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This study was performed to evaluate the antioxidant, anticancer, and toxicity properties of ferutinin, a phytoestrogen derived from Ferula species. The human Michigan Cancer Foundation-7 (MCF-7) breast cancer cell line and normal human fibroblast (HDF) were cultured and treated with different ferutinin concentrations. The cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell death-defining tests (a comparative real-time polymerase chain reaction [for Bax and Bcl-2 genes], flow cytometry, and acridine orange/propidium iodide cell staining). Moreover, 15 white male balb/c mice were divided into three groups of five (one untreated control group and two groups), which received different doses of ferutinin-supplemented water (500 and 1000 µg/kg mice weight) to check the mice liver and kidney pathomorphological alterations and to determine the antioxidant enzymes' expression profile (superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase) in the mentioned tissues. Finally, the liver lipid peroxidation of mice was analyzed. The results of MTT and cell death-defining tests indicate the significant reduction in cell viability and induction of apoptotic death in MCF-7 cells (enhanced sub-G1 peaks, Bax overexpression, Bcl-2 downregulation, and increased apoptotic cells). The antioxidant enzymes (SOD and CAT) in the mice liver and kidney cells were found to be upregulated (p < .05) in response to the increasing doses of ferutinin. Besides, the lipid peroxidation of the liver tissue of mice was significantly reduced. According to the results, we suggest that ferutinin has the potential to be served as a selective anticancer compound for breast cancer treatment., (© 2021 Wiley Periodicals LLC.)

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.

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.)

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as "shilsh Elzallouh". It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant's extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen, both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a coplanar conformation with an adjacent aromatic core favored by the morpholine nitrogen nonbonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 ( 29b ).

In the present study a series of dione-thiophenol conjugates was prepared and evaluated against nasopharyngeal carcinoma (NPC) cells. MTT assay showed that compound 4a reduced proliferation of C666-1 and CNE-1 cells to 26 and 24%, respectively at 10 μmol/l concentration. Flow cytometry revealed that increasing the concentration of compound 4a from 2 to 10 μmol/l increased the proportion of early apoptotic C666-1 cells from 2.76 to 69.43%. A significant (P < 0.001) decrease in the expression of S100P was caused by compound 4a. In compound 4a treated C666-1 cells the expression of RAGE, EGFR, CD44, MMP2 and MMP9 was markedly decreased. In summary, compound 4a inhibits nasopharyngeal cancer cell proliferation and induces apoptosis through down-regulation of S100P. Moreover, compound 4a also decreases MMP-2, MMP-9, EGFR, CD44 and RAGE expression in nasopharyngeal cancer cells. Thus, compound 4a can be investigated further as a drug candidate for the treatment of nasopharyngeal cancer., (Copyright © 2019. Published by Elsevier Masson SAS.)

A new synthetic route for formation of a central cycloheptanone intermediate leading to the nortropane alkaloid calystegine B 2 is described. The approach installs the desired ketone functionality directly in a ring-closing metathesis step. The target compound was prepared over 10 steps from commercially available methyl α-d-xylopyranoside., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Two new monoterpenoid indole alkaloids, alstoscholactine (1) and alstolaxepine (2), were isolated from Alstonia scholaris. Compound 1 represents a rearranged stemmadenine alkaloid with an unprecedented C-6-C-19 connectivity, whereas compound 2 represents a 6,7- seco-angustilobine B-type alkaloid incorporating a rare γ-lactone-bridged oxepane ring system. Their structures and absolute configurations were determined by spectroscopic analyses. Compound 1 was successfully semisynthesized from 19 E-vallesamine. Compound 2 induced marked vasorelaxation in rat isolated aortic rings precontracted with phenylephrine.

A new optical chemical sensor based on medicinal compound, jaeschkeanadiol p-hydroxyben-zoate (Ferutinin), has been designed and utilized for Ca(II) ions detections. This natural optical sensor exhibits immense selectivity including fluorescence and absorption ratiometric for Ca(II) ions within precious physiological pH range. Further, the chelation process of the Ca(II) ions with the medicinal optical sensor ferutinin yields a 1:1 (metal: ligand) complex which is accompanied by fluorescence enhancement of the main emission band centered at 355 nm of the medicinal probe. The fluorescence "turn-on" effect is a clear evidence for the chelation process between ferutinin medicinal probe and Ca(II) ions and this could be simply detected. The new sensor was proposed depending on significant fluorescence mechanism, (MLCT, metal-ligand charge transfer). However, the interaction of the medicinal optical sensor with Ca(II) in presence of other cations was examined without any significant interference. Also, the new developed optical sensor consecutively exhibits low limit of detection (LOD) 1.5 nM for Ca(II) which is detected in very significant physiological pH range (pH = 7.4). Also, the probe provides high binding affinity towards Ca(II) with large binding constant K b 5.97 × 10 4  M -1 . As a result, this optical sensor may apply for detection Ca(II) in cell or biological samples., (Copyright © 2018 Elsevier B.V. All rights reserved.)

