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An efficient and widely applicable method to prepare new triazaacenaphthylenes as well as tetraazaacenaphthylenes is reported. [ABSTRACT FROM AUTHOR]

The Bromodomain and Extra-terminal domain (BET) proteins are promising targets in treating cancers. Although BET inhibitors have been in clinical trials, they are limited by lacking of suitable biomarkers to indicate drug responses in different cancers. Here we identify DHRS2, ETV4 and NOTUM as potential biomarkers to indicate drug resistance in liver cancer cells of a recently discovered BET inhibitor, Hjp-6-171. Furthermore, we confirm that reactivation of WNT pathway, the target of NOTUM, contributes to the drug sensitivity restoration in Hjp-6-171 resistant cells. Specially, combinations of Hjp-6-171 and a GSK3β inhibitor CHIR-98014 show remarkable therapeutic effects in vitro and in vivo. Integrating RNA-seq and ChIP-seq data, we reveal the expression signature of β-catenin regulated genes is contrary in sensitive cells to that in resistant cells. We propose WNT signaling molecules such as β-catenin and ETV4 to be candidate biomarkers to indicate BET inhibitor responses in liver cancer patients. • Biomarkers are needed to indicate BET inhibitor responses in different cancers • WNT pathway hypoactivation leads to BET inhibitor resistance in liver cancer cells • Combinations of BET+GSK3β inhibitors show anti-tumor activity in vitro and in vivo • Expressions of β-catenin and ETV4 can be used for subtype and prognosis predictions [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease and lacks effective therapeutic agents. Dysregulation of transcription mediated by bromodomain and extra-terminal domain (BET) proteins containing two different bromodomains (BD1 and BD2) is an important factor in multiple diseases, including MS. Herein, we identified a series of BD1-biased inhibitors, in which compound 16 showed nanomolar potency for BD1 (K d = 230 nM) and a 60-fold selectivity for BRD4 BD1 over BD2. The co-crystal structure of BRD4 BD1 with 16 indicated that the hydrogen bond interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. 16 showed favorable brain distribution in mice and PK properties in rats. 16 was able to inhibit microglia activation and had significant therapeutic effects on EAE mice including improvement of spinal cord inflammatory conditions and demyelination protection. Overall, these results suggest that brain-permeable BD1 inhibitors have the potential to be further investigated as therapeutic agents for MS. [Display omitted] • Structure-based optimization led to a brain-penetrant BD1 inhibitor 16. • The interaction of 16 with BD1-specific Asp145 is important for BD1 selectivity. • 16 was able to effectively prevent disease progression in EAE mice. [ABSTRACT FROM AUTHOR]

[Display omitted] • Design and synthesis of quinazoline derivatives as pan-JAK inhibitors. • Compound 11n exhibited high potency against JAKs. • Compound 11n showed favorable drug-like properties. • Compound 11n potently inhibits joint swelling in CIA model with good safety. Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure–activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC 50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Tranylcypromine moiety extracted from LSD1 inhibitors and 6-trifluoroethyl thienopyrimidine moiety from menin-MLL1 PPI inhibitors were merged to give new chemotypes for medicinal chemistry study. Among 15 new compounds prepared in this work, some exhibited nanomolar LSD1 activity and good selectivity over MAO-A/B, low micromolar menin-MLL1 PPI inhibitory activity, as well as submicromolar MV4-11 antiprofilative activities. Intracellular LSD1 engagement of compounds with higher enzymatic and antiproliferative activities was confirmed by CD86 m RNA up-regulation experiments. [ABSTRACT FROM AUTHOR]

