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Twelve new grayanoids (1−12) along with five known compounds were isolated from flowers of Rhododendron molle. Their structures were fully characterized using a combination of spectroscopic analyses, computational calculations, and single crystal X-ray diffraction. Rhomollone A (1) possesses an unprecedented 5/6/6/5 tetra-cyclic ring system (B-nor grayanane) incorporating a cyclopentene-1,3-dione scaffold. Rhodomollein XLIII (2) is a dimeric grayanoid, containing a novel 14-membered heterocyclic ring with a C2 symmetry axis. The antinociceptive activities of compounds 3, 4, 6, 7, and 12−17 were evaluated by an acetic acid-induced writhing test. Among them, compounds 3, 7, 12, 15 and 16 displayed significant antinociceptive activities at a dose of 20 mg/kg with inhibition rates ranging from 41.9% to 91.6%. Compounds 6 and 13 inhibited 46.0% and 39.4% of the acetic acid-induced writhes at a dose of 2 mg/kg, while compound 17 inhibited 34.3% of the writhes at a dose of 0.4 mg/kg., Graphical abstract Twelve new grayanane-derived diterpenoids including one possesses an unprecedented 5/6/6/5 tetra-cyclic ring system incorporating a cyclopentene-1,3-dione scaffold were isolated from flowers of Rhododendron molle. Some compounds displayed significant antinociceptive activity.Image 1

A series of novel anaplastic lymphoma kinase (ALK) degraders were designed and synthesized based on proteolysis-targeting chimera (PROTAC) technology by linking two alectinib analogs (36 and 37) with pomalidomide through linkers of different lengths and types. The most promising degrader 17 possessed a high ALK-binding affinity and potent antiproliferative activity in the ALK-dependent cell lines and did not exhibit obvious cytotoxicity in ALK fusion-negative cells. More importantly, the efficacy of compound 17 in a Karpas 299 xenograft mouse model was further evaluated based on its ALK-sustained degradation ability in vivo. The reduction in tumor weight in the compound 17-treated group (10 mg/kg/day, I.V.) reached 75.82%, while alectinib reduced tumor weight by 63.82% at a dose of 20 mg/kg/day (P.O.). Taken together, our findings suggest that alectinib-based PROTACs associated with the degradation of ALK may have promising beneficial effects for treating ALK-driven malignancies.

Archaeological investigations undertaken by the Proyecto Arqueológico Tlajinga Teotihuacán are focused on understanding urban expansion and household economies in this southern district of the city. Our geoarchaeological research addresses similar topics through examination of relevant microstratigraphic and botanical signatures as well as those relevant to reconstructing paleoenvironment. We investigated four different contexts at Tlajinga: the southern extension of the Street of the Dead, an obsidian working area outside Compound 17:S3E1, anthropogenic and natural layers below Compound 18:S3E1, and a soil profile at the San Lorenzo river. We employed micromorphological, pollen, and phytolith analyses as well as standard soil analytics to study the various deposits in these contexts. Our analysis demonstrates artificial lowering of the tepetate for continuing the axis of the Street of the Dead, microdebitage from obsidian working outside Compound 17:S3E1, and the preservation of in situ burning activities at Compound 18:S3E1. Further, we reconstruct alluvial infilling of the Street of the Dead with pedogenetic overprinting and present further evidence on the occurrence and variability of the Black San Pablo Paleosol and its agricultural significance.

Skeletal remains from Tlajinga 33 (33:S3W1) have been the focus of research in the southern sector of Teotihuacan since excavations took place in the 1980s. Recent excavations in Tlajinga Compounds 17 and 18 (17:S3E1 and 18:S3E1, respectively), located along the southern Street of the Dead, recovered nine additional skeletons. This article is a description of the burials from Compounds 17 and 18 and a comparative analysis of health, diet, and chronology across all three compounds (Compounds 17, 18, and 33). Here, we test the hypothesis that individuals between residential compounds at Tlajinga lived similar lives and that health and biogeochemical markers of individuals will reflect these similarities. Although the sample size is small, the paleopathological analysis of individuals at Compounds 17 and 18 indicates morbidity patterns similar to Tlajinga 33, but also that these residents were perhaps less susceptible to stressors during periods of juvenile growth. Stable carbon and nitrogen isotopes suggest that, overall, diets were analogous across compounds, but Compounds 17 and 18 were able to supplement their diet with a greater variety of plant resources. There were no clear dietary differences between higher and lower status individuals, however. Finally, accelerated mass spectrometry radiocarbon (AMS14C) dates indicate that residential living may have occurred later at Compound 18 than at Compound 17 and Tlajinga 33.