(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.)

Estrogen is considered a risk factor for breast cancer since it promotes breast-cell proliferation. The jaesckeanadiol-3-p-hydroxyphenylpropanoate, a hemi-synthetic analogue of the natural phytoestrogen ferutinin (jaesckeanadiol-p-hydroxybenzoate), is designed to be devoid of estrogenic activity. This analogue induces a cytotoxic effect 30 times higher than that of ferutinin towards MCF-7 breast cancer cell line. We compared these two compounds with respect to their effect on proliferation, cell cycle distribution and cancer stem-like cells in the MCF-7 cell line. Treatment with ferutinin (30 μM) and its analogue (1 μM) produced significant accumulation of cells at the pre G0/G1 cell cycle phase and triggered apoptosis. Importantly, this compound retains its anti-proliferative activity against breast cancer stem/progenitor cells that are naturally insensitive to ferutinin at the same dose. These results position ferutinin analogue as an effective compound inhibiting the proliferation of estrogen-dependent breast cancer cells and consistently targeting their stem-like cells., (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.)

Efficient solar energy storage is a key challenge in striving toward a sustainable future. For this reason, molecules capable of solar energy storage and release through valence isomerization, for so-called molecular solar thermal energy storage (MOST), have been investigated. Energy storage by photoconversion of the dihydroazulene/vinylheptafulvene (DHA/VHF) photothermal couple has been evaluated. The robust nature of this system is determined through multiple energy storage and release cycles at elevated temperatures in three different solvents. In a nonpolar solvent such as toluene, the DHA/VHF system can be cycled more than 70 times with less than 0.01 % degradation per cycle. Moreover, the [Cu(CH 3 CN) 4 ]PF 6 -catalyzed conversion of VHF into DHA was demonstrated in a flow reactor. The performance of the DHA/VHF couple was also evaluated in prototype photoconversion devices, both in the laboratory by using a flow chip under simulated sunlight and under outdoor conditions by using a parabolic mirror. Device experiments demonstrated a solar energy storage efficiency of up to 0.13 % in the chip device and up to 0.02 % in the parabolic collector. Avenues for future improvements and optimization of the system are also discussed., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aminopeptidases are ubiquitous hydrolases that cleave the N-terminal residues of proteins and oligopeptides. They are broadly distributed throughout all kingdoms of life and have been implicated in a wide variety of physiological processes, including viral infection, parasite metabolism, protein processing, regulation of peptide hormones, and cancer cell proliferation. Members of the M1 family, also termed gluzincins, are defined by two highly conserved motifs in the catalytic domain: a zinc-binding motif, HEXXH-(X18)-E; and an exopeptidase motif, GXMEN. We report the high-resolution X-ray structures of E. coli aminopeptidase N (PepN) in complex with three aminobenzosuberone scaffolds that display various Ki values (50, 0.33, and 0.034 µM) and provide a compelling view of the outstanding selectivity of these chemical entities for the M1 aminopeptidases. This series of inhibitors interacts as transition state mimics with highly conserved residues of the catalytic machinery and substrate recognition sites. Structural comparisons and model-building studies allowed a deep interpretation of the SAR observed for bacterial, as well as mammalian enzymes. Proteins 2017; 85:1413-1421. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Selective inhibitors of histone deacetylase 6 (HDAC6) are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Herein, the synthesis of ten new benzohydroxamic acids, constructed by employing the tetrahydrobenzothiazepine core as a privileged pharmacophoric unit, is described. This is the first report on the synthesis and isolation of octahydrodibenzothiazepines and octahydro-6H-benzocycloheptathiazepines, which were then used to develop a new class of HDAC6 inhibitors. Evaluations of their HDAC-inhibiting activity resulted in the identification of cis-N-(4-hydroxycarbamoylbenzyl)-1,2,3,4,4a,5,11,11a-octahydrodibenzo[b,e][1,4]thiazepine-10,10-dioxide and cis-N-(4-hydroxycarbamoylbenzyl)-7-trifluoromethyl-1,2,3,4,4a,5,11,11a-octahydrodibenzo[b,e][1,4]thiazepine-10,10-dioxide as highly potent and selective HDAC6 inhibitors with activity in the low nanomolar range, which also show excellent selectivity on the enzymatic and cellular levels. Furthermore, four promising inhibitors were subjected to an Ames fluctuation assay, which revealed no mutagenic effects associated with these structures., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.)