Abstract Through systematical comparison of various N 4-protected cytosine derivatives in the glycosylation step of gemcitabine synthesis, highly beta -stereoselective and high yielding TBAI catalyzed N-glycosylation was achieved with N 4-Bz cytosine and anomeric mixture of 2,2'-difluororibose mesylate donor. The subsequent global deprotection gave gemcitabine efficiently. Meanwhile, the anomeric chloride intermediate and fluoride-displaced side products of this N-glycosylation were identified, too. This new glycosylation method reveals the importance of N 4-protection in the stereoselective preparation of pyrimidine nucleoside, also provides a potential alternative to current industrial process to gemcitabine. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract Although lung adenocarcinoma patients have benefited from the development of targeted therapy, patients with lung squamous cell carcinoma (SqCC) have no effective treatment due to the complexity and heterogeneity of the disease. Therefore, basing on the genetic analysis of mutations in lung squamous cell carcinoma to design multi-target inhibitors represents a potential strategy for the medical treatment. In this study, through screening an in-house focused library, we identified an interesting indazole scaffold. And following with binding analysis, we elaborated the structure-activity relationship of this hit compound by optimizing four parts guided by the DDR2 enzymatic assay, which resulted in a potent lead compound 10a. We conducted further optimization of dual enzymatic inhibitions towards FGFR1 and DDR2, two important kinases in lung squamous cell carcinoma. Finally, from the cellular antiproliferative activity tests and in vivo pharmacokinetic test, 3-substituted indazole derivative 11k was found to be a promising candidate and subjected to in vivo pharmacology study with the mouse xenograft models, demonstrating profound anti-tumor efficacy. Additional in vitro druglike assessment reinforced that compound 11k could be valuable for SqCC drug development. Graphical abstract Image 1 Highlights • Lung Squamous Cell Carcinoma is a complex disease and involves multi-target abnormality. • Kinase focused library was used to identify indazole scaffold for developing multi-target inhibitors. • Promising candidate was selected with the balance of enzymatic potency, antiproliferative inhibition and DMPK. • In vivo PK and pharmacology studies confirmed the potential of compound 11k for further development. [ABSTRACT FROM AUTHOR]

Abstract Although mutated Ras protein is well recognized as an important drug target, direct targeting Ras has proven to be a daunting task. Recent studies demonstrated that Ras protein needs PDEδ to relocate to plasma membrane to execute its signaling transduction function, which provides a new avenue for modulating the Ras protein. To find small molecules antagonizing the interactions between PDEδ and Ras, here we presented a successful application of fragment-based drug discovery of PDEδ inhibitors. Under the guidance of crystal structures, we are able to quickly optimize the initial fragment into highly potent inhibitors, with more than 2000-fold improvement in binding activity, which further adds to the arsenal towards the inhibition of Ras signaling in cancer therapy. Graphical abstract Image 1 Highlights • Fragment-based approach was used to discover a new chemotype targeting PDEδ-Ras interaction. • Scaffold modification was undertaken on the basis of co-crystal structure and resulted in an optimizable hit. • Two rounds of optimization quickly improved the binding activity by more than 1000 fold. • Biological study indicates the PDEδ-Ras inhibitor could affect the downstream Ras signaling. [ABSTRACT FROM AUTHOR]

Recently, several kinase inhibitors were found to also inhibit bromodomains, providing a new strategy for the discovery of bromodomain inhibitors. Along this line, starting from PLK1-BRD4 dual inhibitor BI-2536, we discovered a new series of dihydroquinoxalin-2(1 H )-one with aniline and indoline WPF binders as selective BRD4 inhibitors. They showed better BRD4-BD1 potency and negligible PLK1 kinase activity comparing with BI-2536. Additionally, dihydroquinoxalin-2(1 H )-ones containing indoline group showed profound activities in molecular and cellular based assays. Throughout the study, compounds 9 , 28 and 37 showed significant inhibitory activity for c-Myc or PD-L1 protein expression and mRNA transcription both at concentration of 0.2 and 1 μM. Compound 9 was found possessing the best balance of binding affinity, in vitro metabolic stability and in vivo pharmacokinetic properties. Therefore, it was selected for in vivo pharmacological study. By using MM.1S cell derived xenograft model, we confirmed compound 9 showed comparable in vivo tumor inhibition to phase II investigation drug I-BET762, which, together with the novel WPF binder, further indicated the utility of this series of BRD4 inhibitors. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor receptors (FGFRs), a subfamily of receptor tyrosine kinases, are aberrant in various cancer types, and considered to be promising targets for cancer therapy. We started with a weak-active compound that was identified from our internal hepatocyte growth factor receptor (also called c-Met) inhibitor project, and optimized it with the guidance of a co-crystal structure of compound 8 with FGFR1. Through rational design, synthesis, and the biological evaluation of a series of 5H-pyrrolo[2,3-b]pyrazine derivatives, we discovered several potent FGFR kinase inhibitors. Among them, compound 13 displayed high selectivity and favorable metabolic properties, demonstrating a promising lead for further development. [ABSTRACT FROM AUTHOR]

PTP1B serving as a key negative regulator of insulin signaling is a novel target for type 2 diabetes and obesity. Modification at ring B of N-{4-[(3-Phenyl-ureido)-methyl]-phenyl}-methane-sulfonamide template to interact with residues Arg47 and Lys41 in the C site of PTP1B by molecular docking aided design resulted in the discovery of a series of novel high potent and selective inhibitors of PTP1B. The structure activity relationship interacting with the C site of PTP1B was well illustrated. Compounds 8 and 18 were shown to be the high potent and most promising PTP1B inhibitors with cellular activity and great selectivity over the highly homologous TCPTP and other PTPs. [ABSTRACT FROM AUTHOR]