The original research by the Teotihuacan Mapping Project (TMP) identified a large number of obsidian workshops within Teotihuacan based on surface concentrations of production debris. Clark (1986b) questioned the validity of these identifications and called for subsurface excavation to confirm the presence of in situ workshop locales. This article summarizes the results from the excavation of one of the obsidian workshops identified in the Tlajinga district of Teotihuacan at Compound 17:S3E1 (Compound 17). We describe the excavations, discuss the lithic technology, and examine the subsurface contexts in terms of what they tell us about in situ obsidian craft activity. Excavations confirm that Compound 17 was a locus of large-scale obsidian craft production during the Classic period. While only a single test case, these results suggest that surface remains at Teotihuacan can be a useful guide in identifying craft production areas when they are confirmed through subsurface testing.

Teotihuacan's Tlajinga district is a cluster of neighborhoods on the southern periphery of the city best known for earlier investigations at Compound 33:S3W1. New research includes excavations at two other apartment compounds and along the southern extension of the Street of the Dead. Excavation contexts, major finds, chronology, and preliminary interpretations are the subject of this article. We highlight evidence attesting to a major obsidian-blade workshop at Compound 17:S3E1, offerings, and other features at that compound and Compound 18:S3E1, and the tempo and processes of urbanization viewed through well-recorded stratigraphic sequences of the compounds and the Street of the Dead. We conclude that significant occupation began in the Miccaotli phase, but it was not until some point in the Early Tlamimilolpa phase that the dominant housing type became apartment compounds; the continuation of the axis of Street of the Dead in the district was accomplished by excavating in the volcanic tuft substrate (tepetate) and could have been undertaken by the inhabitants of the district themselves; and the presence of items such as a sculpted stone face, marine shell, and polychrome pottery demonstrates that commoners at Teotihuacan enjoyed some access to finer items within the interregional economy.

[Image: see text] Recent experimental evidence demonstrated an aberrant overexpression of cyclooxygenase-1 (COX-1) in various cancers, which has stimulated the development of COX-1-selective inhibitors as promising anticancer drugs and cancer imaging agents. Herein we describe the synthesis and validation of 3-(furan-2-yl)-N-aryl 5-amino-pyrazoles as a novel class of COX-1 inhibitors, including molecular docking studies. Among all tested compounds, 4-(5-azido-3-(furan-2-yl)-1H-pyrazol-1-yl)benzoic 17 displayed a favorable COX-1 inhibition and selectivity profile (COX-1 IC(50) = 0.1 μM, SI >1000 over COX-2). Compound 17 was selected as a lead structure for developing the novel COX-1-selective fluorescent probe 22. Fluorescent probe 22 was prepared via click chemistry by installing a nitro-benzoxadiazole motif as a fluorophore into the 3-(furan-2-yl)-N-aryl 5-amino-pyrazole scaffold. Fluorescence probe 22 was tested in ovarian cancer cell line OVCAR-3, confirming its usefulness for targeting and visualizing COX-1 in living cells with confocal microscopy.

Background Time consumed and expenses in discovering and synthesizing new hypothetical drugs with improved biological activity have been a major challenge toward the treatment of multi-drug-resistant strain Mycobacterium tuberculosis (TB). To solve the above problem, quantitative structure activity relationship (QSAR) is a recent approach developed to discover novel agents with better biological activity against M. tuberculosis. Results A validated QSAR model was developed in this study to predict the biological activities of some anti-tubercular compounds and to design new hypothetical drugs is influenced with the molecular descriptors, AATS7s, VR1_Dzi, VR1_Dzs, SpMin7_Bhe, and TDB8e, which has been validated through internal and external validation test. Prior to high anti-tubercular activity of the lead compound, compound 17 served as a template structure to design compounds with improved activity. Among the compounds designed, compounds 17i, 17j, and 17n were observed with improved anti-tubercular activities which ranges from 8.8981 to 9.0377 pBA. Conclusion The outcome of this research is recommended for pharmaceutical and medicinal chemists to synthesis and carry out an in vivo and in vitro screening for the proposed designed compounds in order to substantiate the computational findings.

Exploration of alternative structures of the substituted piperidine or piperazine ring which are characteristic in most of the reported GPR119 agonists provided novel spirocyclic cyclohexane derivatives. The representative 17 with a high three-dimensionality exhibited potent agonistic activity (EC50 = 4 nM) with no CYP inhibitory activity (IC50 >10 μM). Compound 17 also displayed hypoglycemic activity with insulin secretion dependent on glucose concentration in an intraperitoneal glucose tolerance test in rats.

Four new phenylpropanoid glycosides, clausenaglycosides A–D (1–4), along with fourteen known compounds (5–18) were isolated from the leaves and twigs of Clausena dunniana var. robusta. The structures of the isolated compounds were determined by a combination of 1D and 2D NMR, MS, and CD spectroscopic data. The NF-κB inhibitory activity was evaluated in HeLa cells. Compound 17 displayed a moderate inhibition against NF-κB activation.