In view of the fact that the phosphorus atom in its low co-ordination state (coordination numbers 1 and 2) has been termed as the carbon copy, there have been attempts to investigate, theoretically as well as experimentally, the effect of the exchange(s) of CH- moiety with phosphorus atom(s) (CH/P) on the structural and other aspects of the classical carbocyclic and heterocyclic systems. Tropylium ion is a well-known non-benzenoid aromatic system and has been studied extensively for its aromatic character. We have now investigated the effect of mono- and poly-CH/P exchange(s) on the aromaticity of the tropylium ion. For this purpose, the parameters based on the geometry and magnetic properties, namely bond equalization, aromatic stabilization energies (ASE), Nucleus-Independent Chemical Shift (NICS) values, (NICS(0), NICS(1), NICS(1)zz), proton nucleus magnetic resonance (¹H-NMR) chemical shifts, magnetic susceptibility exaltation and magnetic anisotropic values of mono-, di-, tri- and tetra-phosphatropylium ions have been determined at the Density Functional Theory (DFT) (B3LYP/6-31+G(d)) level. Geometry optimization reveals bond length equalization. ASEs range from -46.3 kcal/mol to -6.2 kcal/mol in mono- and diphospha-analogues which are planar. However, the ions having three and four phosphorus atoms lose planarity and their ASE values approach the values typical for non-aromatic structures. Of the three NICS values, the NICS(1)zz is consistently negative showing aromatic character of all the systems studied. It is also supported by the magnetic susceptibility exaltations and magnetic anisotropic values. Furthermore, ¹H-NMR chemical shifts also fall in the aromatic region. The conclusion that mono-, di-, tri- and tetra-phosphatropylium ions are aromatic in nature has been further corroborated by determining the energy gap between the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) (HOMO - LUMO gap), which falls in the range, ca. 3 × 10(-19)-9 × 10(-19) J. The systems having more than four phosphorus atoms are not able to sustain their monocyclic structure.

The key step in the concise syntheses of calystegine B2 and its C-2 epimer calystegine B3 was the construction of cycloheptanone 8via an intramolecular Nozaki-Hiyama-Kishi (NHK) reaction of 9, an aldehyde containing a Z-vinyl iodide. Vinyl iodide 9 was obtained by the Stork olefination of aldehyde 10, derived from carbohydrate starting materials. Calystegines B2 (3) and B3 (4) were synthesized from d-xylose and l-arabinose derivatives respectively in 11 steps in excellent overall yields (27% and 19%).

3,5-Dinitrobenzoyl chloride was previously used for the preparation of (R)-phenylglycinol- and (S)-leucinol-derived chiral stationary phases. In this study, 3,5-bis(trifluoromethyl)benzoyl chloride, 2-furoyl chloride, 2-theonyl chloride, 10,11-dihydro-5H-dibenzo[b,f]azepine-5-carbonyl chloride, diphenylcarbamoyl chloride, and 1-adamantanecarbonyl chloride were used to prepare six new phenylglycinol-derived chiral stationary phases (CSPs) and five new leucinol-derived CSPs. Using these 11 CSPs, chiral separation of nine π-acidic amino acid derivatives and five π-basic compounds was performed, and the separation results were compared. An adamantyl-derived CSP showed good separation., (© 2016 Wiley Periodicals, Inc.)

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.

