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The relationship between TLR4 and inflammation-related diseases has been paid more and more attention. The studies have shown that TLR4/NF-κB signaling pathway plays an important role in the transmission of inflammatory signals. A large number of pro-inflammatory factors, chemokines, adhesion factors, TLR4 and its ligands interact with each other, and jointly promote the development of diseases. In this work, 8 target compounds were synthesized to screen the inhibitory activity of TLR4 in vitro. The results of TLR4 inhibition test in vitro showed that the double-ring conjugated enones had a good inhibitory activity, and the IC 50 value of compound 4f was 0.56 ± 0.10 μM, and it was superior to the positive control methotrexate. To further study the anti-inflammatory effect and mechanism of double-ring conjugated enones by using LPS induced rat synovial cell inflammation model. The results of the mechanism test showed that compound 4f could effectively promote the apoptosis of rat synovial cells, and the mechanism might be related to the up-regulation of the expression of apoptosis-related protein Caspase-3. In addition, compound 4f could significantly inhibit the increase of inflammatory factors TNF-α, IL-1β and IL-6 in rat synovial cells induced by LPS, showing a good anti-inflammatory activity. In the TLR4/NF-κB signaling pathway test of rat synovial cells, compound 4f can effectively regulate the expression levels of TLR4, MyD88, NF-κB and IκB related proteins in TLR4/NF-κB signaling pathway, which may be due to its inhibition of LPS-induced inflammation in rat synovial cells. At the same time, it inhibits the abnormal proliferation of cells and its important mechanism promoted of apoptosis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Transient strained cyclic intermediates have become valuable intermediates in modern synthetic chemistry. Although silyl triflate precursors to strained intermediates are most often employed, the instability of some silyl triflates warrants the development of alternative precursors. We report the syntheses of silyl tosylate precursors to cyclohexyne, 1,2-cyclohexadiene, and 1,2-cycloheptadiene. The resultant strained intermediates undergo trapping in situ to give cycloaddition products. Additionally, the results of competition experiments between silyl triflates and silyl tosylates are reported.

Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC 50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A rhodium-catalyzed direct insertion of ethylene into a relatively unstrained carbon-carbon bond in 1-indanones is reported, which provides a two-carbon ring expansion strategy for preparing seven-membered cyclic ketones. As many 1-indanones are commercially available and ethylene is inexpensive, this strategy simplifies synthesis of benzocycloheptenones that are valuable synthetic intermediates for bioactive compounds but challenging to prepare otherwise. In addition, the reaction is byproduct-free, redox neutral, and tolerant of a wide range of functional groups, which may have implications on unconventional strategic bond disconnections for preparing complex cyclic molecules.

(4+3) Cycloadditions have been widely applied in synthesis, and in this review article, we summarize some of the more recent applications, including formal (4+3) cycloadditions, in the synthesis of natural products. Many of these natural product target frameworks have cycloheptane subunits, for which the (4+3) cycloaddition is a convergent strategy for their assembly. Some natural product targets do not possess seven membered rings, and their syntheses have exploited the functional group endowed (4+3) cycloadducts resulting from these reactions, highlighting the utility of this methodology for the synthesis of a range of complex molecules.

A short and efficient route to 4-(4-hydroxyphenyl)cycloheptanemethanol was developed, which resulted in the preparation of a mixture of 4 stereoisomers. The stereoisomers were separated by preparative HPLC, and two of the stereoisomers identified by X-ray crystallography. The stereoisomers, as well as a small family of 4-cycloheptylphenol derivatives, were evaluated as estrogen receptor-beta agonists. The lead compound, 4-(4-hydroxyphenyl)cycloheptanemethanol was selective for activating ER relative to seven other nuclear hormone receptors, with 300-fold selectivity for the β over α isoform and with EC 50 of 30-50 nM in cell-based and direct binding assays., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