Sorafenib, is a relatively new cytostatic drug approved for the treatment of renal cell and hepatocellular carcinoma. The development of new sorafenib analogues offers the possibility of generating structures of increased potency. To this end, a series of arylated-diphenylurea analogues 17–31 were synthesized via Suzuki-Miyaura coupling reaction, related to sorafenib by treatment of three diarylureas 2–4 having 3-bromo, 4-chloro and 2-iodo groups with various arylboronic acids. Conformational analysis of the new arylated urea analogues has been investigated using MOPAC 2016 of semi empirical PM7 Hamiltonian computational method. Our results showed that all compounds preferred the trans-trans conformations. Compound 17 has been selected to calculate the torsional energy profiles for rotation around the urea bonds and found to be existed predominantly in the trans-trans conformation with only very minimal fluctuation in conformation.

Chemical investigation of the red alga Laurencia tristicha led to the discovery of eight new halogenated chamigrane-type sesquiterpenoids (1-8) and one new bromocuparane-type sesquiterpene (9), along with nine known related metabolites (10-18). Their structures were elucidated on the basis of extensive spectroscopic analyses, and the absolute configurations of 1-8 were proposed by comparison to the biosynthetically related known compound 12. Cytotoxicity, antibacterial, and anti-inflammatory activities of these isolates were also investigated. The results showed that compound 11 exhibited good antibacterial activity against Serratia marcescens compared to the positive control ampicillin at a dosage of 100 μg/disk. Compound 17 showed strong inhibition toward elastase release generation at 10 μM.

A new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized from matrinine ( 1 ) and evaluated for their anti-HCV activity, taking compound 2 as the lead. SAR revealed that the introduction of a suitable substituent at the N ′-end of matrinic amide might greatly enhance the potency. Among them, matrinic acid 17 and N ′-substituted matrinic amides 18a – d exhibited promising potency with low micromolar EC 50 values ranging from 1.03 μmol/L to 7.54 μmol/L, and better therapeutic window with SI from 66 to 132. Moreover, compound 17 displayed an excellent PK and safety profile in vivo , demonstrating good drug-like characteristics. Thus, it has been selected for further investigation, with an advantage of decreased chances of inducing drug-resistance mutations.

This report presents the synthesis of four derivatives of 6-chloro-11-azabenzo[a]phenothiazine-5 one, of the type 15,16,17 and 18 .The starting material, 2-aminopyridine 8 was subjected to thiocynation and subsequently, to hydrolysis to furnish one of the key intermediates, 2 aminopyridine-3-thiol 10 .This was condensed with 2,3-dichloro-1,4-naphthoquinone 11 to yield 6 chloro-11-azabenzo[a]phenothiazinone 5. In the presence of a complex palladium catalyst system, compound 5 was coupled with arylphenylboronic acids, 6 and 7 to give 6-phenyl-11 azabenzo[a]phenothiazine-5-one 15 and 6-(3-nitrophenyl)-11- azabenzo[a]phenothiazine-5-one, 16 respectively. Reduction of the nitro-group in 16, furnished 6-(3- aminophenyl)-11 azabenzo[a]phenothiazine-5-one 17, while the oxidation of the amino-group in compound 17, produced 6-(3-hydroxyphenyl)-11-azabenzo[a]phenothiazine-5-one 18. Treatment of the above compounds 15, 16 ,17 and 18 respectively, with sodium dithionite gave color discharged unstable basis of the types 19, 20, 21 and 22 which could not be isolated, but reverted to the original compounds 15, 16,17 and 18 above immediately they were exposed to air. This property suggests that they can be used as vat dyes. The graphical representation of the schemes is shown below

Overexpressing myeloid cell leukemia sequence 1 (Mcl-1) protein is an important way to confer the resistance of cancer cells to conventional anti-cancer treatments. Therefore, developing Mcl-1 inhibitors has become an attractive strategy for cancer therapy. In the studies, a series of new indazole-acylsulfonamide hybrids were designed, synthesized and evaluated as potent Mcl-1 inhibitors. Among them, the most potent compound 17 (Ki = 0.43 μM) showed a little better inhibitory activity against Mcl-1 protein than positive control AT-101 (Ki = 0.45 μM). Pleasingly, it displayed > 40-fold selectivity over Bcl-2 (Ki = 18 μM) and Bcl-xL (no activity). Furthermore, compound 17 had good inhibitory activities against PC-3, MDA-MB-231 and K562 cells (IC50 = 12.3, 10.6 and 6.62 μM, respectively) and could effectively induce apoptosis and the activation of caspase-3 in a dose-dependent manner in K562 cells.

A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1 μg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5 μg/mL against S. aureus, MRSA, MSSA and VRE and 0.25 μg/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.

N-substituted azaindoles were discovered as promising pan-PIM inhibitors. Lead optimization is described en route toward the identification of a clinical candidate. Modulation of physico-chemical properties allowed to solve inherent hERG and permeability liabilities. Compound 17 showed tumor growth inhibition in a KG1 tumor-bearing mouse model.