Treatment of pain with morphine and its congeners in sickle cell anemia is suboptimal, warranting the need for analgesics devoid of side effects, addiction and tolerance liability. Small-molecule nociceptin opioid receptor ligands show analgesic efficacy in acute and chronic pain models. We show that AT-200, a high affinity nociceptin opioid receptor agonist with low efficacy at the mu opioid receptor, ameliorated chronic and hypoxia/reoxygenation-induced mechanical, thermal and deep tissue/musculoskeletal hyperalgesia in HbSS-BERK sickle mice. The antinociceptive effect of AT-200 was antagonized by SB-612111, a nociceptin opioid receptor antagonist, but not naloxone, a non-selective mu opioid receptor antagonist. Daily 7-day treatment with AT-200 did not develop tolerance and showed a sustained anti-nociceptive effect, which improved over time and led to reduced plasma serum amyloid protein, neuropeptides, inflammatory cytokines and mast cell activation in the periphery. These data suggest that AT-200 ameliorates pain in sickle mice via the nociceptin opioid receptor by reducing inflammation and mast cell activation without causing tolerance. Thus, nociceptin opioid receptor agonists are promising drugs for treating pain in sickle cell anemia., (Copyright© Ferrata Storti Foundation.)

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.

Calcium ionophoretic properties of ferutinin were re-evaluated in solvent-containing bilayer lipid membranes. The slopes of conductance-concentration curves suggest that in the presence of a solvent in the membrane the majority of complexes appear to consist of a single terpenoid molecule bound to one Ca ion. By contrast, the stoichiometry of ferutinin-Ca(2+) complexes in acetone determined using the conductometric method was 2 : 1. While the cation-cation selectivity of ferutinin did not change, the cation-anion selectivity slightly decreased in solvent containing membranes. FT-IR and NMR data together with DFT calculations at the B3LYP/6-31G(d) level of theory indicate that in the absence of Ca ions ferutinin molecules are hydrogen-bonded at the phenol hydroxyl groups. The variations of absorption assigned to -OH and -C-O stretching mode suggest that ferutinin interacts strongly with Ca ions via the hydroxyl group of ferutinol and carboxyl oxygen of the complex ether bond. The coordination through the carbonyl group of ferutinin was demonstrated by theoretical calculations. Taken together, ferutinin molecules form H-bonded dimers, while complexation of Ca(2+) by ferutinin ruptures this hydrogen bond due to spatial re-orientation of the ferutinin molecules from parallel to antiparallel alignment.

A novel type of 14-membered cyclic polyphosphine, namely 1,8-diaza-3,6,10,13-tetraphosphacyclotetradecanes 2a–4ahas been synthesized by the condensation of 1,2-bis(phenylphosphino)ethane, formaldehyde and alkylamines (isopropylamine, ethylamine and cyclohexylamine) as a RRRR/SSSS-stereoisomer. The structure of macrocycle 2a was investigated by NMR-spectroscopy and X-ray crystal structure analysis. The unique reversible processes of macrocycles 2a–4a splitting onto the corresponding rac- (2b–4b) and meso- (2c–4c) stereoisomers of 1-aza-3,6-diphosphacycloheptanes were discovered.

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.

The Diels-Alder reactions of cyclopentadiene, cyclohexadiene, and cycloheptadiene with a series of dienophiles were studied with quantum mechanical calculations (M06-2X density functional theory) and analyzed with the distortion/interaction model. The poor reactivities of cyclohexadiene and cycloheptadiene with dienophiles that give relatively synchronous transition states result from the substantial distortion required to achieve a transition state involving the formation of two bonds of the diene simultaneously. However, highly asynchronous or stepwise reactions result in less distortion of the diene and less differences in reactivities of different dienes. The transition state geometry of cyclopentadiene is less distorted in the asynchronous reaction with 1,1-dicyanoethylene compared to that with cis- and trans-1,2-dicyanoethylenes, which react through synchronous transition states.

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.

The phenolic constituents of lahpet-so, a traditional postfermented tea of Myanmar produced under anaerobic conditions, were examined. The major polyphenols were identified to be pyrogallol and 4'-hydroxyphenyl-3-(2'',4'',6''-trihydroxyphenyl)-propan-2-ol, 3',4'-dihydroxyphenyl-3-(2'',4'',6''-trihydroxyphenyl)-propan-2-ol, and 3',4',5'-trihydroxyphenyl-3-(2'',4'',6''-trihydroxyphenyl)-propan-2-ol. The hydroxydiphenylpropan-2-ols were identical to the initial metabolites produced from green tea catechins by mammalian intestinal bacteria. In addition, an anaerobic mixed-fermentation experiment using lahpet-so and Japanese commercial green tea afforded two new catechin degradation products together with known compound bruguierol B and the above-mentioned catechin metabolites. Based on spectroscopic evidence, the structures of the new compounds were concluded to be 4-(2,5-dihydroxyhexyl)benzene-1,2-diol and (5S,8R)-6,7,8,9-tetrahydro-5-methyl-5·8-epoxy-5H-benzocycloheptene-2,3,4-triol. Interestingly, the production mechanism was deduced to be the inverse of the biosynthesis of the flavan-3-ol A ring.