From a readily available 5- C -Me ribofuranoside, we have realized a reliable route to valuable 5′-deoxy-5′-amino-5′- C -methyl adenosine derivatives at gram scale with confirmed stereochemistry. These adenosine derivatives are useful starting materials for the preparation of 5′-deoxy-5′-amino-5′- C -methyl adenosine derivatives with higher complexity. From one of the new adenosine derivatives, some 5′-deoxy-5′-amino-5′- C -methyl adenosine DOT1L inhibitors were prepared in several steps. Data from DOT1L assay indicated that additional 5′- C -Me group improved the enzyme inhibitory activity. [ABSTRACT FROM AUTHOR]

Recent years have seen much effort to discover new chemotypes of BRD4 inhibitors. Interestingly, some kinase inhibitors have been demonstrated to be potent bromodomain inhibitors, especially the PLK1 inhibitor BI-2536 and the JAK2 inhibitor TG101209, which can bind to BRD4 with IC 50 values of 0.025 μM and 0.13 μM, respectively. Although the concept of dual inhibition is intriguing, selective BRD4 inhibitors are preferred as they may diminish off-target effects and provide more flexibility in anticancer drug combination therapy. Inspired by BI-2536, we designed and prepared a series of dihydroquinoxalin-2(1 H )-one derivatives as selective bromodomain inhibitors. We found compound 54 had slightly higher activity than (+)-JQ1 in the fluorescence anisotropy assay and potent antiproliferative cellular activity in the MM.1S cell line. We have successfully solved the cocrystal structure of 52 in complex with BRD4-BD1, providing a solid structural basis for the binding mode of compounds of this series. Compound 54 exhibited high selectivity over most non-BET subfamily members and did not show bioactivity towards the PLK1 kinase at 10 or 1 μM. From in vivo studies, compound 54 demonstrated a good PK profile, and the results from in vivo pharmacological studies clearly showed the efficacy of 54 in the mouse MM.1S xenograft model. [ABSTRACT FROM AUTHOR]

Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2- a ]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin. [ABSTRACT FROM AUTHOR]

Addition of a wide range of Grignard reagents to acetone protected (2-methyl-5- tert -butyl)phenyl 1-thio- β - D -ribopentodialdo-1,4-furanoside 3b produced useful 5( R ) C -substituted products with moderate to good yields, and moderate to perfect stereoselectivities, with no need of additives. n.O.e. Analysis of 3b showed that 1- S -aryl group could contribute to the stereoselectivity of addition reaction. The stereochemistry of 4 representative 5- C -substituted ribofuranoside products was further confirmed by NMR study of corresponding Mosher esters, by chemical derivatization, or by single crystal study. [ABSTRACT FROM AUTHOR]

We have discovered a unique stabilization condition forbeta-amino ketone7. With compound7as an unprecedented intermediate, omarigliptin1could be prepared in a highly efficient one-pot procedure with good yield. Also with this intermediate7, some analogues of omarigliptin1were readily prepared for the first time. [ABSTRACT FROM AUTHOR]

A readily available intermediate obtained from d-arabinose was identified as a versatile starting material for the stereoselective synthesis of C-pentopyranosides in one pot. For two of the C-pentopyranosides, subsequent epoxide ring formation and a regioselective opening process was proven to be a robust approach to 3-deoxy C-pentopyranosides in two to four steps. A key intermediate used in the preparation of omarigliptin was obtained in four steps. Most of the conversions were high-yielding and proceeded with high selectivities on a multigram scale. [ABSTRACT FROM AUTHOR]

Menin is an essential oncogenic cofactor for mixed lineage leukemia (MLL)-mediated leukemogenesis, functioning through its direct interaction with MLL1 protein. Therefore, targeting the menin–MLL1 protein–protein interface represents a promising strategy to block MLL-mediated leukemogenesis. On the basis of co-crystal structure analysis, starting from thienopyrimidine chemotype, we have investigated the detailed structure–activity relationship of the piperazinyl-dihydrothiazole moiety. Several compounds were found with potent inhibitory activity against menin and better activities in cell-based experiments than MI-2-2. Molecular docking analysis revealed a less explored subpocket, which could be used for the design of new menin–MLL1 inhibitors. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) as a key negative regulator of both insulin and leptin receptor pathways has been an attractive therapeutic target for the treatment of type 2 diabetes mellitus (T2DM) and obesity. With the goal of enhancing potency and selectivity of the PTP1B inhibitors, a series of methyl salicylate derivatives as ABC type PTP1B inhibitors ( P1–P7 ) were discovered. More importantly, compound P6 exhibited high potent inhibitory activity (IC 50 = 50 nM) for PTP1B with 15-fold selectivity over T-cell PTPase (TCPTP). Further studies on cellular activities revealed that compound P6 could enhance insulin-mediated insulin receptor β (IRβ) phosphorylation and insulin-stimulated glucose uptake. [ABSTRACT FROM AUTHOR]

