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Journal of Medicinal Chemistry Dec 2020The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol...
The biological responses to dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been studied extensively. Despite their expected general thiol reactivity, these compounds display considerable degrees of tumor cell selectivity. Here we review and preclinical studies of dienone compounds including b-AP15, VLX1570, RA-9, RA-190, EF24, HO-3867, and MCB-613. A common property of these compounds is their targeting of the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. Gene expression profiling experiments have shown induction of responses characteristic of UPS inhibition, and experiments using cellular reporter proteins have shown that proteasome inhibition is associated with cell death. Other mechanisms of action such as reactivation of mutant p53, stimulation of steroid receptor coactivators, and induction of protein cross-linking have also been described. Although unsuitable as biological probes due to widespread reactivity, dienone compounds are cytotoxic to apoptosis-resistant tumor cells and show activity in animal tumor models.
Topics: Alkenes; Animals; Antineoplastic Agents; Antiprotozoal Agents; Apoptosis; Azepines; Benzylidene Compounds; Cell Line; Humans; Neoplasms; Oxidative Stress; Piperidones; Plasmodium falciparum; Proteasome Endopeptidase Complex; Receptors, Steroid; Ubiquitin
PubMed: 33146523
DOI: 10.1021/acs.jmedchem.0c00812 -
Nature Reviews. Cardiology Jul 2017
Review
Topics: Animals; Azepines; Cell Cycle Proteins; Disease Progression; Heart Failure; Humans; Nuclear Proteins; Transcription Factors; Triazoles
PubMed: 28569271
DOI: 10.1038/nrcardio.2017.86 -
Current Organic Synthesis 20191,4-Diazepines are two nitrogen containing seven membered heterocyclic compounds and associated with a wide range of biological activities. Due to its medicinal... (Review)
Review
BACKGROUND
1,4-Diazepines are two nitrogen containing seven membered heterocyclic compounds and associated with a wide range of biological activities. Due to its medicinal importance, scientists are actively involved in the synthesis, reactions and biological evaluation of 1,4-diazepines since number of decades.
OBJECTIVE
The primary purpose of this review is to discuss the synthetic schemes and reactivity of 1,4- diazepines. This article also describes biological aspects of 1,4-diazepine derivatives, that can be usefully exploited for the pharmaceutical sector.
CONCLUSION
This review summarizes the abundant literature on synthetic routes, chemical reactions and biological attributes of 1,4-diazepine derivatives. We concluded that 1,4-diazepines have significant importance due to their biological activities like antipsychotic, anxiolytic, anthelmintic, anticonvulsant, antibacterial, antifungal and anticancer. 1,4-diazepine derivatives with significant biological activities could be explored for potential use in the pharmaceutical industries.
Topics: Animals; Anti-Infective Agents; Anticonvulsants; Antineoplastic Agents; Azepines; Humans
PubMed: 31984889
DOI: 10.2174/1570179416666190703113807 -
Anti-cancer Agents in Medicinal... 2019Cancer remains a major health concern throughout history and is responsible for huge numbers of deaths globally. The sensitivity of cancer cells to anticancer drugs is a...
BACKGROUND
Cancer remains a major health concern throughout history and is responsible for huge numbers of deaths globally. The sensitivity of cancer cells to anticancer drugs is a crucial factor for developing effective treatments.
METHODS
Pyrrolo[1,2-a]azepines coupled with benzothiazole and fluorinated aryl thiourea scaffolds have been synthesized, and their potential as cytotoxic agents was investigated against different cancer cell lines such as human ovarian cancer (SK-OV-3), cervical cancer (HeLa), colon adenocarcinoma (HT-29) and non-small-cell lung carcinoma (A549). Cytotoxicity of new compounds was confirmed using SRB assay against non-cancer MDCK cell line. In addition, free radical scavenging activity of new pyrrolo[1,2-a]azepines was examined by adopting DPPH and ABTS assays.
RESULTS
The results concluded that the presence and position of fluorine atom(s) on the thiourea unit played a significant role in order to gain anticipated efficacies. Results of the cytotoxic assay against non-cancer MDCK cells showed that these new derivatives are safe to study further. New structures were confirmed using spectral and elemental analyses.
CONCLUSION
Pyrrolo[1,2-a]azepines endowed with a benzothiazole entity and fluorinated aryl thiourea substituents were derived aiming to furnish remarkable antioxidant and anticancer activities. New molecules generated showed interesting biological result correlated with the structure and substituent of the final derivatives. Specifically, numbers and position of fluorine atoms on the thiourea unit influenced the biological profile of the mentioned compounds.
Topics: Antineoplastic Agents; Antioxidants; Azepines; Benzothiazoles; Cell Line, Tumor; Cell Survival; Drug Evaluation, Preclinical; Halogenation; Humans; Molecular Structure; Structure-Activity Relationship; Thiourea
PubMed: 31429695
DOI: 10.2174/1871520619666190820151043 -
Nature Nanotechnology Jul 2018
Topics: Animals; Antineoplastic Agents; Azepines; Blood-Brain Barrier; Brain; Brain Neoplasms; Drug Carriers; Drug Delivery Systems; Glioblastoma; Humans; Mice; Nanomedicine; Polyethylene Glycols; Temozolomide; Transferrin; Triazoles
PubMed: 29921944
DOI: 10.1038/s41565-018-0182-3 -
Organic Letters Oct 2022The asymmetric synthesis of bridged tetrahydrobenzo[]azepine and oxepine derivatives through chiral Brønsted acid catalyzed asymmetric aza-Piancatelli...