A series of biotinylated camptothecin derivatives were designed and synthesized. The key to the synthesis was achieved by employing an esterification reaction and click chemistry. All of the new derivatives were tested for cytotoxicity against five human tumor cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values ranging from 0.13 to 21.53 μM. Most of the derivatives exhibited potent cytotoxicity, especially compound 17 (IC50 = 0.13–3.31 μM) and compound 18 (IC50 = 0.23–1.48 μM), which exhibited the highest potencies. The structure-activity relationships (SARs) of the biotinylated camptothecin derivatives were discussed for exploring novel anticancer agents.

Eighteen new 2-chloro-4-aminopyrimidine and 2,6-dimethyl-4-aminopyrimidine derivatives were synthesized and evaluated as tubulin polymerization inhibitor for the treatment of cancer. Among them, compounds 10, 17, 20 and 21 exhibited potent antiproliferative activities against five human cancer cell lines. Microtubule dynamics assay showed that compound 17 could effectively inhibit tubulin polymerization. Molecular docking studies were also carried out to understand the binding pattern. Further mechanism studies revealed that 17 could induce G2/M phase arrest, disrupt the organization of the cellular microtubule network and induce cell apoptosis and mitochondrial dysfunction.

Phenyl thiazole hydrazone derivatives 1–21 have been synthesized and screened for their in vitro antiglycation activity. Hydrazones 1–21 displayed assorted antiglycation activities having IC50 values in the range of 187.61 ± 1.12–886.98 ± 5.29 µM as compared to standard rutin (IC50 = 269.07 ± 3.79 µM). Compounds 5 (IC50 = 187.61 ± 1.12 µM), 3 (IC50 = 191.92 ± 3.08 µM), 4 (IC50 = 193.77 ± 3.06 µM), 6 (IC50 = 217.90 ± 2.48 µM), 15 (IC50 = 221.98 ± 2.34 µM), 2 (IC50 = 226.59 ± 1.19 µM), 21 (IC50 = 229.67 ± 1.95 µM), 18 (IC50 = 231.09 ± 0.38 µM), 12 (IC50 = 242.94 ± 2.05 µM), and 1 (IC50 = 264.22 ± 5.60 µM), respectively, showed excellent antiglycation activities superior to standard rutin. Compound 17 (IC50 = 269.94 ± 1.11 µM) demonstrated a comparable activity to the standard. Compounds 7, 8, 9, 10, 11, 13, 14, and 16 exhibited weaker activities than standard. However, compounds 19 and 20 showed no activity. When evaluated for cytotoxicity against rat fibroblast cell line (3T3 cell line), all compounds were found to be non-toxic in cellular model.

A series of novel 1,2,3-triazole-pyrimidine hybrids were designed, synthesized and evaluated for their anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Most of the synthesized compounds exhibited moderate to good activity against all the cancer cell lines selected. Compound 17 showed the most excellent anticancer activity with single-digit micromolar IC50 values ranging from 1.42 to 6.52 μM. Further mechanism studies revealed that compound 17 could obviously inhibit the proliferation of EC-109 cancer cells by inducing apoptosis and arresting the cell cycle at G2/M phase.

The discovery of selective inhibitors for acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) is extremely important for the development of drugs that can be used in the treatment of patients diagnosed with the Alzheimer's disease (AD). For this reason, there is a growing interest in developing rapid and effective assays techniques for cholinesterases (ChE) enzymes ligand screening. Herein is presented the results of selective screening assays of a coumarin derivatives library using BChE and AChE covalently immobilized onto silica fused capillaries (ICERs, 15 cm × 0.1 mm ID). The statistical comparison of the ICERs screening assay with that of the free enzymes is reported and highlights the advantages of the on-flow ICERs assay. Two out of 20 coumarin derivatives could be highlighted: compound 17 is more active toward BChE (IC₅₀=109 ± 21 μM) and 19 showed activity against both enzymes (BChE IC₅₀=128 ± 28 μM and hu-AChE IC₅₀=144 ± 40 μM). The statistical evaluation of the results of the ICERs and free enzyme assays showed no difference between them, further validating the ICERs assay model. The ICERs ability to recognize selective ligands and its use for characterization of the inhibition mechanisms of the hits consolidates the approach here reported.

Starting from TGX-221, we designed a series of 9-(1-anilinoethyl)-2-morpholino-4-oxo-pyrido[1,2-a]pyrimidine-7-carboxamides as potent and selective PI3Kβ/δ inhibitors. Structure–activity relationships and structure–property relationships around the aniline and the amide substituents are discussed. We identified compounds 17 and 18, which showed profound pharmacodynamic modulation of phosphorylated Akt in the PC3 prostate tumour xenograft, after a single oral dose. Compound 17 also gave significant inhibition of tumour growth in the PC3 prostate tumour xenograft model after chronic oral dosing.