New series of cyclopenta(hepta)[b]thiophene and fused cyclohepta[b]thiophene analogs were synthesized. The new analogs were assessed for antibacterial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85 and Staphylococcus aureus. Compounds 5a, 6b and 12 showed eminent activity toward all selected bacterial strains compared to ampicillin. The antifungal efficacy of the same analogs was also examined toward Candida albicans and Aspergillus fumigatus 293, whereas 5a,b and 12 showed excellent efficacy toward both of the tested fungi. Moreover, 4b, 6a, 14a and 17 demonstrated interesting antifungal efficacy toward A. fumigatus. The same analogs were assessed for antiquorum-sensing efficacy toward Chromobacterium violacium ATCC 12472, whereas 5a, 12 and 15a demonstrated moderate activity. The new analogs were also esteemed for in vitro antitumor activity over HepG2, MCF-7 and HT-29 cancer cell lines. Results indicated that 6b and 10 are the most potent analogs against the three tested cell lines. In addition, 5a, 6a, 7 and 15a displayed interesting activity toward all tested cell lines. The active in vitro antitumor analogs were screened for in vivo antitumor activity over EAC in mice as well as in vitro cytotoxicity toward W138 human normal cell line. Results demonstrated that 6a,b and 10 have the highest in vivo activity, and that all tested compounds were found to be less cytotoxic than 5-FU toward W138 normal cell line. The DNA-binding affinity of the active antimicrobial and/or antitumor analogs was also assessed, whereas 4a, 5b, 10 and 15a exhibited the highest affinity. In silico studies affirmed that the inspected compounds are compatible with Lipinski's rule of five with expected good oral absorption., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Seven-membered rings fused with an indole are termed cyclohepta[b]indoles. Compounds exhibiting this structure motif display a broad spectrum of biological activities, ranging from inhibition of adipocyte fatty-acid-binding protein (A-FABP), deacetylation of histones, inhibition of leukotriene production p53, antituberculosis activities, and anti-HIV activities. These biological profiles are found in natural products containing the cyclohepta[b]indole motif, as well as in pharmaceuticals that contain this structure motif. Therefore, the biology of molecules derived from the skeleton of cyclohepta[b]indoles, as well as cyclopenta- and cyclohexa[b]indoles, has attracted considerable interest from the pharmaceutical industry as potential therapeutics in recent years. This is reflected by more than two dozen patents that have been issued in the past decade, solely based on the cyclohepta[b]indole structure motif. The efficient preparation of highly functionalized and unsymmetrically substituted cyclohepta[b]indoles has therefore become of central interest for synthetic organic chemists. Historically, this structure motif most often has been prepared by means of a Fischer indole synthesis. Although very robust and useful, this reaction poses certain limitations. Especially unsymmetrically functionalized cyclohepta[b]indoles are not suitable for a Fischer indole type synthesis, since product mixtures are inevitable. Therefore, novel methodologies to overcome these synthetic obstacles have been developed in recent years. This Account introduces all natural products and pharmaceutical compounds exhibiting the cyclohepta[b]indole motif. The structural variability within cyclohepta[b]indole alkaloids in combination with the broad range of organisms where these alkaloids have been isolated from, strongly suggests that the cyclohepta[b]indole is somehow a "privileged" structure motif. The organisms producing these compounds range from evergreen trees (actinophyllic acid) to cyanobacteria (ambiguinines). The synthetic methodologies to construct these molecular scaffolds (natural and unnatural in origin) are in turn highlighted and discussed with regard to their potential to access highly functionalized and unsymmetrical cyclohepta[b]indoles, for which they specifically have been designed. The methods are classified with respect to reaction type and whether or not they are enantioselective. Finally, the syntheses of cyclohepta[b]indole natural products are presented, thereby in each case, focusing on the construction of this structure motif in the course of the respective total synthesis. As a conclusion, we end by contrasting the methodological progress in the field with the actual successful application of the newly developed methods to the synthesis of complex structures to pinpoint the urgent requirement for further synthetic development for efficient synthetic design of this "privileged" structure motif.

