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Tranylcypromine

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https://www.readbyqxmd.com/read/29037950/discovery-of-tranylcypromine-analogs-with-an-acylhydrazone-substituent-as-lsd1-inactivators-design-synthesis-and-their-biological-evaluation
#1
Kai Sun, Jia-Di Peng, Feng-Zhi Suo, Ting Zhang, Yun-Dong Fu, Yi-Chao Zheng, Hong-Min Liu
Lysine specific demethylase 1 (LSD1), the first identified histone demethylase, plays an important role in epigenetic regulation of gene activation and repression, has been reported to be up-regulated and involved in numbers of solid malignant tumors. In this study, we identified a series of phenylalanyl hydrazones based LSD1 inhibitors, and the most potent one, compound 4q, can inactivate LSD1 with IC50 = 91.83 nM. In cellular level, compound 4q can induce the accumulation of CD86 as well as H3K4me2, and inhibit gastric cancer cell proliferation by inactivating LSD1...
November 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29031059/tying-up-tranylcypromine-novel-selective-histone-lysine-specific-demethylase-1-lsd1-inhibitors
#2
Yue-Yang Ji, Sen-Dong Lin, Yu-Jie Wang, Ming-Bo Su, Wei Zhang, Hendra Gunosewoyo, Fan Yang, Jia Li, Jie Tang, Yu-Bo Zhou, Li-Fang Yu
Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials...
December 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28988449/surfactant-assisted-electromembrane-extraction-combined-with-cyclodextrin-modified-capillary-electrophoresis-for-the-separation-and-quantification-of-tranylcypromine-enantiomers-in-biological-samples
#3
Ali Reza Fakhari, Hasan Mohammadi Kosalar, Sajad Asadi, Kobra Sadat Hasheminasab
Surfactant-assisted electromembrane extraction coupled with cyclodextrin-modified capillary electrophoresis was developed for the separation and determination of tranylcypromine enantiomers in biological samples. This combination would provide a new strategy for selective and sensitive determination of target analytes. The addition of surfactant in the donor solution improved the analyte transport into the lumen of hollow fiber that resulted in an enhancement in the analytes migration into acceptor solution...
October 8, 2017: Journal of Separation Science
https://www.readbyqxmd.com/read/28987602/design-and-synthesis-of-tranylcypromine-derivatives-as-novel-lsd1-hdacs-dual-inhibitors-for-cancer-treatment
#4
Ying-Chao Duan, Yong-Cheng Ma, Wen-Ping Qin, Li-Na Ding, Yi-Chao Zheng, Ying-Li Zhu, Xiao-Yu Zhai, Jing Yang, Chao-Ya Ma, Yuan-Yuan Guan
Lysine specific demethylase 1 (LSD1) and Histone deacetylases (HDACs) are promising drug targets for cancers. Recent studies reveal an important functional interplay between LSD1 and HDACs, and there is evidence for the synergistic effect of combined LSD1 and HDAC inhibitors on cancers. Therefore, development of inhibitors targeting both LSD1 and HDACs might be a promising strategy for epigenetic therapy of cancers. We report herein the synthesis of a series of tranylcypromine derivatives as LSD1/HDACs dual inhibitors...
November 10, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28892629/development-of-4-cyanophenyl-glycine-derivatives-as-reversible-inhibitors-of-lysine-specific-demethylase-1
#5
Daniel P Mould, Cristina Alli, Ulf Bremberg, Sharon Cartic, Allan M Jordan, Matthis Geitmann, Alba Maiques-Diaz, Alison E McGonagle, Tim C P Somervaille, Gary J Spencer, Fabrice Turlais, Donald Ogilvie
Inhibition of lysine specific demethylase 1 (LSD1) has been shown to induce the differentiation of leukemia stem cells in acute myeloid leukemia (AML). Irreversible inhibitors developed from the nonspecific inhibitor tranylcypromine have entered clinical trials; however, the development of effective reversible inhibitors has proved more challenging. Herein, we describe our efforts to identify reversible inhibitors of LSD1 from a high throughput screen and subsequent in silico modeling approaches. From a single hit (12) validated by biochemical and biophysical assays, we describe our efforts to develop acyclic scaffold-hops from GSK-690 (1)...
October 12, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28881812/a-combination-of-valproic-acid-sodium-salt-chir99021-e-616452-tranylcypromine-and-3-deazaneplanocin-a-causes-stem-cell-like-characteristics-in-cancer-cells
#6
Shuang Sha, Yuanfen Zhai, Chengzhao Lin, Heyong Wang, Qing Chang, Shuang Song, Mingqiang Ren, Gentao Liu
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1...
