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Journal of Natural Products Apr 2020Phytochemical investigation of the alkaloid extract of the aerial parts of led to the isolation and characterization of 10 azepine-indole alkaloids, i.e.,...
Phytochemical investigation of the alkaloid extract of the aerial parts of led to the isolation and characterization of 10 azepine-indole alkaloids, i.e., cimitrypazepine (), fargesine (), nemorosines A (), and B (), nemorosinosides A-F (-), as well as two β-carboline derivatives, 10-hydroxyisodolichantoside () and 10-hydroxydolichantoside (), an isoxazole alkaloid, nemorosinoside G (), serotonin (), bufotenine (), and ()-gentianol (). Compounds - have not yet been described. These compounds were isolated by semipreparative HPLC, and their structures were determined by means of HRMS, NMR, and ECD measurements. In addition, the monoamine oxidase-A (MAO-A), MAO-B, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activities were evaluated. Alkaloids - inhibited the MAO-A activity with IC values of 1.4, 1.4, and 0.9 μM, respectively.
Topics: Azepines; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Circular Dichroism; Indole Alkaloids; Magnetic Resonance Spectroscopy; Mass Spectrometry; Molecular Structure; Monoamine Oxidase Inhibitors; Plant Components, Aerial; Plant Extracts; Plant Leaves; Psychotria; Spectrometry, Mass, Electrospray Ionization
PubMed: 32150413
DOI: 10.1021/acs.jnatprod.9b00469 -
Cell Research Nov 2015BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the... (Review)
Review
BET inhibition has emerged as a promising epigenetic therapy for malignancies in the last five years, but little consensus has developed regarding what may mediate the axis between sensitivity and resistance. Two recent papers published in Nature attempt to address this question in acute myeloid leukemia (AML) and independently identify the Wnt signaling pathway as a driver and biomarker of therapeutic resistance.
Topics: Animals; Azepines; Biomarkers, Tumor; Drug Resistance; Mice; Models, Animal; Neoplasms; Triazoles; Wnt Proteins; Wnt Signaling Pathway
PubMed: 26516144
DOI: 10.1038/cr.2015.127 -
Molecules (Basel, Switzerland) Mar 2020Biological systems usually respond differently to enantiomers of a chiral molecule due to the inherent chirality of the active receptor sites of enzymes in nature [...].
Biological systems usually respond differently to enantiomers of a chiral molecule due to the inherent chirality of the active receptor sites of enzymes in nature [...].
Topics: Azepines; Benzyl Alcohols; Butyrates; Catalysis; Chemistry Techniques, Synthetic; Epoxy Compounds; Humans; Hydrocarbons, Fluorinated; Propanols; Ruthenium Compounds; Schiff Bases; Stereoisomerism
PubMed: 32168826
DOI: 10.3390/molecules25061266 -
Bioorganic Chemistry Jun 2023Cancer is associated with uncontrolled cell proliferation invading adjoining tissues and organs. Despite the availability of several chemotherapeutic agents, the...