A tandem allene aziridination/[4+3]/reduction sequence converts simple homoallenic sulfamates into densely functionalized aminated cycloheptenes, where the relative stereochemistry at five contiguous asymmetric centers can be controlled through the choice of the solvent and the reductant. The products resulting from this chemistry can be readily transformed into complex molecular scaffolds which contain up to seven contiguous stereocenters., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An asymmetric synthesis of novel heterocyclic analogue of the CGRP receptor antagonist rimegepant (BMS-927711, 3) is reported. The cycloheptane ring was constructed by an intramolecular Heck reaction. The application of Hayashi-Miyaura and Ellman reactions furnished the aryl and the amine chiral centers, while the separable diastereomeric third chiral center alcohols led to both carbamate and urea analogues. This synthetic approach was applicable to both 6- and 5-membered heterocycles as exemplified by pyrazine and thiazole derivatives.

Aldehydes undergo a smooth coupling with (E/Z)-non-3-en-8-yn-1-ol in the presence of 10 mol% of CuX and BF3·OEt2 under mild conditions to produce a novel class of octahydrocyclohepta[c]pyran-6(1H)-one derivatives in good yields with excellent diastereoselectivity through a sequential Prins/alkynylation/hydration. This is the first report on the termination of Prins cyclization with a tethered alkyne.

A route to enantiopure (R)-(+)-3-methyl-6-isopropenyl-cyclohept-3-enone-1, an intermediate for terpenoids, has been developed and includes a highly chemo- and regioselective Tiffeneau-Demjanov reaction. Starting from readily available (R)-(-)-carvone, this robust sequence is available on a deca-gram scale and uses flow chemistry for the initial epoxidation reaction. The stereochemistry of the addition of two nucleophiles to the carbonyl group of (R)-(-)-carvone has been determined by X-ray diffraction studies and chemical correlation.

An enantioselective alkoxylation/Claisen rearrangement reaction was achieved by a strategic desymmetrization of 1,4-dienes under the catalysis of (S)-DTBM-Segphos(AuCl)2/AgBF4. This reaction system was highly selective for the formation of 3,3-rearrangement products, providing cycloheptenes with various substitutions in good yield and good to excellent enantioselectivity. This transformation was further extended to bicyclic ring substrates, providing the opportunity to easily assemble 5,6- and 6,7-fused ring systems., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An efficient [4 + 3] cycloaddition reaction of D-A cyclopropanes with dienes has been successfully developed. The reaction proceeds well with various dienolsilyl ethers in the presence of Lewis acid, delivering a variety of cycloheptenes and [n,5,0]carbobicycles with excellent stereoselectivity. The asymmetric version of this reaction is also realized using a newly designed chiral Cy-TOX ligand, providing a new approach to access optically active cycloheptenes and [n,5,0]carbobicycles. Mechanisic study reveals that the reaction involves a stepwise pathway, which undergoes an unusual ring opening of five-membered [3 + 2] intermediate and sequential intramolecular cyclization to afford the thermodynamically stable [4 + 3] annulation product.

A series of new N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl) sulfonamide derivatives (8a-i) and ethyl 2,2-dimethyl-1-(3-(2-(sulfonamido)ethyl)ureido) cyclopropanecarbox-ylate derivatives (9a-i) were designed, synthesized and evaluated for their anticonvulsant activities using maximal electroshock shock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4-fluoroben- zenesulfonamide (8f) and N-(2-(1,1-dimethyl-5,7-dioxo-4,6-diazaspiro[2.4]heptan-6-yl)ethyl)-4- methylbenzenesulfonamide (8e) have shown promising anticonvulsant activities in MES model. The most active compound 8f has shown the MES-induced seizures with ED50 value of 28.05 mg/kg and TD50 value of 561 mg/kg after intraperitoneal injection to mice, which provided compound 8f with a protective index (TD50/ED50) of 20 in the MES test. Further, rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

The Sc(OTf)3-catalyzed [3 + 2]-annulation reaction between cyclopropenones and donor–acceptor cyclopropanes is described. The process leads directly to the formation of 4-oxaspiro[2.4]hept-1-ene derivatives in good to excellent reaction yields. Density functional theory calculations suggest that the [3 + 2]-annulation pathway is strongly preferred over the possible [3 + 3]-process.