From multi-substituted 8-aminoimidazo[1,2- a ]pyrazines, prepared via modified Groebke–Blackburn–Bienaymé reaction, a Pd-catalyzed cyclization reaction was discovered, leading to a rare ( Z )-4,5-dihydro-3 H -[1,3]diazocine system. Conditions of this cyclization were screened and DMF solvent was found as one of the key factors for the cyclization. [ABSTRACT FROM AUTHOR]

A series of 2-aryl-imidazo-pyridines/pyrazines derivatives has been designed, synthesized and evaluated for their biological activities. Among them, several investigated compounds ( 1a , 3b and 3d ) displayed potent antiproliferative activity against HeLa cell, and also displayed comparable tubulin polymerization inhibitory activity to colchicine. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin. [ABSTRACT FROM AUTHOR]

The histone methylation on lysine residues is one of the most studied post-translational modifications, and its aberrant states have been associated with many human diseases. In 2012, Kruidenier et al. reported GSK-J1 as a selective Jumonji H3K27 demethylase (JMJD3 and UTX) inhibitor. However, there is limited information on the structure–activity relationship of this series of compounds. Moreover, there are few scaffolds reported as chelating groups for Fe(II) ion in Jumonji demethylase inhibitors development. To further elaborate the structure–activity relationship of selective JMJD3 inhibitors and to explore the novel chelating groups for Fe(II) ion, we initialized a medicinal chemistry modification based on the GSK-J1 structure. Finally, we found that several compounds bearing different chelating groups showed similar activities with respect to GSK-J1 and excellent metabolic stability in liver microsomes. The ethyl ester prodrugs of these inhibitors also showed a better activity than GSK-J4 for inhibition of TNF-α production in LPS-stimulated murine macrophage cell line Raw 264.7 cells. Taking together, the current study not only discovered alternative potent JMJD3 inhibitors, but also can benefit other researchers to design new series of Jumonji demethylase inhibitors based on the identified chelating groups. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatase 1B (PTP1B) which plays an important role in the negative regulation of insulin and leptin pathway has emerged as a novel promising therapeutic target for the treatment of type 2 diabetes mellitus and obesity. Upon careful study, a series of novel scaffold and simple synthesis method inhibitors were discovered based on the analysis of X-ray crystal structures of PTP1B/inhibitor complexes and docking simulations. Among them, compound P7 exhibited high inhibitory activity (IC 50 = 222 nM) with moderate selectivity (8-fold) over T-cell PTPase (TCPTP) through interacting with the A, B and C binding sites of PTP1B enzyme. Further studies on cellular activities revealed that compound P7 could enhance insulin-mediated IRβ phosphorylation and insulin-stimulated glucose uptake. [ABSTRACT FROM AUTHOR]

From adenosine and 2′- C -Me adenosine, a 3-step route towards nucleoside DOT1L inhibitors, including pinometostat, EPZ5677, and FED1, was established. With useful structural-activity relationship information, the newly prepared 2′- C -Me adenosine derivatives contribute to the limited repertoire of ribose-modified nucleoside DOT1L inhibitors. In general, this new synthetic method will facilitate not only the study of nucleoside DOT1L inhibitors, but also the synthetic and medicinal chemistry research of 5′-deoxy-5′-amino adenosine derivatives. [ABSTRACT FROM AUTHOR]

Fragment-docking-oriented de novel design for both the catalytic site and the C phosphotyrosine binding site led to the discovery of novel scaffold and chemical easy N -(2,5-diethoxy-phenyl)-methanesulfonamide based phosphotyrosine mimetics that when incorporated into ureas are high potent and selective inhibitors of protein tyrosine phosphatase 1B. Among them, compound 15 was shown to be the most potent PTP1B inhibitor with great selectivity over the highly homologous T-cell protein tyrosine phosphatase. [ABSTRACT FROM AUTHOR]