A series of novel 2-hydrazinyl-4-morpholinothieno[3,2-d]pyrimidine derivatives was designed and synthesized. All of them were screened for their cytotoxic activities against large cell lung cancer(H460), colon cancer (HT-29) and adenocarcinomic lung cancer(A549) cell lines in vitro. The pharmacological results indicate that most of the target compounds show moderate to significant activities. Especially compound 17 exhibits the most potent antitumor activities against H460, HT-29 and A549 cell lines with IC50 values of 0.57, 0.45 and 1.45 μmol/L, respectively.

Recent studies have shown that nitroxyl (HNO) (1HNO/3NO−), which is the one-electron-reduced form of nitric oxide (NO), has unique biological activities, especially in the cardiovascular system, and HNO-releasing agents may have therapeutic potential. Since few HNO donors are available for use under physiological conditions, we synthesized and evaluated a series of Piloty’s acid (PA) derivatives and evaluated their HNO-releasing activity under physiological conditions. N-Hydroxy-2-nitrobenzenesulfonamide (17) was the most efficient HNO donor among our synthesized PA derivatives, including the lead compound, 2-bromo-N-hydroxybenzenesulfonamide (2). The high HNO-releasing activity is suggested to be due to electronic and steric effects. Compound 17 may be a useful tool for biological experiments.

Chemical constituents investigation on the seeds of Machilus yunnanensis led to two new phenolic compounds 8-O-acetyl-phenylethanoid-4-O-β-D-glucopyranoside (1) and (E)-2,3-bis(4-hydroxyphenyl)acrylaldehyde (2), together with 16 known compounds. Their structures were elucidated on the basis of spectroscopic data analysis (IR, MS, 1D, and 2D NMR). Meanwhile, compounds 1–3, 6–13, 17, and 18 were evaluated for vasorelaxant effects on the rat endothelium-intact thoracic aorta rings precontracted with phenylephrine (PE) or KCl. The bioassay results showed that compound 17 had significant vasorelaxant effect on the endothelium-intact thoracic aorta rings precontracted with KCl.

To elucidate the structure-geometry-activity relationship in diarylpyrimidine family (DAPYs) containing carbonyl linker between the central pyrimidine core and phenyl type B-arm, a series of (2,6-difluorophenyl)(2-(phenylamino)pyrimidin-4-yl)methanones was designed, prepared and tested for their anti-HIV-1 activity. The carbonyl linker bearing B phenyl arm was successfully attached at both C-2 and C-4 positions of the central pyrimidine ring using a new synthetic approach. Further modifications of target compounds are present at C-5 position of the pyrimidine ring. In vitro anti-HIV-1 activity study performed on a series of 22 compounds confirmed the crucial importance of both conformational rigidity between phenyl B arm and the pyrimidine core linked through the carbonyl bridge, as well as presence of fluoro substituents in ortho-positions of phenyl B moiety. The most potent derivative of the series, compound 17, having almost perpendicular angle within the two planes made from the B aromatic arm and the pyrimidine ring, exhibited low nanomolar anti-HIV-1 activity (EC50 = 4 nM) with no significant toxicity (CC50 > 57.1 μM).

A series of 2,5-disubstituted pyrimido[5,4- c ]quinoline derivatives were synthesized and their cytotoxic activity against H460, HT-29 and MDA-MB-231 cell lines was evaluated in vitro . It was found that most of the tested compounds especially compound 17 , shown stronger activity to the selected three cell lines than ZM447439.

The synthesis of new dioxa-cage compound 8 and diacetal trioxa-cage compound 17 has been accomplished from dicyclopentadiene in a short sequence. A preliminary study on the π-facial selectivity of 17, which possesses a new rigid skeleton, is also reported.

To find novel PPARdelta-selective agonists, we designed and synthesized phenylpropanoic acid derivatives bearing 6-substituted benzothiazoles. Optimization of this series led to the identification of a potent and selective PPARdelta agonist 17. Molecular modeling suggested that compound 17 occupies the Y-shaped pocket of PPARdelta appropriately.

Synthesis of different N 10 -substituted-4-methyl acridones are described. The compounds are prepared with varying alkyl side chain length with propyl and butyl substitution and a tertiary amine group at the terminal end of the alkyl side chain. The structural requirement of in-vitro anti-cancer and reversal of drug resistance are studied. These compounds have been tested against the breast cancer cell lines MCF-7 and MCF- 7/Adr. The results show that compound 17 with four carbon spacer exhibited promising in-vitro anti-cancer and reversal of drug resistance in comparison to the other analogues. The studies show that the reversal of drug resistance is by P-gp inhibition.

β‐Secretase inhibitors with a Leu*Ala hydroxyethylene dipeptide (HED) isostere have been an especially interesting topic in recent years. In this study, a template compound 17 was synthesized, featuring truncation at the P2′ position and changes at P2 and P3, which differs from other reported potent inhibitors. The purpose was to explore optimal reaction conditions and construct an inhibitor library to investigate ideal protein–substrate interaction.

