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Chemistry, An Asian Journal Jan 2022The azepine- and oxepine-embedded polycyclic aromatic hydrocarbons (PAH) 1-3, as the hexa-peri-hexabenzocoronene (HBC)-based nanographenes (NG) were designed and...
The azepine- and oxepine-embedded polycyclic aromatic hydrocarbons (PAH) 1-3, as the hexa-peri-hexabenzocoronene (HBC)-based nanographenes (NG) were designed and synthesized by Diels-Alder reaction of cyclic alkene with tetrachlorothiophene-S,S-dioxide, followed by Suzuki-Miyaura cross-coupling and Scholl-type cyclodehydrogenation. Due to the strained seven-membered ring and the inherent structural pattern, heteroatom-doped NGs 1-3 show C symmetrical, double saddle-helix hybrid conformation, which represents a new shape for HBC based nanographenes. The calculation studies reveal the low aromaticity of the 8π heterocycles themselves and the heterocycles also decrease the electron delocalization of benzenes surrounding them. Dynamics-based calculation suggests the C symmetry would maintain druing the saddle-inversion process. Meanwhile, we show property perturbation by doping with different heteroatoms.
Topics: Azepines; Cycloaddition Reaction; Electrons; Molecular Conformation; Oxepins
PubMed: 34904381
DOI: 10.1002/asia.202101365 -
Organic & Biomolecular Chemistry May 2017Various oxepine and azepine fused N-heterocyclic derivatives were synthesized using a new and one-pot reaction of 2,3-dichloro quinoxaline/pyrazine with...
Various oxepine and azepine fused N-heterocyclic derivatives were synthesized using a new and one-pot reaction of 2,3-dichloro quinoxaline/pyrazine with 2-(1H-indol-2-yl)phenol/aniline in the presence of 25 mol% FeCl. The reaction proceeded via C-C bond followed by C-X (X = O or N) bond formation to construct the central 7-membered ring, affording the desired products in good yields. The structure assignment was confirmed by the single crystal X-ray analysis of a synthesized oxepine fused N-heterocycle derivative. Most of the synthesized compounds were found to be promising when tested for their anti-proliferative properties against cervical and breast cancer cell lines.
Topics: Antineoplastic Agents; Azepines; Catalysis; Cell Line, Tumor; Cell Proliferation; Chlorides; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Ferric Compounds; HeLa Cells; Heterocyclic Compounds; Humans; Indoles; MCF-7 Cells; Models, Molecular; Molecular Structure; Oxepins; Structure-Activity Relationship
PubMed: 28497830
DOI: 10.1039/c7ob00715a -
Current Medicinal Chemistry 2018Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of... (Review)
Review
Since its discovery in 1983, followed by gene cloning in 1999, the histamine H3 receptor served as an outstanding target for drug discovery. The wide spectrum of possible therapeutic implications makes H3R's one of the most researched areas in the vast GPCR ligands field - started from imidazole containing ligands, through various successful imidazole replacements, with recent introduction of Wakix® to pharmaceutical market. One such replacement is piperazine moiety, a significant versatile scaffold in rational drug design for most of the GPCR ligands. Therefore, herein, we review ligands built on piperazine, as well as its seven membered analogue azepine, that target H3R's and their potential therapeutical applications, in order to elucidate the current state of the art in this vast field. Due to a high level of structural divergence among compounds described herein, we decided to divide them into groups, where the key division element was the position of nitrogen basicity decreasing moieties in (homo)piperazine ring. Paying attention to a number of published structures and their overall high biological activity, one can realize that the (homo)piperazine scaffold bids a versatile template also for histamine H3 receptor ligands. With two possible substitution sites and therefore a number of possible structural combinations, piperazine derivatives stand as one of the largest group of high importance among H3R ligands.
Topics: Animals; Azepines; Drug Design; Histamine H3 Antagonists; Humans; Ligands; Molecular Structure; Piperazines
PubMed: 29173145
DOI: 10.2174/0929867325666171123203550 -
Bioorganic & Medicinal Chemistry Letters Dec 2010Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated...