The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the aniline nitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.

Conformationally constrained bithiazoles were previously found to have improved efficacy over nonconstrained bithiazoles for correction of defective cellular processing of the ΔF508 mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. In this study, two sets of constrained bithiazoles were designed, synthesized, and tested in vitro using ΔF508-CFTR expressing epithelial cells. The SAR data demonstrated that modulating the constraining ring size between 7- versus 8-membered in these constrained bithiazole correctors did not significantly enhance their potency (IC50), but strongly affected maximum efficacy (Vmax), with constrained bithiazoles 9e and 10c increasing Vmax by 1.5-fold compared to benchmark bithiazole corr4a. The data suggest that the 7- and 8-membered constrained ring bithiazoles are similar in their ability to accommodate the requisite geometric constraints during protein binding.

Conjugated cyclic trienes without nonbenzenoid aromatic characteristic were successfully employed as fine-tunable dipolarophiles in the Cu(I)-catalyzed asymmetric azomethine ylide-involved 1,3-dipolar [3 + 6] cycloaddition for the first time, affording a variety of bridged heterocycles bearing piperidine moiety in good yield with exclusive regioselectivity and excellent stereoselectivity. 2-Acyl group is the key factor that determines the annulation preferentially through [3 + 6]-pathway, while 2-ester group modulates the annulation through [3 + 2]-pathway.

Tamoxifen has biologically active metabolites: 4-hydroxytamoxifen (4OHT) and endoxifen. The E-isomers are not stable in solution as Z-isomerization occurs. We have synthesized fixed ring (FR) analogues of 4OHT and endoxifen as well as FR E and Z isomers with methoxy and ethoxy side chains. Pharmacologic properties were documented in the MCF-7 cell line, and prolactin synthesis was assessed in GH3 rat pituitary tumor cells. The FR Z-isomers of 4OHT and endoxifen were equivalent to 4OHT and endoxifen. Other test compounds used possessed partial estrogenic activity. The E-isomers of FR 4OHT and endoxifen had no estrogenic activity at therapeutic serum concentrations. None of the newly synthesized compounds were able to down-regulate ER levels. Molecular modeling demonstrated that some compounds would each create a best fit with a novel agonist conformation of the ER. The results demonstrate modulation by the ER complex of cell replication or gene transcription in cancer.

Radermachol has been synthesized in four steps and an overall yield of 22% via key ytterbium triflate catalyzed furannulation and intramolecular nucleophilic acylation reactions.

A synthesis of iodo-substituted dibenzocyclohepten-5-ones by the iodine monochloride (or iodine)-induced intramolecular 7-endo-dig cyclization of 1-([1,1'-biphenyl]-2-yl)alkynones is reported. Detailed investigations on the substituent effects during the electrophilic iodocyclization of the alkynones show that they play a crucial role in determining the reaction pathways of the cyclization. By modifying the substitution pattern on the alkynone substrates, the cyclization takes place regioselectively, leading to either dibenzocyclohepten-5-ones, via a 7-endo-dig cyclization, or spiroconjugated compounds, via a 6-endo-dig cyclization.

A new method for manganous acetate tetrahydrate mediated formal intermolecular [2 + 2 + 2 + 1] cycloaddition was developed for the synthesis of fused cycloheptatriene derivatives from N-(acylmethyl)pyridinium iodides and naphthoquinone. This method provides an innovative route for the efficient and convenient construction of fused seven-membered carbocycles from simple starting materials.

A rhodium(II) catalyzed nitrene-alkyne cycloaddition of stereochemically well-defined homopropargylic ethers is followed by arene cyclopropanation to afford unique tetracyclic norcaradiene products bearing a cyclic sulfamate. Products from the arene cyclopropanation (Buchner reaction) can be converted to fused cycloheptatrienes via a ring enlarging electrocyclization after nucleophilic ring opening of the cyclic sulfamate ester.