3-Phosphoinositide-dependent kinase-1 (PDK1) plays a key role in the regulation of physiological processes and its catalytic activity is tightly regulated by allosteric modulators which bind to the PDK1 Interacting Fragment (PIF) pocket. However, details on the allosteric modulators regulation of the PDK1 catalytic activity remain elusive. Here, molecular docking and molecular dynamics (MD) simulations were performed to investigate the allosteric regulation of PDK1 induced by one of the benzoazepin-2-ones, the most potent compound 17 (BAZ2O). Molecular docking and MD simulation revealed that BAZ2O was located in the PIF pocket formed by residues from β4 and β5 sheets and helices αB and αC. BAZ2O formed a hydrogen bond with Arg131 and participated in hydrophobic interactions with Ile119, Thr148, Gln150, Leu155 and Phe157. Further comparative analyses of PDK1 in its apo and BAZ2O-bound states unveiled that BAZ2O promoted the structural coupling between the important catalytic domains of PDK1, including the activation loop and the helices αB and αC, thereby stabilizing the PDK1 conformation for catalysis. Understanding the allosteric interaction of PDK1 with small molecules provides a potentially valuable possibility of designing more potent allosteric modulators with therapeutic implications for lung cancer.

The reaction of Os3(CO)12 with Ph3SnH yielded the bimetallic Os−Sn cluster complexes Os3(CO)11(SnPh3)(μ-H) (16) and Os3(CO)9(μ-SnPh2)3 (17) in 20 and 21% yields, respectively. Compound 16 consists of an Os3 triangle with a terminal SnPh3 group on one of the Os atoms and a bridging hydrido ligand across one of the Os−Os bonds. Compound 17 consists of a central Os3 triangle with SnPh2 groups bridging each of the three Os−Os bonds. Pt(PBut3)2 reacts with compound 17 to afford Os3(CO)9[Pt(PBut3)](μ-SnPh2)3 (18), a Pt(PBut3) adduct of 17, in 29% yield by adding a Pt(PBut3) group across one of the Os−Sn bonds. The osmium and tin atoms lie in a plane, while the Pt(PBut3) group is displaced slightly out of that plane. Pt(PPh3)4 reacts with 17 to give the cluster complex Os3(CO)9[Pt(Ph)(PPh3)2](μ-SnPh2)2(μ3-SnPh) (19) in 21% yield by insertion of a Pt(PPh3)2 into one of the Sn−C bonds to one of the phenyl groups. The osmium and tin atoms are coplanar, and there is a Pt(Ph)(PPh3)2 group terminally bonded to one of ...

We report the synthesis and evaluation of a series of novel terphenyls. Compound 17 had the most potent anticancer activity, indicating that the phenolic hydroxyl was a key group. A DNA relaxation test showed that compound 17 had a strong inhibitory effect on TOP2α, but not on TOP1, which was consistent with the docking analysis results. We performed a 3D-QSAR study using CoMFA and CoMSIA to determine, for the first time, the chemical-biological relationship in the inhibition of TOP by terphenyls. The CoMFA and CoMSIA model had good modeling statistics: leave-one-out q(2) of 0.605 and 0.622, r(2) of 0.998 and 0.994, and r(2)pred (test set) of 0.742 and 0.660. These results suggest that the ortho-phenolic hydroxyl on ring A is important for producing terphenyls with more efficacious activity.

A convenient large-scalable synthesis of 1-benzazepines 19 as an important intermediate of CCR5 antagonist, oral HIV-1 therapy, was established. The anilination of o -halogenobenzaldehyde 9 with alkylamino-acid 16 gave o -formylaniline-acid 17 . Compound 17 was esterified followed by the improved reaction using the combination of alcoholate and dialkyl carbonate in one-pot, to easily produce 19 . Namely, these new processes afforded the desired product 19 in only two steps from the starting materials, as compared with the previous 10 steps. Moreover, these convenient methodologies were applied to other heterocycles to give 8–10 membered rings, such as 1-benzazocine, 1-benzazonine, and 1-benzazecine.

5′-Thioalkyl derivatives 4–6 were prepared from direct displacement of the 5′-O-tosylate analogue 3 in moderate yields. Oxidation of 4 and 5 with 1.0 aq. MMMP gave the sulfones 7 and 8, respectively, while similar treatment with 0.5 eq. MMPP or soudium periodate, 4 afforded the sulfoxide 9. Treatment of 4 and 5 with diphenyl sulphite furnished the 2,2′ anhydro analogues 10 and 11, which gave the 2′-ethylsulfanyl derivetives 12 and 13 on treatment with sodium ethanethiolate, respectively. Similarly, 10 gave the 2′-azido derivative 14. Compound 17 might obtained from 13, via the episulphonium ion 16. Basic hydrolysis of 10 furnished the arabino analogue 15.