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 novel Lewis acid catalyzed annulation reaction has been established for the synthesis of benzocyclohepta[b]indoles. This method represents a new annulation strategy to a seven-membered carbocyclic ring system from two 3-(1H-isochromen-1-yl)-1H-indole molecules using Cu(OTf)2 catalyst; moreover, the products, benzocyclohepta[b]indoles, can be used as the rapid mercuric ion colorimetric detection reagents.

A recently developed (4+3) cycloaddition between dienes and furfuryl alcohols, as precursors of oxyallyl-type cations, has been used as a key step in the racemic syntheses of two natural products: frondosin B and liphagal. This work demonstrates the synthetic potential of this cycloaddition reaction, and offers a short synthetic route to an interesting family of natural products. A full account of these synthetic studies is presented, further illustrating the mechanism, scope, and limitations of this straightforward synthetic method for seven-membered rings., (Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.)

A current hurdle in cancer management is the intrinsic or acquired resistance of cancer cells to chemical agents that restricts the efficacy of therapeutic strategies. Accordingly, there is an increasing desire to discover new natural compounds with selective toxicity to combat malignancies. In present study, the cytotoxic and apoptosis- inducing activities of ferutinin, a terpenoid derivative from Ferula ovina, were investigated on human breast (MCF7) and bladder (TCC) cancer cells as well as normal fibroblasts (HFF3).The toxicity and DNA damage inducing effects of ferutinin were studied by MTT and comet assays, DAPI and PI staining and DNA laddering. The IC50 values of ferutinin were identified and compared with routine prescribed drugs, doxorubicin and vincristine, by MTT test. Alkaline comet assay and DAPI staining revealed DNA damage due to ferutinin, which was significantly (p<0.001) higher in MCF7 and TCC than HFF3 cells. Apoptosis induction was evidenced by PI staining and DNA laddering. Our results suggest that ferutinin could be considered as an effective anticancer agent for future in vivo and clinical experiments.

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.

The in vitro biotransformation of karahanaenone was examined in cytochrome P450 (CYP) 2A6. The biotransformation of karahanaenone by CYP2A6 was investigated by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Karahanaenone was found to be oxidized to two metabolites by CYP2A6. In order to produce large quantity of metabolites by CYP2A6, the biotransformation of karahanaenone by Salmonella typhimurium OY1002/2A6 was investigated. Similarly, two metabolites were confirmed by GC and GC-MS. The structure of metabolites was determined by 1D NMR, 2D NMR, and infrared, as a result there were new compounds, (6R)-hydroxykarahanaenone and 10-hydroxykarahanaenone.

A toxicologic and dermatologic review of 1-(2,5,5-trimethylcycloheptyl)ethan-1-one when used as a fragrance ingredient is presented. 1-(2,5,5-Trimethylcycloheptyl)ethan-1-one is a member of the fragrance structural group Alkyl Cyclic Ketones. These fragrances can be described as being composed of an alkyl, R1, and various substituted and bicyclic saturated or unsaturated cyclic hydrocarbons, R2, in which one of the rings may include up to 12 carbons. Alternatively, R2 may be a carbon bridge of C2-C4 carbon chain length between the ketone and cyclic hydrocarbon. This review contains a detailed summary of all available toxicology and dermatology papers that are related to this individual fragrance ingredient and is not intended as a stand-alone document. Available data for 1-(2,5,5-trimethylcycloheptyl)ethan-1-one were evaluated then summarized and includes physical properties, skin irritation, mucous membrane (eye) irritation, and skin sensitization data. A safety assessment of the entire Alkyl Cyclic Ketones will be published simultaneously with this document; please refer to Belsito et al. (Belsito, D., Bickers, D., Bruze, M., Calow, P., Dagli, M., Fryer, A.D., Greim, H., Miyachi, Y., Saurat, J.H., Sipes, I.G., 2013. A toxicologic and dermatologic assessment of alkyl cyclic ketones when used as fragrance ingredients. (submitted for publication)) for an overall assessment of the safe use of this material and all Alkyl Cyclic Ketones in fragrances., (Copyright © 2013. Published by Elsevier Ltd.)