Based upon a previously reported lead compound 1, a series of 1,2-diamino-ethane-substituted-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepines were synthesized and evaluated for improved physiochemical and pharmacokinetic properties while maintaining TRPV1 antagonist activity. Structure-activity relationship studies directed toward improving the aqueous solubility (pH 2 and fasted-state simulated intestinal fluid (SIF)) and rat pharmacokinetics led to the discovery of compound 13. Aqueous solubility of compound 13 (pH 2 ≥237 μg/mL and SIF=11 μg/mL) was significantly improved over compound 1 (pH 2=5 μg/mL and SIF=0.5 μg/mL). In addition, compound 13 afforded improved rat pharmacokinetics (CL=0.7 L/kg/h) compared to compound 1 (CL=3.1 L/kg/h). Compound 13 was orally bioavailable and afforded a significant reversal of carrageenan-induced thermal hyperalgesia at 5 and 30 mg/kg in rats.
Topics: Animals; Azepines; Dose-Response Relationship, Drug; Humans; Hydrogen-Ion Concentration; Hyperalgesia; Rats; Solubility; Structure-Activity Relationship; TRPV Cation Channels
PubMed: 20932750
DOI: 10.1016/j.bmcl.2010.09.006 -
Journal of Natural Products Mar 2017This review focuses entirely on the natural bengamides and selected synthetic analogues that have inspired decades of research. Bengamide A was first reported in 1986... (Review)
Review
This review focuses entirely on the natural bengamides and selected synthetic analogues that have inspired decades of research. Bengamide A was first reported in 1986 from the sponge Jaspis cf. coriacea, and bengamide-containing sponges have been gathered from many biogeographic sites. In 2005, a terrestrial Gram-negative bacterium, Myxococcus virescens, was added as a source for bengamides. Biological activity data using varying bengamide-based scaffolds has enabled fine-tuning of structure-activity relationships. Molecular target finding contributed to the creation of a synthetic "lead" compound, LAF389, that was the subject of a phase I anticancer clinical trial. Despite clinical trial termination, the bengamide compound class is still attracting worldwide attention. Future breakthroughs based on the bengamide scaffold are possible and could build on their nanomolar in vitro and positive in vivo antiproliferative and antiangiogenic properties. Bengamide molecular targets include methionine aminopeptidases (MetAP1 and MetAP2) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). A mixed PKS/NRPS biosynthetic gene cluster appears to be responsible for creation of the bengamides. This review highlights that the bengamides have driven inspirational studies and that they will remain relevant for future research, even 30 years after the discovery of the first structures.
Topics: Aminopeptidases; Angiogenesis Inhibitors; Animals; Azepines; Humans; Metalloendopeptidases; Methionyl Aminopeptidases; Molecular Structure; NF-kappa B; Porifera
PubMed: 28185457
DOI: 10.1021/acs.jnatprod.6b00970 -
Organic & Biomolecular Chemistry May 2011An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino...
An effective approach to azepino-fused heterocycles is described. trans-1-Aryl-7,11b-dihydro-1H-azirino[1,2-a]dibenzo[c,f]azepines were synthesised via a domino sequence: isomerization of gem-dichloroaziridine-intramolecular Friedel-Crafts acylation of the tethered benzene ring catalysed by SnCl(4) and subsequent hydride induced intramolecular cyclization. Cycloaddition of dibenzazepinium ylides, generated by heating these aziridines, to activated C[double bond]C, C[triple bond]C dipolarophiles and fullerene C(60), leads to derivatives of dibenzo[c,f]pyrrolo[1,2-a]azepine. The reaction proceeds with complete stereoselectivity via cycloaddition of only W-ylide, which due to the high barrier does not undergo E,Z-isomerization under the reaction conditions. It was found that 2,3,9,13b-tetrahydro-1H-dibenzo[c,f]pyrrolo[1,2-a]azepine systems can exist in conformations of two types depending on the substituents at the pyrrolidine carbons in β-position with respect to nitrogen. Details of cycloaddition reactions and the conformational behavior of cycloadducts were studied by DFT calculations at the B3LYP/6-31G(d) level.