Novel representative of the important group of biologically active benzosuberones bearing 2, 4-thiazolidenone moiety was synthesized as potential anticancer agents (6a-j). These compounds were synthesized in good yields from Knoevenagel condensation of compounds 2a-b with thiazolidenone derivatives 3a-e in the presence of sodium acetate and glacial acetic acid. The in vitro cytotoxicity of these compounds was evaluated against different human cancer cell lines (A549, HeLa, MDA-MB-231, MCF-7) and normal cell line, HEK293. Compound 6a exhibited promising cytotoxicity with IC₅₀ values ranging from 2.98 to 13.34 μM against all the tested cancer cell lines, HeLa, A549, MCF-7 and MDA-MB-231, while compound 6g showed potent cytotoxicity against human breast adenocarcinoma cell line (MCF-7, IC₅₀ value of 1.91 μM)., (Copyright © 2013. Published by Elsevier Masson SAS.)

Selective uncompetitive antagonists of the phencyclidine (PCP) binding site of the N-methyl-D-aspartate receptor (NMDAR) are known to have therapeutic potential as anticonvulsants and neuroprotective agents. Several fluorinated molecules with each containing a cycloheptane ring were designed to probe the PCP pharmacophore and test the influence of fluorine substitution on NMDAR binding and in vivo efficacy. Syntheses and analyses of six novel compounds, 1-(4- fluorophenyl)cycloheptanamine (3), 1-(1-(4-fluorophenyl)cycloheptyl)piperidine (4), 1-(1-(4-fluorophenyl)cycloheptyl) pyrrolidine (5), 1-(3-fluorophenyl)cycloheptanamine (6), 1-(1-(3-fluorophenyl)cycloheptyl)piperidine (7), 1-(1-(3-fluorophenyl) cycloheptyl)pyrrolidine (8) and several related reference arylcyloalkylamines are described. Receptor binding was performed at the PCP site of NMDAR for each compound using [(3)H]-(+)-MK-801 displacement. Unexpectedly, the 3- fluoro- primary amine 6 had the greatest affinity of the series and these binding results support a different structure activity relationship (SAR) profile for arylcycloheptylamines when compared to arylcyclohexylamines like PCP. Five of the novel compounds have affinity (Ki) in the hundred nM (10(-7)) range. In addition, compounds 3, 5, 6, 7 and 8 were evaluated and found to exhibit neuroprotective effects from NMDA induced toxicity in vitro and compounds 6, 7 and 8 exhibited anticonvulsant activities in rats. An ED50 of 13.84 mg/kg was found for compound 6 in rat maximal electroshock (MES) test with a protective index (PI) of 3.66 against ataxia. These results support further investigation of the arylcycloheptylamine class.

Dibenzoselenacycloheptynes were prepared in three steps from commercially available reagents and trapped in situ with benzyl azide to form the corresponding triazoles. Surprisingly, the dibenzoselenacycloheptynes also abstracted hydrogen atoms from solvents such as THF or toluene, forming dibenzoselenacycloheptene products. These alkenyl compounds arise from a hydrogen transfer reaction from solvent to the unisolable intermediate, and we postulate that the reaction proceeds via a radical mechanism originating from the strained alkynyl bond that has unusually high radical character.

A simple and effective method for the synthesis of 7-oxabicyclo[2.2.1]heptanes and 8-oxabicyclo[3.2.1]octanes from acetonyl C-glycoside substrates is described, which involves an intramolecular cyclization reaction through a nucleophilic substitution at C-5 or C-6 of C-glycosides by a 2'-enamine intermediate formed in the presence of pyrrolidine. Because anomeric epimerization occurs under these conditions, C-glycoside substrates with either anomeric configuration were converted to the same product(s) in same stereoselectivity and similar chemical yield.