The signal transduction of acetylatedhistone can be processedthrough a recognition module, bromodomain. Several inhibitors targetingBRD4, one of the bromodomain members, are in clinical trials as anticancerdrugs. Hereby, we report our efforts on discovery and optimizationof a new series of 2-thiazolidinones as BRD4 inhibitors along ourprevious study. In this work, guided by crystal structure analysis,we reversed the sulfonamide group and identified a new binding mode.A structure–activity relationship study on this new seriesled to several potent BRD4 inhibitors with IC50of about0.05–0.1 μM in FP binding assay and GI50of0.1–0.3 μM in cell based assays. To complete the lead-likeassessment of this series, we further checked its effects on BRD4downstream protein c-Myc, investigated its selectivity among fivedifferent bromodomain proteins, as well as the metabolic stabilitytest, and reinforced the utility of 2-thiazolidinone scaffold as BETbromodomain inhibitors in novel anticancer drug development. [ABSTRACT FROM AUTHOR]

GatekeeperT790 M mutation in EGFR is the most prevalent factorunderlying acquired resistance. Acrylamide-bearing quinazoline derivativesare powerful irreversible inhibitors for overcoming resistance. Nevertheless,concerns about the risk of nonspecific covalent modification havemotivated the development of novel cysteine-targeting inhibitors.In this paper, we demonstrate that fluoro-substituted olefins canbe tuned to alter Michael addition reactivity. Incorporation of theseolefins into the quinazoline templates produced potent EGFR inhibitorswith improved safety and pharmacokinetic properties. A lead compound 5awas validated against EGFRWT, EGFRT790Mas well as A431 and H1975 cancer cell lines. Additionally, compound 5adisplayed a weaker inhibition against the EGFR-independentcancer cell line SW620 when compared with afatinib. Oral administrationof 5aat a dose of 30 mg/kg induced tumor regressionin a murine-EGFRL858R/T790Mdriven H1975 xenograft model.Also, 5aexhibited improved oral bioavailability andsafety as well as favorable tissue distribution properties and enhancedbrain uptake. These findings provide the basis of a promising strategytoward the treatment of NSCLC patients with drug resistance. [ABSTRACT FROM AUTHOR]

Upregulation of pyruvate dehydrogenasekinase (PDHK) has been observedin a variety of cancers. Inhibition of PDHK offers an attractive opportunityfor the development of novel cancer therapies. To obtain novel PDHKinhibitors, we took advantage of the homology of the ATP-binding pocketbetween Heat Shock Protein 90 (HSP90) and PDHK, and utilized 4,5-diarylisoxazolebased HSP90 inhibitor for structural design. Our efforts led to theidentification of 5kthat inhibited PDHK1 with an IC50value of 17 nM, which, however, showed marginal cellularactivity. Further structural optimization resulted in compound 11awith improved cellular activity which could effectivelymodulate the metabolic profile of cancer cells and lead to the inhibitionof cancer cell proliferation, evidenced by the increased oxidativephosphorylation and decreased glycolysis and associated oxidativestress. Our results suggested 11aas an excellent leadcompound and a favorable biological tool to further evaluate the therapeuticpotential of PDHK and HSP90 dual inhibitors in the treatment of cancer. [ABSTRACT FROM AUTHOR]

HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N -(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide ( 108 ) showed high affinity for binding to HSP90 (FP binding assay, IC 50 = 0.030 μM) and inhibited the proliferation of various human cancer cell lines with averaging GI 50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study. [ABSTRACT FROM AUTHOR]

Activated by NBS, readily available 1,2- trans -1-dihydroxyboryl benzyl S -glycosides served as glycosyl donors and reacted with certain simple alcohol acceptors to produce pure 1,2- cis - O -glycosides in moderate yields. The boronic acid moiety was revealed essential in the glycosylation for product formation and good anomeric ratio. The preliminary model reactions suggested that glycosyl aryl boronic acids could be used for stereoselective glycosylation. [ABSTRACT FROM AUTHOR]

Nucleophilic addition of difluoromethyl-2-pyridyl sulfone to sugar lactones proceeded with good yield and excellent stereoselectivity. The hitherto unknown direct addition intermediates are stable and capable of useful conversions: Formal elimination of the anomeric hydroxy and sulfonyl groups yielded a 1-deoxy-1-difluoromethylene mannopyranose derivative. Directly from sugar lactones, by nucleophilic addition and subsequent one-pot reduction with allylmagnesium chloride, unprecedented fluorinated 2-ketose analogues were prepared efficiently. [ABSTRACT FROM AUTHOR]