Cancer is associated with uncontrolled cell proliferation invading adjoining tissues and organs. Despite the availability of several chemotherapeutic agents, the constant search for newer approaches and drugs is necessitated owing to the ever-growing challenge of resistance. Over the years, DNA has emerged as an important druggable therapeutic drug due to its role in critical cellular processes such as cell division and maintenance. Further, evading apoptosis stands out as a hallmark of cancer. Hence, designing new compounds that would target DNA and induce apoptosis plays an important role in cancer therapy. In the current work, we carried out the synthesis and anticancer evaluation of 1-aryl-4,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(1H)-ones/thiones (26 compounds) against selected human cancer cell lines. Among these, compounds 8ae, 8ad, 8cf, 10ad and Kenpaullone have shown good inhibitory properties against HeLa cells (IC < 2 µM) with good selectivity over the non-cancerous human embryonic kidney (Hek293T) cells. In cell cycle analysis, the compounds 8ad and 8cf have exhibited G/M cell cycle arrest in HeLa cells. In addition, the compounds 8ad and 8cf induced apoptosis in a dose-dependent manner in the Annexin-V FITC staining assay. The DAPI staining clearly demonstrated the condensed and fragmented nuclei in 8ad, 8cf, 8ae and Kenpaullone-treated HeLa cells. In addition, these compounds strongly suppressed the healing after 48 h in in vitro cell migration assay. The DNA binding experiments indicated that compounds 8ae, 8cf, and 8ad as well as Kenpaullone interact with double-stranded DNA by binding in grooves which may interrupt the DNA replication and kill fast-growing cells. Molecular docking studies revealed the binding pose of 8ad and Kenpaullone at HT1 binding pocket of double-stranded DNA. Compounds 8ad and 8cf demonstrated moderate topo II inhibition which could be a possible reason for their anticancer properties. Compounds 8ad and 8cf may cause the topo II and DNA covalent complex, which leads to the inhibition of DNA replication and transcription. This eventually increases the DNA damage in cells and promotes cell apoptosis. With the above interesting biological profile, the new 1-aryl-2,6-dihydrobenzo[b]pyrazolo[3,4-d]azepin-5(4H)-one/thione derivatives have emerged as promising leads for the discovery of new anticancer agents.
Topics: Humans; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; HEK293 Cells; HeLa Cells; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Thiones; Azepines
PubMed: 36958121
DOI: 10.1016/j.bioorg.2023.106478 -
Journal of Enzyme Inhibition and... Dec 2023In this research, two novel series of dibenzo[]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported...
Design and synthesis of novel rigid dibenzo[]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.
In this research, two novel series of dibenzo[]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates () were evaluated for their ability to inhibit topoisomerase II, where was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, studies of showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate ().HighlightsTwo novel series of dibenzo[]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. was the most active anti-topo II congener (IC = 6.36 ± 0.36 µM). was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC = 13.05 ± 0.62 µM). studies of significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm compared to doxorubicin treatment.
Topics: Humans; Topoisomerase II Inhibitors; Structure-Activity Relationship; Intercalating Agents; Molecular Docking Simulation; Cell Line, Tumor; Azepines; Antineoplastic Agents; Doxorubicin; Leukemia; DNA; Cell Proliferation; Molecular Structure; Drug Screening Assays, Antitumor; DNA Topoisomerases, Type II
PubMed: 36629421
DOI: 10.1080/14756366.2022.2157825 -
Organic Letters Oct 2022Herein, we report the first asymmetric total synthesis of iheyamine B from 2,2'-bisindoloazepinone using the stereoselective construction of the -vicinal 2-oxopropyl...
Herein, we report the first asymmetric total synthesis of iheyamine B from 2,2'-bisindoloazepinone using the stereoselective construction of the -vicinal 2-oxopropyl moiety in the azepine scaffold. The asymmetric decarboxylative allylic alkylation provided the α-allylated 2,2'-bisindoloazepinone intermediate. The subsequent conversion of the lactam moiety into another allyl group in a -selective manner followed by Wacker oxidation of each allyl unit to the corresponding 2-oxopropyl group completed the total synthesis of iheyamine B.