A highly strained 1,3-fused tricyclic cyclopropene, tricyclo[3.2.2.0(2,4)]nona-2,6-diene (15), was designed for use in the synthesis of a new highly strained anti-Bredt compound, bicyclo[3.2.2]nona-1,6,8-triene (17). Tricyclic cyclopropene 15 was subjected to a ring-opening reaction followed by insertion of the resulting carbene to produce an anti-Bredt compound 17. The tricyclic cyclopropene 15 was prepared by the fluoride-induced elimination of 2-chloro-3-trimethylsilyltricyclo[3.2.2.0(2,4)]non-6-ene (20), via the reaction of 1-chloro-3-trimethylsilylcyclopropene with 1,3-cyclohexadiene. Both the tricyclic cyclopropene 15 and the anti-Bredt compound 17 were trapped by diphenylisobenzofuran (DPIBF).

The majority of tetrazolylacetyl derivatives 2 and 7, when treated with lead tetraacetate in dry 1,4-dioxane at room or lower temperature, are oxidized with elimination of molecular nitrogen mainly to the corresponding alkynoyl derivatives 4 and 8, respectively. Vinylidenes (25) have been shown to be the intermediates of the reaction. The reaction does not take place when either the tetrazolyl group is N-substituted or the carbon atom separating the tetrazolyl and the carbonyl groups is disubstituted or these two groups are separated by two carbon atoms as in compound 17. The reaction offers a convenient method for the conversion of 2-cyanoacetyl derivatives into alk-2-ynoyl derivatives via intermediate tetrazolylacetyl derivatives. The 4-methoxyanilide 7o reacts differently, affording the fused heterocyclic compounds 19o and 20o.

A new series of antimicrobial derivatives [3-(4,5-diaryl-1H-imidazol-2-yl)-1H-indole)] have been synthesized with potent activity against strains of Staphylococcus aureus, including methicillin-resistant strains (MRSA). Compound 17 [3-(4,5-bis(4-fluorophenyl)-1H-imidazol-2-yl)-5-bromo-1H-indole], the most active derivative was shown to inhibit the growth of all Gram-positive strains tested, including vancomycin resistant Enterococcus faecalis and Enterococcus faecium with no activity against Gram-negative bacteria.

A series of physostigmine analogues were prepared and evaluated for cholinesterase inhibition activities, including acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Most of them showed potent inhibition activities against AChE, in which compound 17 especially exhibited significantly higher selectivity over BChE than phenserine, a compound currently on clinical trial. Discussion about the relationships between structure and activity of these derivatives was also presented.

3,4-Diamino-2,5-dicarbethoxythieno(2,3b)thiophene (1) was reacted with triethylonhoformate to afford compound 2. The reaction of compounds 2 or 3 with S,S-acetals and N,S-acetals, afforded compounds 4–6. Treatment of compound 1 with 2,5-dimethoxytetrahydrofuran gave the corresponding bipyrrolyl derivative 7, which was reacted with hydrazine hydrate to get the corresponding hydrazide derivative 8. Treating compound 8 with sodium nitrite afforded the corresponding carboazide derivative 9, which in turn cyclized to compound 10. Compound 12 was obtained via the reaction of compound 1 with PhNCS or through treating compound 11 with CS2 PhNH2, and KOH. Also, compound 13 was prepared through treatment of compound 12 with Lawesson's reagent or via the reaction of compound 11 with CS, followed by treating the resulting compound 14 with PhNH2. The reaction of compounds 1 or 3 with Lawesson's reagent gave compound 15. Benzoylation of compound 1 afforded compound 16, which treated with NH3 gave compound 17. ...

The synthesis of 7α,15α-ethano bridged steroids is described. Diels-Alder reaction of 3-methoxyestra-1,3,5(10),7,14-pentaen-17-one 4 with ethylene under high pressure provides efficient synthetic access to this class of steroids. Compounds 15 and 17 were tested for their binding affinities to the progesterone receptor (PR). Two low energy conformations 17a and 17b could be identified by force field calculations of compound 17. Both conformations were analysed in complex with the ligand binding domain of the human progesterone receptor (hPR LBD).

Two new C 9 protecting groups for the anomeric position of carbohydrates are reported. Methods both for their introduction and removal are described. The C 9 -protected compounds are much less polar than the corresponding allyl protected analogues. The new protecting group chemistry has been used to prepare compound 17 en route to a disaccharide analogue of the antibiotic moenomycin A.

A series of 2-aryl-5-alkyl-7-methoxylbenzo[b]furan derivatives have been synthesized by utilizing the coupling of methyl 3-methoxy-4-hydroxy-5-bromocinnamate with cuprous phenylacetylide as the key step. The structures of the new compounds were confirmed by 1H NMR, IR and MS. The structure of compound 14 was further confirmed by single crystal X-ray. Compound 17 showed cytotoxic activity against human lung carcinoma A549.

