good yields with broad substrate scope. [ABSTRACT FROM AUTHOR]

Insulin degrading enzyme (IDE) is a zinc metalloprotease that degrades small amyloid peptides such as amyloid-â and insulin. So far the dearth of IDE-specific pharmacological inhibitors impacts the understanding of its role in the physiopathology of Alzheimer's disease, amyloid-â clearance, and its validation as a potential therapeutic target. Hit 1 was previously discovered by high-throughput screening. Here we describe the structure-activity study, that required the synthesis of 48 analogues. We found that while the carboxylic acid, the imidazole and the tertiary amine were critical for activity, the methyl ester was successfully optimized to an amide or a 1,2,4-oxadiazole. Along with improving their activity, compounds were optimized for solubility, lipophilicity and stability in plasma and microsomes. The docking or co-crystallization of some compounds at the exosite or the catalytic site of IDE provided the structural basis for IDE inhibition. The pharmacokinetic properties of best compounds 44 and 46 were measured in vivo . As a result, 44 (BDM43079) and its methyl ester precursor 48 (BDM43124) are useful chemical probes for the exploration of IDE's role. [ABSTRACT FROM AUTHOR]

Abstract: Proton-exchanged montmorillonite (H-mont) was found to be an eco-friendly and cost-effective catalyst for the generation of O-methylated quinone methides (QM) from the corresponding p or o-methoxybenzyl esters and ethers. Nucleophilic trapping of the O-methylated QM with arenes, alcohols, 1,3-dicarbonyl compounds, silyl enol ethers, and allylsilanes has been carried out, respectively, leading to eco-friendly benzylation reactions. Using this protocol, H-mont-mediated deprotection of PMB-protected esters and ethers have been realized for the first time. This work would pave the way for further exploration in O-alkylated QM that are of chemical and biological significance. [Copyright &y& Elsevier]

Antidiabetic agents simultaneously inhibiting hepatic glucose production and stimulating hepatic glucose consumption could apply a better control over hyperglycemia. A series of oleanolic acid derivatives with bulky substituents at C-3 position were designed and synthesized in order to search for this kind of agents. All of the compounds were evaluated biologically in vitro using glycogen phosphorylase and HepG2 cells. The results indicated that several derivatives exhibited moderate-to-good inhibitory activities against glycogen phosphorylase. Compound 8g showed the best inhibition with an IC50 value of 5.4 μ m. Moreover, most of the derivatives were found to increase the glucose consumption in HepG2 cells in a dose-dependent manner. The possible binding mode of compound 8g with glycogen phosphorylase was also explored by docking study. 8g was found to have hydrogen bonding interactions with Arg193, Arg310, and Arg60 of the allosteric site. [ABSTRACT FROM AUTHOR]

Abstract: All eight stereoisomers of saxagliptin have been synthesized and evaluated for their inhibitory activity against DPP-IV. It was unambiguously confirmed that the configuration of saxagliptin was critical to potent inhibition of DPP-IV. Docking study was performed to elucidate the configuration–activity relationship of saxagliptin stereoisomers. Tyr662 and Tyr470 have been suggested as the key residues of DPP-IV interacting with the inhibitors. This work provides valuable information for further inhibitor design against DPP-IV. [Copyright &y& Elsevier]

Abstract: The intramolecular Schmidt reaction of simple azido secondary benzyl alcohols has been realized for the first time. Investigation of the electronic and steric effects of the substrates on the product outcome was conducted. Unique intramolecular Schmidt rearrangements were observed with the formation of a cinnamaldehyde derivative and aryl aldehydes, respectively. Using this protocol, an efficient synthesis of dihydrobenzotriazine derivatives was achieved. Moreover, a practical approach to 2-aryl-1-pyrrolines was also accessed. [Copyright &y& Elsevier]

Abstract: Naturally occurring pentacyclic triterpenes (PT), a novel class of inhibitors against glycogen phosphorylase (GP), hold promise for the treatment of type-2 diabetes and other diseases with disorders in glycogen metabolism. To identify novel and more potent GP inhibitors, the receptor-based comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) approaches were performed to investigate the quantitative structure–activity relationships (QSAR) among 106 PT analogues. The validated models demonstrated that the elongated or bulky substitutions in C17 position and/or C2, C3 positions are favorable. Then based on the structural information extracted from these models, 56 derivatives were synthesized and biochemically tested in this study. The IC50 value of the most potent compound P50 was found to be 1.1μM. [Copyright &y& Elsevier]