Abstract: Heat shock protein 90 (HSP90) is a molecular chaperone to fold and maintain the proper conformation of many signaling proteins, especially some oncogenic proteins and mutated unstable proteins. Inhibition of HSP90 was recognized as an effective approach to simultaneously suppress several aberrant signaling pathways, and therefore it was considered as a novel target for cancer therapy. Here, by integrating several techniques including the fragment-based drug discovery method, fragment merging, computer aided inhibitor optimization, and structure-based drug design, we were able to identify a series of HSP90 inhibitors. Among them, inhibitors 13, 32, 36 and 40 can inhibit HSP90 with IC50 about 20–40nM, which is at least 200-fold more potent than initial fragments in the protein binding assay. These new HSP90 inhibitors not only explore interactions with an under-studied subpocket, also offer new chemotypes for the development of novel HSP90 inhibitors as anticancer drugs. [Copyright &y& Elsevier]

Abstract: A series of 6H-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones have been synthesized and evaluated for their antiproliferative activities. Among them, compounds 2j and 4d displayed potent cytotoxic activities in vitro against HeLa cell line with IC50 values of 0.07 and 0.06μM, respectively. In general, the antiproliferative activities are correlated with the inhibitory effect on tubulin polymerization and binding property of the colchicine binding site. In addition, flow cytometry and immunofluorescence analysis revealed selected compounds caused G2/M phase arrest of the cell cycle and disruption of the mitotic spindle assembly, which had correlation with proliferation inhibitory activity. [Copyright &y& Elsevier]

Abstract: We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous Aβ1–40 production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure–activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50 = 0.025 μM) and compound 33 showed moderate inhibition effects on Aβ production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. [Copyright &y& Elsevier]

An efficient tandem route to the synthesis of 2,2a1,4-triazacyclopenta[ cd]indene derivatives of the cyclazine family has been developed. The target compounds were obtained in moderate to good yields by an ytterbium(III) triflate/palladium(II) acetate-catalyzed three-component domino reaction involving a palladium-catalyzed intramolecular α-arylation of an α-aminocarbonyl functionality. This in turn will set the stage for a wide application of this useful reaction for the synthesis of structurally diverse polyheterocyclic skeletons containing the privileged imidazo[1,2- a]pyridine structure. [ABSTRACT FROM AUTHOR]

Abstract: 36 new compounds with the typical skeleton of 4-anilino-5-vinyl/ethynyl pyrimidine, 4-anilino-3-cyano-5-vinyl/ethynyl/phenyl pyridine, and m-amino-N-phenylbenzamide, are designed, synthesized and selectively tested on EGFR, ErbB-2 kinases, and A-549, HL60 cells growth inhibition. Results from the bioactivity and chemical structures yield preliminary structure–activity relationships (SARs). The most potent 5-ethynylpyrimidine derivative 20a has an IC50 value of 45nM to EGFR kinase. Several compounds of other series also show IC50 values <1μM for EGFR and <5μM for A-549 and HL60 cells growth inhibition. [Copyright &y& Elsevier]

Abstract: The potential roles of 11β-HSD1 inhibitors in metabolic syndrome, T2D and obesity were well established and currently several classes of 11β-HSD1 inhibitors have been developed as promising agents against metabolic diseases. To find potent compounds with good pharmacokinetics, we used the bioisosterism approach, and designed the compound 2 and 3 bearing an 1,2,4-oxadiazole ring to replace the amide group in compound 1. Guided by docking study, we then transformed compound 3 into a potent lead compound 4a by changing sulfonamide group to amide. To elaborate this series of piperidyl–oxadiazole derivatives as human 11β-HSD1 inhibitors, we explored the structure–activity relationship of several parts of the lead compound. Based on their potency toward human 11β-HSD1 two compounds 4h and 4q were advanced to pharmacokinetic study. It was found that 4h and 4q are potent and selective human 11β-HSD1 inhibitors with better pharmacokinetic properties than those of the original piperidine-3-carboxamide compound 1, and suitable for further in vivo preclinical study in primate model. [Copyright &y& Elsevier]