We have developed an efficient and stereoselective route to trans-fused octahydrocyclohepta[b]pyrrol-4(1H)-ones. The key features of our synthesis include the regioselective epoxide ring-opening of alkynyl oxiranes and a stereoselective aza-Cope-Mannich reaction. The target compounds were prepared in 3-6 steps from commercially available starting materials (61-75% overall yield) with minimal chromatographic purification. We have devised an stereoselective route to target compounds using Shi epoxidation or (R)-1-phenylethylamine as a source of chirality.

5,6,7,8-Tetrahydro-4H-cyclohepta[d]isoxazole derivatives were synthesized and evaluated as a novel class of inhibitors for α-melanocyte-stimulating hormone (α-MSH) induced melanogenesis in a mouse melanoma B16F10 cell line. Compound 8e (IC(50)=0.67 μM), 8h (IC(50)=1.01 μM) and 9b (IC(50)=0.99 μM) exhibited a potent inhibitory activity approximately 85- to 126-fold greater than kojic acid, a well-known potent inhibitor. A biochemical study indicates that the activity of this series should be displayed via down-regulation of the expression of tyrosinase., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Racemic 5-substituted 7-aminobenzocyclohepten-6-one were synthesized and evaluated for their ability to inhibit metalloaminopeptidase activities. Unexpectedly, 5-thio substituted compounds showed enhanced inhibition potency with K(i) values in the nanomolar range against the 'one zinc' aminopeptidases from the M1 family, while most of them were rather poor inhibitors of the 'two zincs' enzymes from the M17 family. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.

To develop estrogen receptor (ER) ligands having novel structures and activities, we have explored compounds in which the central hydrophobic core has a more three-dimensional topology than typically found in estrogen ligands and thus exploits the unfilled space in the ligand-binding pocket. Here, we build upon our previous investigations of 7-oxabicyclo[2.2.1]heptene core ligands, by replacing the oxygen bridge with a sulfoxide. These new 7-thiabicyclo[2.2.1]hept-2-ene-7-oxides were conveniently prepared by a Diels-Alder reaction of 3,4-diarylthiophenes with dienophiles in the presence of an oxidant and give cycloadducts with endo stereochemistry. Several new compounds demonstrated high binding affinities with excellent ERα selectivity, but unlike oxabicyclic compounds, which are transcriptional antagonists, most thiabicyclic compounds are potent, ERα-selective agonists. Modeling suggests that the gain in activity of the thiabicyclic compounds arises from their endo stereochemistry that stabilizes an active ER conformation. Further, the disposition of methyl substituents in the phenyl groups attached to the bicyclic core unit contributes to their binding affinity and subtype selectivity.

1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.

As an important member of metabotropic glutamate receptors (mGluR), metabotropic glutamate receptor 1 (mGluR1) plays an important role in the signal transduction of central nervous system. Selective mGluR1 antagonists can block the signaling pathway activated by mGluR1 and exert a series of physiological actions including analgesia, antianxiety, antidepression, etc. Currently, the discovery and modification of selective mGluR1 antagonists have become a hot research focus. This paper reviews the structural catalogs of selective mGluR1 antagonists and their structure-activity relationships in the last decade.

A new class of low molecular weight, highly potent and selective non peptidic inhibitors of aminopeptidase N (APN/CD13) is described. We report the synthesis and in vitro evaluation of racemic substituted analogues of 7-amino-benzocyclohepten-6-one 1a. We investigated various substitutions on the aromatic ring with phenyl and halogen groups. In vitro kinetic studies revealed that these compounds are among the most effective APN/CD13 inhibitors found so far. Hydrophobic substituents placed at position 1 or 4 on the cycloheptenone 1a led to the potent compounds 1c-h,b'-c',f',h' with K(i) in the nanomolar range. The key finding of the present work was the observed additive effect of 1,4-disubstitutions which led to the discovery of the picomolar inhibitor 1d' (K(i)=60 pM). The designed inhibitors retain the selectivity of our lead structure 1a towards selected members of the aminopeptidase family, combined with an impressive increase in inhibitory potency and a conserved stability., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The coupling of pentenylcarbene complexes and 2-alkynylbenzoyl derivatives affords naphthocycloheptanones in a single step involving simultaneous construction of both the seven-membered ring and one of the aromatic rings. Aryl tethered systems undergo intramolecular cyclopropanation.