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. Based on these findings, 23 saponin derivatives of δ-oleanolic acid were synthesized in order to find more potent anti-inflammatory agents with improved pharmacokinetic properties. The results of cellular assays showed that saponin 29 significantly inhibited LPS-induced secretion of pro-inflammatory factors TNF-α and IL-6 in THP1-derived macrophages. Preliminary mechanistic studies showed that 29 stimulated the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC). The bioavailability of 29 was significantly improved in comparison with its aglycon. More importantly, 29 showed significant anti-inflammatory and liver-protective effects in LPS/D-GalN-induced fulminant hepatic failure mice. Taken together, PTs saponins hold promise as therapeutic agents for inflammatory diseases. Image 1 • δ-Oleanolic acid was identified as a potent AMPK activator. • 23 new saponin derivatives of δ-oleanolic acid were synthesized and biologically evaluated. • The bioavailability of saponins 29 and 33 was much better than their aglycon. • Saponin 29 exhibited significant in vitro and in vivo anti-inflammatory effects. [ABSTRACT FROM AUTHOR]

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. In order to find novel AdipoRon analogues that activate AMPK without inhibition of complex I, 27 analogues of AdipoRon were designed, synthesized and biologically evaluated. As results, benzyloxy arylamide B10 was identified as a potent AMPK activator without inhibition of complex I. B10 dose-dependently improved glucose tolerance in normal mice, and significantly lowered fasting blood glucose level and ameliorated insulin resistance in db/db diabetic mice. More importantly, unlike the pan-AMPK activator MK-8722, B10 did not cause cardiac hypertrophy, probably owing to its selective activation of AMPK in the muscle tissue but not in the heart tissue. Together, B10 represents a novel class of AMPK activators with promising therapeutic potential against metabolic disease. Image 1 • A series of novel AdipoRon analogues were designed and synthesized. • Six analogues exhibited much more potency of AMPK activation than AdipoRon. • B10 exhibited significant in vitro and in vivo hypoglycemic effects in mice. • B10 did not inhibit mitochondrial complex I. • B10 did not cause cardiac hypertrophy in mice. [ABSTRACT FROM AUTHOR]

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 50 = 40.8 nM, K D = 78.3 nM). X-ray crystallographic studies revealed that L55 bound to USP7 with a new pose that was very different from the previously reported inhibitors. The results of cellular assays showed that L55 had strong antitumor activity against LNCaP (IC 50 = 29.6 nM) and RS4; 11 (IC 50 = 41.6 nM) cells, probably through inducing cell death and restricting G0/G1 and S phases. Moreover, L55 dose-dependently reduced the protein levels of MDM2 and DNMT1 and increased the protein levels of p53 and p21. These findings could have valuable implications for designing novel structural classes of USP7 inhibitors. Image 1 • Fifty-five piperidinol derivatives were synthesized and biologically evaluated. • Compound L55 exhibited potent USP7 inhibitory activity (IC 50 = 40.8 nM). • X-ray crystallographic studies revealed a new pose for L55 to bind to USP7. • L55 downregulated MDM2 and DNMT1 and upregulated p53 and p21 in RS4; 11 cells. • LNCaP (IC 50 = 29.6 nM) and RS4; 11 (IC 50 = 41.6 nM) were highly sensitive to L55. [ABSTRACT FROM AUTHOR]