Water is an important component in living systems and deserves better understanding in chemistry and biology. However, due to the difficulty of investigating the water functions in protein structures, it is usually ignored in computational modeling, especially in the field of computer-aided drug design. Here, using the potential of mean forces (PMFs) approach, we constructed a water PMF (wPMF) based on 3946 non-redundant high resolution crystal structures. The extracted wPMF potential was first used to investigate the structure pattern of water and analyze the residue hydrophilicity. Then, the relationship between wPMF score and the B factor value of crystal waters was studied. It was found that wPMF agrees well with some previously reported experimental observations. In addition, the wPMF score was also tested in parallel with 3D-RISM to measure the ability of retrieving experimentally observed waters, and showed comparable performance but with much less computational cost. In the end, we proposed a grid-based clustering scheme together with a distance weighted wPMF score to further extend wPMF to predict the potential hydration sites of protein structure. From the test, this approach can predict the hydration site at the accuracy about 80% when the calculated score lower than −4.0. It also allows the assessment of whether or not a given water molecule should be targeted for displacement in ligand design. Overall, the wPMF presented here provides an optional solution to many water related computational modeling problems, some of which can be highly valuable as part of a rational drug design strategy. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: 1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-methane (CbOCH2Ts, Cb=N,N-diisopropylcarbamoyl) was readily prepared from p-TolSH, paraformaldehyde and CbCl. With the dual activation of CbO- and Ts-substitutions, deprotonation of CbOCH2Ts could be effected not only by n-BuLi, but also by Grignard reagents. Upon deprotonation, the title compound adds to various carbonyl structures. By choosing proper organometallic reagents for consecutive steps, the addition intermediate undergoes in situ conversions to efficiently yield regioselectively O-Cb protected and unprotected 1,2-diols. [Copyright &y& Elsevier]

A new practical method for the synthesis of tetracyclic pyrido[2′,1′:2,3]imidazo[5,1- a]isoquinolinium compounds by a Yb(OTf)3/AgOTf-catalyzed (Tf = triflate) three-component domino reaction was developed. Significantly, the strategy presents a straightforward and efficient approach to constructing a series of compounds with potent cytotoxic activities. [ABSTRACT FROM AUTHOR]

Abstract: The introduction of the multi-objective optimization has dramatically changed the virtual combinatorial library design, which can consider many objectives simultaneously, such as synthesis cost and drug-likeness, thus may increase positive rates of biological active compounds. Here we described a software called CCLab (Combinatorial Chemistry Laboratory) for combinatorial library design based on the multi-objective genetic algorithm. Tests of the convergence ability and the ratio to re-take the building blocks in the reference library were conducted to assess the software in silico, and then it was applied to a real case of designing a 5×6 HDAC inhibitor library. Sixteen compounds in the resulted library were synthesized, and the histone deactetylase (HDAC) enzymatic assays proved that 14 compounds showed inhibitory ratios more than 50% against tested 3 HDAC enzymes at concentration of 20μg/mL, with IC50 values of 3 compounds comparable to SAHA. These results demonstrated that the CCLab software could enhance the hit rates of the designed library and would be beneficial for medicinal chemists to design focused library in drug development (the software can be downloaded at: http://202.127.30.184:8080/drugdesign.html). [Copyright &y& Elsevier]

Abstract: Several classes of non-steroid 11β-HSD1 inhibitors have been developed as promising treatments for Type 2 Diabetes (T2D). Using a human 11β-HSD1 selective inhibitor as a starting point, we designed and synthesized a new class of derivatives of 1-arylsulfonyl piperidine-3-carboxamides. It was found that the large lipophilic group on the amino moiety may lead to cross-species potency towards human and mouse, allowing drug development by evaluating compounds in rodent model. By exploring structure–activity-relationship, the (R)-(+)-bornylamine derivative is identified as the most potent inhibitor of mouse enzyme 11β-HSD1 with an IC50 of 18nM. Docking studies revealed the different possible interaction modes of the S-enantiomer and R-enantiomer bound to h11β-HSD1, and explained why the S-enantiomer is more active than the R-enantiomer. Finally, two potent and isoform-selective compounds, (+)-isopinocampheylamine derivative 8m and (R)-(+)-bornylamine derivative 8l, with suitable in vitro properties, could be selected for future PK/PD evaluation in rodent models. Then, 8l was subjected a pharmacodynamics study in vivo with rodent model. It was shown that 8l have 71% and 63% inhibition in adipose and liver tissue at 1h after administration, but it was a short-acting compound displaying a significant drop in potency in the subsequent 3h. This study not only provides compounds as novel h11β-HSD1 inhibitors, but also presents structure–activity relationships for designing potent human/mouse 11β-HSD1 inhibitors suitable for in vivo evaluation in rodent models. [Copyright &y& Elsevier]

Abstract: We recently discovered and reported a novel series of benzhydrylpiperazine derivatives bearing an asymmetric carbon atom that are potent and selective hCB1 inverse agonists. In the present study, we used Davis-Ellmann-type sulfonamide chemistry to asymmetrically synthesize two enantiomers of the most potent racemic N-cyclohexyl-4-[1-(2,4-dichlorophenyl)-1-(p-tolyl)methyl]piperazine-1-carbo-xamide . Enantiomer separation and configuration assignment were carried out. Our results indicate that the R-configuration is the more active enantiomer, displaying enhanced antagonistic activity for hCB1 receptor, better oral bioavailability, and greater efficacy in the reduction of body weight in diet-induced obese mice. [Copyright &y& Elsevier]