The asymmetric synthesis of bridged tetrahydrobenzo[]azepine and oxepine derivatives through chiral Brønsted acid catalyzed asymmetric aza-Piancatelli rearrangement/Michael addition sequence has been developed. The reaction proceeds under mild reaction conditions to afford the final bridged cyclic products in good yields with excellent enantio- and diastereoselectivities.
Topics: Azepines; Catalysis; Molecular Structure; Stereoisomerism
PubMed: 36169238
DOI: 10.1021/acs.orglett.2c02833 -
Psychogeriatrics : the Official Journal... Mar 2022Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether... (Meta-Analysis)
Meta-Analysis Review
Delirium is a common and serious neurobehavioral syndrome, associated with prolonged hospital stays, and increased morbidity and mortality. As it remains unclear whether suvorexant with or without ramelteon prevents delirium in elderly hospitalized patients, we conducted a systematic review and meta-analysis to evaluate, searching the PubMed, Cochrane Library, Web of Science, EMBASE, and EBSCOhost databases for all randomized controlled trials (RCTs), case-control studies, and cohort studies that investigated the effects of suvorexant with or without ramelteon on delirium in adult hospitalized patients. The primary outcome was the incidence of delirium. Two randomized controlled trials, 7 cohort studies and 2 case-control studies involving 2594 patients were included in this meta-analysis. The results showed that both suvorexant alone (odds ratio (OR) = 0.30, 95% confidence interval (CI): 0.14-0.65, P = 0.002) and suvorexant with ramelteon (OR = 0.39, 95% CI 0.23-0.65, P = 0.0003) reduced the incidence of delirium in adult hospitalized patients. Six studies involved the use of benzodiazepines; subgroup analysis performed separately in the suvorexant alone and suvorexant with ramelteon groups indicated that when benzodiazepine was administered, suvorexant with ramelteon was effective at reducing the incidence of delirium (OR = 0.53, 95% CI 0.37-0.74, P = 0.0002), but no significant difference was observed for suvorexant alone (OR = 0.40, 95% CI 0.11-1.53, P = 0.18). The current literature thus supports the effectiveness of suvorexant with or without ramelteon for delirium prevention, although suvorexant alone failed to significantly reduce the incidence of delirium when benzodiazepine was administered. The present study was limited by the significant heterogeneity among the included studies, and caution should be exercised when interpreting the results. This study was registered in the PROSPERO database (CRD4202017964).
Topics: Aged; Azepines; Delirium; Humans; Indenes; Randomized Controlled Trials as Topic; Triazoles
PubMed: 34881812
DOI: 10.1111/psyg.12792 -
Chemical Reviews Nov 2015
Review
Topics: Acetyltransferases; Azepines; Azo Compounds; Carbazoles; Diamines; Drug Evaluation, Preclinical; Humans; Protein Binding; Protein Structure, Tertiary; Quinolines; Small Molecule Libraries; Transcription Factors
PubMed: 26492937
DOI: 10.1021/acs.chemrev.5b00205 -
The Consultant Pharmacist : the Journal... Mar 2017Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines,... (Review)
Review
Geriatric patients often experience insomnia because of physiological and neurological changes that occur during the aging process. Use of benzodiazepines, nonbenzodiazepine hypnotics, and diphenhydramine for the treatment of insomnia pose an increased risk of cognitive impairment, falls, and fractures in this patient population. Therapeutic alternatives approved by the Food and Drug Administration include suvorexant, doxepin, ramelteon, and tasimelteon, which have shown efficacy and safety in various studies. This paper explores and outlines the available safety and efficacy data associated with these medications and reviews their potential place in therapy in treating insomnia in the geriatric population.
Topics: Aged; Aged, 80 and over; Azepines; Benzofurans; Cyclopropanes; Doxepin; Humans; Hypnotics and Sedatives; Indenes; Randomized Controlled Trials as Topic; Sleep Initiation and Maintenance Disorders; Triazoles
PubMed: 28270270
DOI: 10.4140/TCP.n.2017.156 -
Angewandte Chemie (International Ed. in... Dec 2017Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the...
Biocatalytic retrosynthetic analysis of dibenz[c,e]azepines has highlighted the use of imine reductase (IRED) and ω-transaminase (ω-TA) biocatalysts to establish the key stereocentres of these molecules. Several enantiocomplementary IREDs were identified for the synthesis of (R)- and (S)-5-methyl-6,7-dihydro-5H-dibenz[c,e]azepine with excellent enantioselectivity, by reduction of the parent imines. Crystallographic evidence suggests that IREDs may be able to bind one conformer of the imine substrate such that, upon reduction, the major product conformer is generated directly. ω-TA biocatalysts were also successfully employed for the production of enantiopure 1-(2-bromophenyl)ethan-1-amine, thus enabling an orthogonal route for the installation of chirality into dibenz[c,e]azepine framework.
Topics: Azepines; Biocatalysis; Molecular Structure; Oxidoreductases Acting on CH-NH Group Donors; Stereoisomerism; Transaminases
PubMed: 29024400
DOI: 10.1002/anie.201708453