• A series of ursolic acid 3β-ester derivatives were synthesized and evaluated for the CETP inhibiting activities. • Compound U12 exhibited the most active with the IC 50 value of 2.4 μM. • Molecular docking studies were carried out to investigate the binding mode of these compounds to CETP. Cholesteryl ester transfer protein (CETP) is an attractive therapeutic target for the prevention and treatment of cardiovascular diseases by lowering low-density lipoprotein cholesterol levels as well as raising high-density lipoprotein cholesterol levels in human plasma. Herein, a series of ursolic acid 3β-ester derivatives were designed, synthesized and evaluated for the CETP inhibiting activities. Among these compounds, the most active compound is U12 with an IC 50 value of 2.4 μM in enzymatic assay. The docking studies showed that the possible hydrogen bond interactions between the carboxyl groups at both ends of the molecule skeleton and several polar residues (such as Ser191, Cys13 and Ser230) in the active site region of CETP could significantly enhance the inhibition activity. This study provides structural insight of the interactions between these pentacyclic triterpenoid 3β-ester derivatives and CETP protein for the further modification and optimization. [ABSTRACT FROM AUTHOR]

On the one hand, the multi-target agents have been promising for overcoming the deficiency of the single targeted anticancer metal agents, on the other hand, bismuth (Bi) complexes have shown significant antiproliferative activity and minimal side effects. Therefore, to develop the next-generation anticancer metal agents, we designed and synthesized four novel binuclear Bi(III) complexes by modifying the N-4 position of a series of 2-Acetyl-3-ethylpyrazine thiosemicarbazides, and then investigated their structure-activity relationships to human cancer cell lines, obtaining a lead Bi drug (C4) with significant antiproliferative activity to human bladder cancer cells (T24). C4 arrested the cell cycle in the S-phase by regulation of cyclin and cyclin-dependent kinases, and exerted a chemotherapeutic effect via multi-target mechanism including the activation of apoptotic and autophagic cell signaling pathways. Besides, C4 effectively inhibited metastasis of T24 cell. Our results suggested that C4 can be developed as a potential multi-target anticancer candidate. Image 1 • Four binuclear Bi(III) complexes modified at the N-4 position of the ligand thiosemicarbazides were synthesized. • Bi(III) complexes had high cytotoxicity against human bladder cancer cell. • Bi(III) complexes inhibited the growth and metastasis in T-24 cell. • Bi(III) complexes exerted chemotherapeutic effect against T-24 cell via the multi-target mechanism. [ABSTRACT FROM AUTHOR]

Acetyl-coA carboxylase 1 (ACC1) is the first and rate-limiting enzyme in the de novo fatty acid synthesis (FASyn) pathway. In this study, through public database analysis and clinic sample test, we for the first time verified that ACC1 mRNA is overexpressed in non-small-cell lung cancer (NSCLC), which is accompanied by reduced DNA methylation at CpG island S shore of ACC1. Our study further demonstrated that higher ACC1 levels are associated with poor prognosis in NSCLC patients. Besides, we developed a novel synthetic route for preparation of a known ACC inhibitor ND-646 , synthesized a series of its derivatives and evaluated their activity against the enzyme ACC1 and the A549 cell. As results, most of the tested compounds showed potent ACC1 inhibitory activity with IC 50 values 3–10 nM. Among them, compounds A2 , A7 and A9 displayed strong cancer inhibitory activity with IC 50 values 9–17 nM by impairing cell growth and inducing cell death. Preliminary SAR analysis clearly suggested that (R)-configuration and amide group were vital to ACC1 and A549 inhibition, since compound (S)-A1 (the enantiomer of ND-646) had poor activity of ACC1 inhibition and the carboxylic acid ND-630 almost lost anticancer effect on A549 cells. Collectively, these findings indicate that ACC1 is a potential biomarker and target for non-small-cell lung cancer, and ND-646 and its derivatives as ACC1 inhibitors deserve further study for treatment of NSCLC. Unlabelled Image [ABSTRACT FROM AUTHOR]

The article presents chemical equations for the article "Dearomatization of Indole Derivatives via Palladium-Catalyzed C-H Bond Functionalization of Pyrroles: Convenient Construction of Spiroindolenines" by X. Lei and others published in "Advanced Synthesis and Catalysis" in 2016.

The reaction can be readily scaled up. [ABSTRACT FROM AUTHOR]

Lewis acid-promoted reactions of pyrrolidine- or tetrahydroisoquinoline-containing nitrones afford oxadiazepines in good yields. [ABSTRACT FROM AUTHOR]

Bridged-ring heterocycles are diastereoselectively synthesized from easily accessible educts by an atom-economical, transition-metal-free approach under mild reaction conditions. [ABSTRACT FROM AUTHOR]