An enantioselective synthesis of (+)-ginnol ( 17 ) illustrates how Sharpless' asymmetric dihydroxylation may be used for the asymmetric synthesis of monoalcohols. The dihydroxylation was perfomed with AD mix α and the unsaturated ester trans - 9 . The resulting lactone cis - 13 was dehydrated giving butenolide 13 (96.2% ee ) from where we proceeded to the title compound 17 in three steps. Butenolide 13 showed 88–94% ee when ester trans - 9 contained cis -isomer due to too forcing reaction condition on the way to the precursor acids trans - and cis - 7 .

A series of tetravalent glycocyclopeptides functionalized with GlcNAc was synthesized using copper(i)-catalysed alkyne-azide cycloaddition, oxime ligation and thiol-ene coupling. The binding ability of these compounds towards wheat germ agglutinin was studied by a competitive ELLA test and ITC experiments. While all compounds were able to inhibit WGA binding to GlcNAc-polymer coated surfaces at low concentrations, derivative 17 having an aliphatic spacer and thioether linkage was 4.9 × 10(6) times more potent on a per sugar basis than GlcNAc. This remarkably strong effect was confirmed by ITC experiments as these revealed an association constant of 9 nM for this compound, therefore presenting a gain of 200,000 times over GlcNAc. These results for compound 17 represent the highest binding properties reported for WGA.

A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.

Treatment of [Fe 2 (CO) 9 ] with bis(diphenylphosphino)amine, Ph 2 PNHPPh 2 , dppa ( 1 ) in THF yields [(OC) 4 Fe(μ-dppa)Fe(CO) 4 ] ( 5 ) and [Fe 2 (CO) 6 (μ-CO)(μ-dppa)]·THF ( 6 ·THF). Further reaction of 6 ·THF with dppa gives [Fe 2 (CO) 4 (μ-CO)(μ-dppa) 2 ]·2 THF ( 9 ·2 THF) by CO-substitution, whereas P(n-Bu)Ph 2 , PPh 3 and PMe 3 add themselves to 6 · THF by forming the linear complexes [(OC) 4 Fe(μ-dppa)Fe(CO) 3 P(n-Bu)Ph 2 ] (7a), [(OC) 4 Fe(μ-dppa)Fe(CO) 3 PPh 3 ] (7b) and [(OC) 4 Fe(μ-dppa)Fe(CO) 3 PMe 3 ] (7c). The reaction of 6 · THF with HPPh 2 or ClPPh 2 results in carbonyl loss and oxidative addition of the phosphorus-hydride, respectively the phosphorus-chloride, to the diiron centre yielding the iron(I) compounds [Fe 2 (H)(μ-PPh 2 )(CO) 5 (μ-dppa) · THF ( 15 · THF) or [Fe 2 (μ-Cl)(μ-PPh 2 )(CO) 4 (μ-dppa)] · THF ( 16 · THF). Electrophilic attac of NOBF 4 leads to cleavage of the diiron complex 6 · THF into [Fe(CO) 2 (NO)dppa]BF 4 ( 17 ) and [Fe(CO) 3 ] without oxidation of the iron centres. In the solid state, compound 17 forms linear asv well as symmetrical bifureated H-bonds to the BF 4 anions. Furthermore, the NH group of 6 · THF can be deprotonated by n-BuLi. Treatment of 6 in its lithiated form with ClPPh 2 yields [Fe 2 (μ-PPh 2 )(μ-Ph 2 P-N-PPh 2 (CO) 0 ] ( 10 ) by simultaneous CO loss. The structures of 5 , 6 · THF, 7b, 9 · 2 THF, 10, 15 · CHCl 3 and 17 were determined by X-ray crystallography. As the X-ray crystallography studies show, the PNP backbone of the coordinated ligand 1 is conformatively highly flexible. All the compounds were also characterized by 1 H NMR, 13 C( 1 H) NMR, 31 P( 1 H) NMR, mass, and IR spectroscopy.

Chitosan was modified to give N -1-naphthylmethylenechitosan (d.s. 0.92, 1 ), which was tritylated to give N -1-naphthylmethylene)-6- O -tritylchitosan (d.s. 0.97 for trityl, 2 ). Compound 2 was acylated to give a series of 3- O -acyl derivatives (d.s. 0.24–1.0, 4–14 ), and was treated with 2- d , l -chloropropionic acid to give 3- O -(1- d , l -carboxyethyl) derivative (d.s. 0.37, 15 ). Compound 15 was treated in aqueous 1 N HCl to give 3- O -(1- d , l -carboxyethyl) chitosan (d.s. 0.37, 16 , muraminan). Compound 2 was treated with 2- d , l -halopropionic acids in sodium methylsulfinylcarbanion to give 3- O -(1- d , l -carboxyethyl)- N , N -(1- d , l -dicarboxyethyl)- O -tritylchitosan (d.s. 2.9 for carboxyethyl, 17 ). Compound 17 was treated with HCl in methanol to afford 3- O -(1-carboxyethyl)- N , N -(1-dicarboxyethyl) chitosan (d.s. 2.4 for carboxyethyl, 18 ). Compounds 16 and 18 were soluble in water.