Topics: Alkylation; Allyl Compounds; Azepines; Catalysis; Lactams; Palladium; Stereoisomerism
PubMed: 36169573
DOI: 10.1021/acs.orglett.2c02788 -
Pharmacology & Therapeutics Jun 2018Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms... (Review)
Review
Sleep, a mysterious behavior, has recently been recognized as a crucial factor for health and longevity. The daily sleep/wake cycle provides the basis of biorhythms controlling whole-body homeostasis and homeodynamics; therefore, disruption of sleep causes several physical and psychological disorders, including cardiovascular disease, obesity, diabetes, cancer, anxiety, depression, and cognitive dysfunction. However, the mechanism linking sleep disturbances and sleep-related disorders remains unknown. Orexin (also known as hypocretin) is a neuropeptide produced in the hypothalamus. Central levels of orexin oscillate with the daily rhythm and peak at the awake phase. Orexin plays a major role in stabilizing the wakefulness state. Orexin deficiency causes sleep/wake-state instability, resulting in narcolepsy. Hyper-activation of the orexin system also causes sleep disturbances, such as insomnia, and hence, suvorexant, an orexin receptor antagonist, has been clinically used to treat insomnia. Importantly, central actions of orexin regulate motivated behaviors, stress response, and energy/glucose metabolism by coordinating the central-autonomic nervous systems and endocrine systems. These multiple actions of orexin maintain survival. However, it remains unknown whether chronopharmacological interventions targeting the orexin system ameliorate sleep-related disorders as well as sleep in humans. To understand the significance of adequate orexin action for prevention of these disorders, this review summarizes the physiological functions of daily orexin action and pathological implications of its mistimed or reduced action in sleep disturbances and sleep-related disorders (lifestyle-related physical and neurological disorders in particular). Timed administration of drugs targeting the orexin system may prevent lifestyle-related diseases by improving the quality of life in patients with sleep disturbances.
Topics: Azepines; Circadian Rhythm; Humans; Life Style; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Quality of Life; Sleep Aids, Pharmaceutical; Sleep Wake Disorders; Triazoles
PubMed: 29289556
DOI: 10.1016/j.pharmthera.2017.12.010 -
Bioorganic & Medicinal Chemistry Letters Nov 2021The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug...
The HBV core protein serves multiple essential functions in the viral life cycle that enable chronic HBV infection to persist, and as such, represents a promising drug target. Modulation of the HBV capsid assembly has shown efficacy in early clinical trials through use of small molecule capsid assembly modulators (CAMs). Herein is described the evolution and SAR of a novel pyrazolo piperidine lead series into advanced oxadiazepinone HBV CAMs.
Topics: Antiviral Agents; Azepines; Capsid Proteins; Dose-Response Relationship, Drug; Hepatitis B virus; Humans; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship
PubMed: 34492302
DOI: 10.1016/j.bmcl.2021.128353 -
Bioorganic & Medicinal Chemistry Letters Feb 2020The SAR of a series of benzopyrimidodiazepinone inhibitors of TNK2 was developed, starting from the potent and selective compound XMD8-87. A diverse set of anilines was...
The SAR of a series of benzopyrimidodiazepinone inhibitors of TNK2 was developed, starting from the potent and selective compound XMD8-87. A diverse set of anilines was introduced in an effort to improve the in vivo PK profile and minimize the risk of quinone diimine formation.
Topics: Animals; Azepines; Cell Line, Tumor; Half-Life; Humans; Inhibitory Concentration 50; Mice; Microsomes, Liver; Protein Binding; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Structure-Activity Relationship
PubMed: 31928839
DOI: 10.1016/j.bmcl.2020.126948 -
Sleep Medicine Reviews Oct 2017Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and... (Meta-Analysis)
Meta-Analysis Review
Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and meta-analysis to assess the efficacy and safety of suvorexant for the treatment of primary insomnia. We searched PubMed, EMBASE, and the Cochrane central register of controlled trials, contacted a relevant pharmaceutical company, and accessed websites of the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) for published and unpublished data. A total of four randomized trials involving 3076 patients with primary insomnia were included in our analysis. Our analysis suggested that suvorexant was associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective quality of sleep at 1 mo and 3 mo. Somnolence, fatigue, and abnormal dreams were the most common adverse effects. We concluded that suvorexant was associated with improvement in some sleep parameters and some adverse effects. To determine the place of suvorexant in the treatment of insomnia, comparative effectiveness trials are needed.
Topics: Azepines; Humans; Japan; Randomized Controlled Trials as Topic; Sleep Aids, Pharmaceutical; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Triazoles; United States
PubMed: 28365447
DOI: 10.1016/j.smrv.2016.09.004