Abstract: Several potent and novel 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors were discovered from in silico screening the commercially available Maybridge database. Among them, seven hit compounds showed good affinity, with IC50 values lower than 100nM and the best one 3.7nM. To select the lead for further optimization, computational ADME/T prediction, the CYP3A4 inhibition and 11β-HSD1 over 11β-HSD2 selectivity test were also performed. Taking all of the above factors into consideration, two promising compounds were selected as lead structures for further development. The employed hierarchical virtual screening protocol not only demonstrates its efficiency, but also provides novel and selective compounds for developing 11β-HSD1 inhibitors to protect against metabolic syndrome. [Copyright &y& Elsevier]

Abstract: A novel class of non-steroidal progesterone receptor antagonists with aromatic β-amino-ketone scaffold have been synthesized and characterized with high binding affinity and great selectivity for the cognate receptors. Among them, compound 22 was shown to be the most potent progesterone receptor antagonist in cotransfection assay and a murine model of ligand-induced decidualization. [Copyright &y& Elsevier]

Abstract: The present study describes the identification via privileged structure-based approach of the benzhydrylpiperazine moiety as a potential scaffold to develop novel CB1 receptor modulators. Efficient structural optimization of the initial four hit compounds led to a high quality lead series, represented by compound 6c. Compound 6c is a highly potent and selective CB1 receptor inverse agonist that is able to reduce body weight in diet-induced obese Sprague–Dawley rats. The preparation of privileged structure-based library, the progression from hit to lead, the structure–activity relationships in the lead series and in vitro and in vivo activity of compound 6c are discussed. [Copyright &y& Elsevier]

Abstract: To explore novel effective drugs for the treatment of Alzheimer’s disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and β-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC50 =0.567μM; AChE: IC50 =1.83μM), and also showed excellent inhibitory effects on Aβ production of APP transfected HEK293 cells (IC50 =98.7nM) and mild protective effect against hydrogen peroxide (H2O2)-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Aβ1–40 production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients. [Copyright &y& Elsevier]

Abstract: A novel synthesis of the human leukocyte common antigen-related (LAR) phosphatase inhibitor, illudalic acid, has been achieved by a route more amenable to structure modifications. A series of simpler analogues of illudalic acid was synthesized and evaluated for potency in inhibiting LAR. The structure–activity relationship (SAR) study has shown that the 5-formyl group and the hemi-acetal lactone are crucial for effective inhibition of LAR activity, and are the key pharmacophores of illudalic acid. The fused dimethylcyclopentene ring moiety evidently helps to enhance the potency of illudalic acid against LAR. A preliminary study of the mechanism of action of illudalic acid against LAR was conducted using electrospray ionization mass spectrometry (ESI-MS) and molecular docking techniques. The results are in full agreement with the described mechanism. [Copyright &y& Elsevier]

Abstract: A series of quinoxalinylurea-based inhibitors are synthesized and shown to be the novel and potent inhibitors against Jnk Stimulatory Phosphatase-1 (JSP-1), which is a special member of dual-specificity protein phosphatase (DSP) family. Biological assay and computational modeling studies showed the compounds were reversible and noncompetitive inhibitors of JSP-1. JSP-1 inhibitors may be useful for the treatment of inflammatory, vascular, neurodegenerative, metabolic, and oncological diseases in humans associated with dysfunctional Jnk signaling. [Copyright &y& Elsevier]

Abstract: Cyclophilin A (CypA) is a ubiquitous cellular enzyme playing critical roles in many biological processes, and its inhibitor has been reported to have potential immunosuppressive activity. In this work, we reported a novel quinoxaline derivative, 2,3-di(furan-2-yl)-6-(3-N,N-diethylcarbamoyl-piperidino)carbonylamino quinoxaline (DC838, 3), which was confirmed to be a potent inhibitor against human CypA. By using the surface plasmon resonance (SPR) and fluorescence titration techniques, the kinetic analysis of CypA/DC838 interaction was quantitatively performed. CypA peptidyl prolyl cis–trans isomerase (PPIase) activity inhibition assay showed that DC838 demonstrated highly CypA PPIase inhibitory activity. In vivo assay results showed that DC838 could inhibit mouse spleen cell proliferation induced by concanavalin A (Con A). Molecular docking simulation further elucidated the specific DC838 binding to CypA at the atomic level. The current work should provide useful information in the discovery of immunosuppressor based on CypA inhibitor. [Copyright &y& Elsevier]