A short access to homocalystegine analogues silylated at C7 is described. The synthesis involves the desymmetrization of a (phenyldimethylsilyl)methylcycloheptatriene using osmium-mediated dihydroxylation, followed by the diol protection and a cycloaddition involving the remaining diene moiety and an acylnitroso reagent. Additions of the osmium and acylnitroso reagents were shown, through X-ray diffraction studies of the resulting major isomers, to occur anti and syn, respectively, relative to the SiCH(2) substituent. N-O bond cleavage on the resulting cycloadduct then produces the aminopolyol having a silylmethyl substituent. Oxidation of the C-Si bond also afforded an access to unusual amino-heptitols having five contiguous stereogenic centers. In the course of this work, we finally observed a unusual rearrangement taking place on cycloheptanone 18 substituted by two acetyl groups and a neighboring Boc-protected amine. A profound reorganization of the substituents on the seven-membered ring effectively took place under acidic conditions (TFA) leading to the thermodynamically more stable homocalystegine-type compound. DFT calculations of the conformational energy of isomeric silyl homocalystegines indicated that the product observed upon the acid-mediated rearrangement was the most stable of a series of analogues with various distributions of substituents along the seven-membered ring backbone. A tentative mechanism is proposed to rationalize the acetate migrations and inversions of the stereochemistry at various stereocenters.

A Pd(OAc)(2)-catalyzed reaction of 2,3-alkadienyl malonates or 2,3-allenols with o-iodobenzaldehyde or its N-tosyl imine occurred smoothly in MeCN at 80 °C to form the oxa- or aza-bridged benzocycloheptane derivatives with important biological potential. With the optically active 2,3-allenols, the absolute configurations of all the three chiral centers have been conveniently established.

[6 + 2] Cycloadditions between cycloheptatrienes with allenes have been investigated. Cobalt salts were found to promote this transformation efficiently. Moreover, this reaction was found to be highly selective since only one regioisomer was obtained with an excellent E/Z-selectivity.

The p38 MAP kinase is a key enzyme in inflammatory diseases as it is involved in the biosynthesis of proinflammatory cytokines such as TNF-alpha and IL-1beta. Small molecule p38 inhibitors suppress the production of these cytokines and therefore p38 is a promising drug target for novel anti-inflammatory therapeutics. In this study, we report the design, synthesis, and SAR of novel N-substituted 11H-dibenzo[b,f]oxepin-10-ones and 5,11-dihydro-dibenzo[a,d]cyclohepten-10-ones as p38 inhibitors., (Copyright 2010 Elsevier Ltd. All rights reserved.)

A cationic rhodium(I) complex--[(C(10)H(8))Rh(cod)](+) SbF(6)(-)--catalyzes the remarkably efficient intermolecular [5 + 2] cycloaddition of vinylcyclopropanes (VCPs) and various alkynes, providing cycloheptene cycloadducts in excellent yields in minutes at room temperature. The efficacy and selectivity of this catalyst are also shown in a novel diversification strategy, affording a cycloadduct library in one step from nine commercially available components.

A palladium-catalyzed decarboxylative [4 + 3] cyclization of gamma-methylidene-delta-valerolactones with 1,1-dicyanocyclopropanes has been developed to produce cycloheptane derivatives in a convergent manner. This method can be applied to the synthesis of azepanes by reacting with aziridines, and their asymmetric variants have also been described. In addition, selective ring-expansion reactions can be achieved for certain gamma-methylidene-delta-valerolactones to give nondecarboxylated nine-membered lactones.