Topics: Azepines; Dibenzazepines; Models, Molecular; Molecular Conformation; Oxazepines; Pyrroles
PubMed: 21465044
DOI: 10.1039/c1ob05081h -
Drug Development and Industrial Pharmacy Mar 2006Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components... (Review)
Review
Absorption enhancers are substances used for temporarily increasing a membrane's permeability (e.g., the skin and mucosa), either by interacting with its components (lipids or proteins) or by increasing the membrane/vehicle partition coefficient. This article presents the results of biophysical and permeability studies performed with Laurocapram and its analogues. As shown, Laurocapram and its analogues present different enhancing efficacies, for most of both hydrophilic and lipophilic substances. The enhancing effect of Laurocapram (Azone) is attributed to different mechanisms, such as insertion of its dodecyl group into the intercellular lipidic bilayer, increase of the motion of the alkylic chains of lipids, and fluidization of the hydrophobic regions of the lamellate structure. Toxicological studies reveal a low toxicity for Laurocapram, and for some derivatives, a relationship exists between toxicity and the number of carbons in the alkylic chain. Very important, when applied to human skin, Laurocapram shows a minimal absorption, being quickly eliminated from circulation. However, although Laurocapram and its derivatives have been shown to provide enhancement, they have not been widely accepted because of their suspected pharmacological activity or questions about their safety.
Topics: Animals; Azepines; Chemistry, Pharmaceutical; Humans; In Vitro Techniques; Skin Absorption; Structure-Activity Relationship
PubMed: 16556532
DOI: 10.1080/03639040500518708 -
Annual Review of Pharmacology and... 2015γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their... (Review)
Review
γ-Secretases are a group of widely expressed, intramembrane-cleaving proteases involved in many physiological processes. Their clinical relevance comes from their involvement in Alzheimer's disease, cancer, and other disorders. A clinical trial with the wide-spectrum γ-secretase inhibitor semagacestat has, however, demonstrated that global inhibition of all γ-secretases causes serious toxicity. Evolving insights suggest that selective inhibition of one of these proteases, or more subtle modulation of γ-secretases by stimulating their carboxypeptidase-like activity but sparing their endopeptidase activity, are potentially highly interesting approaches. The rapidly growing knowledge of regulation, assembly, and specificity of these intriguing protein complexes and the potential advent of high-resolution structural information could dramatically change the perspective on safe and efficacious γ-secretase inhibition in various disorders.
Topics: Alanine; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Azepines; Drug Design; Humans; Molecular Structure; Molecular Targeted Therapy; Protease Inhibitors; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Treatment Failure
PubMed: 25292430
DOI: 10.1146/annurev-pharmtox-010814-124309 -
European Journal of Medicinal Chemistry Apr 2012A series of novel methylene bis-isoxazolo[4,5-b]azepines have been synthesized by reaction of 3,5-dimethyl-4-nitroisoxazole 6 with an appropriate methylene bis-chalcones...
A series of novel methylene bis-isoxazolo[4,5-b]azepines have been synthesized by reaction of 3,5-dimethyl-4-nitroisoxazole 6 with an appropriate methylene bis-chalcones 7 to obtain various Michael adducts 8a-i, which on treatment with SnCl(2)-MeOH underwent reductive cyclization to afford the title compounds 9a-i. Structure of these compounds were established on the basis of IR, (1)H NMR, (13)C NMR and mass spectral data. The title compounds 9a-i were evaluated for their in vitro antimicrobial and anticancer activities. Compounds 9h and 9i exhibited potent antimicrobial and anticancer activities as that of standard drugs.
Topics: Anti-Bacterial Agents; Antineoplastic Agents; Azepines; Bacteria; Breast Neoplasms; Cell Proliferation; Cells, Cultured; Drug Design; Female; Humans; Isoxazoles; Kidney; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship
PubMed: 22385674
DOI: 10.1016/j.ejmech.2012.02.013 -
Nature May 2016
Topics: Access to Information; Animals; Azepines; Clinical Trials as Topic; Drug Discovery; Histones; Humans; Information Dissemination; Male; Mice; Neoplasms; Patents as Topic; Protein Binding; Protein Structure, Tertiary; Triazoles; Xenograft Model Antitumor Assays
PubMed: 27167393
DOI: 10.1038/533S60a