A method is described for the identification of molecular species of acylphosphatidylglycerols containing a branched cyclo fatty acid ((S)-11-cycloheptyl-4-methylundecanoic acid; brc19:0) from Alicyclobacillus acidoterrestris and its identification as picolinyl ester by means of GC-MS. The combination of TLC, negative RP-HPLC-ESI-MS/MS, enzymatic hydrolysis, and GC-MS was used to identify unusual molecular species of acylphosphatidylglycerols with cyclic and branched FA. The acid, brc19:0, was also synthesized to unambiguously confirm its structure. According to feeding experiments with (13)C-labeled propionate, the C(3) internal unit (branched methyl) of brc19:0 is assembled from propionate and not from methionine.

A common strategy for the synthesis of a 7-membered-ring system with a Suzuki-Miyaura coupling followed by an acid/base-promoted intramolecular aldol condensation reaction has been developed. The reaction of 2'-bromoacetophenones with 2-formylphenylboronic acids in the presence of Pd(OAc)(2) and CataCXium PIntB L8 efficiently provided biaryl compounds, which were transformed to a wide array of dibenzo[a,c]cyclohepten-5-ones in excellent yields by a sequential treatment with p-TsOH, followed by 10% aq NaOH.

Insertion of one methylene unit into the C-C bond of cyclohexanones is a potentially useful, straightforward method for the construction of seven-membered carbocycles. An especially appealing but largely unexplored method in this arena is the nucleophilic addition of diazoalkanes to the Lewis acid-activated cyclohexanones and subsequent ring expansion accompanied by the extrusion of nitrogen (direct Tiffeneau-Demjanov-type ring expansion). Our primary finding is the unprecedented insertion of alpha-alkyldiazoacetates to cyclohexanone and its heteroanalogues, generating seven-membered rings with one all-carbon quaternary center. On the basis of this finding, highly diastereoselective ring expansion of substituted cyclohexanones was developed, furnishing seven-membered rings with 1,4-quaternary-tertiary, 1,4-quaternary-quaternary, or 1,3,5-quaternary-tertiary-tertiary stereogenic centers in a single operation starting from readily available materials. The stereochemical outcome of the product can be easily predicted from the conformation of starting cyclohexanones. Enantioenriched products could be also accessed by the use of (-)-phenylmenthyl alpha-alkyldiazoacetates.

By adjustment of the electronic properties of the ancilliary ligands, high selectivity can be achieved for either [4 + 2] or [4 + 3] cycloaddition reactions of allene-dienes catalyzed by gold(I). Triarylphosphitegold(I) complexes are employed as catalysts for a [4 + 2] cycloaddition reaction leading to alkylidenecyclohexenes. Conversely, di-tert-butylbiphenylphosphinegold(I)-catalyzed reactions afford cycloheptadienes via [4 + 3] cycloaddition reactions.

An efficient method for the asymmetric gold(I)-catalyzed preparation of medium sized rings has been developed. The method provides 7- to 9-membered rings in excellent yield. High enantioselectivities can be achieved for 7- and 8-membered ring products employing chiral gold(I) complexes. The results provide insight into the mechanism, showing the fluxional nature of gold(I)-stabilized vinyl carbenoid intermediates.

The reactivity of (2-alkenyl-3-pentene-1,5-diyl)iron complexes toward olefin metathesis, cycloaddition, and mild oxidations (MnO 2 or mCPBA) was examined. Cycloaddition reactions were observed to occur with modest diastereoselectivity (33-63% de). Decomplexation of the (3-pentenediyl) ligand may be accomplished by oxidation with either CAN or alkaline hydrogen peroxide to afford vinylcyclopropanecarboxylates or divinylcyclopropanecarboxylates. Reduction of the latter, followed by Cope rearrangement generates cycloheptadienylmethanols. These studies demonstrate that (2-alkenyl-3-pentene-1,5-diyl)iron complexes can serve as organometallic scaffolds for the preparation of a wide variety of structural motifs containing up to 5 contiguous stereocenters.