August 8, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722470/novel-potent-inhibitors-of-the-histone-demethylase-kdm1a-lsd1-orally-active-in-a-murine-promyelocitic-leukemia-model
#7
Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello
BACKGROUND: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor...
July 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28698144/inhibiting-glycogen-synthase-kinase-3-and-transforming-growth-factor-%C3%AE-signaling-to-promote-epithelial-transition-of-human-adipose-mesenchymal-stem-cells
#8
Melina Setiawan, Xiao-Wei Tan, Tze-Wei Goh, Gary Hin-Fai Yam, Jodhbir S Mehta
BACKGROUND: This study was aimed to investigate the epithelial differentiation of human adipose-derived mesenchymal stem cells (ADSCs) by inhibiting glycogen synthase kinase-3 (GSK3) and transforming growth factor β (TGFβ) signaling. METHODS AND RESULTS: STEMPRO human ADSCs at passage 2 were treated with CHIR99021 (GSK3 inhibitor), E-616452 (TGFβ1 receptor kinase inhibitor), A-83-01 (TGFβ type 1 receptor inhibitor), valproic acid (histone deacetylase inhibitor), tranylcypromine (monoamine oxidase inhibitor) and all-trans retinoic acid for 72 h...
September 2, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28690895/discrimination-between-drug-abuse-and-medical-therapy-case-report-of-a-tranylcypromine-overdose-related-fatality
#9
Maryam Akhgari, Farzaneh Jokar, Afshar Etemadi-Aleagha, Ali Ghasemi
Tranylcypromine is an effective antidepressant from the class of monoamine oxidase inhibitors and is structurally related to amphetamine. However, reports differ regarding the potential metabolism of tranylcypromine to amphetamine and methamphetamine within the human body. We report a 25-year-old woman with severe depression who died due to a fatal tranylcypromine overdose in 2016. She had been prescribed tranylcypromine one day previously and had no history of previous suicide attempts or substance abuse. The body was transferred to a forensic medicine department in Tehran, Iran for the autopsy...
May 2017: Sultan Qaboos University Medical Journal
https://www.readbyqxmd.com/read/28655495/tranylcypromine-in-mind-part-i-review-of-pharmacology
#10
REVIEW
Sven Ulrich, Roland Ricken, Mazda Adli
It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: Part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and Part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. Pharmacological data of this review part I characterize TCP as an irreversible and nonselective MAO-A/B inhibitor at low therapeutic doses of 20mg/day with supplementary norepinephrine reuptake inhibition at higher doses of 40-60mg/day...
June 24, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28645134/-arterial-hyper-and-hypotension-associated-with-psychiatric-medications-a-risk-assessment-based-on-the-summaries-of-product-characteristics-smpcs
#11
Roland W Freudenmann, Ninja Freudenmann, Bartosz Zurowski, Carlos Schönfeldt-Lecuona, Ludwig Maier, Roland E Schmieder, Christian Lange-Asschenfeldt, Maximilian Gahr
Introduction Psychiatric medications are well-known triggers of clinically relevant blood pressure changes. Therefore, we aimed at creating ranking lists for their risk of causing arterial hyper- or hypotension. Methods We analyzed 784 Summaries of Product characteristics (SmPCs, available online from "Rote Liste" or "Gelbe Liste" websites) from 105 psychiatric medications registered in adult psychiatry in Germany and extracted the standardized reported risks of increasing or decreasing arterial blood pressure...
August 2017: Deutsche Medizinische Wochenschrift
https://www.readbyqxmd.com/read/28637014/a-combination-of-valproic-acid-sodium-salt-chir99021-e-616452-tranylcypromine-and-3-deazaneplanocin-a-causes-stem-cell-like-characteristics-in-cancer-cells
#12
Shuang Sha, Yuanfen Zhai, Chengzhao Lin, Heyong Wang, Qing Chang, Shuang Song, Mingqiang Ren, Gentao Liu
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1...
June 7, 2017: Oncotarget
https://www.readbyqxmd.com/read/28613369/-hypertension-en-orthostatic-hypotension-during-use-of-monoamine-oxidase-mao-inhibitors
#13
W T Zandee, J Alsma, T K Birkenhäger, A H VAN den Meiracker, M van Hoek, J Versmissen
Monoamine oxidase (mao) inhibitors are antidepressants with potentially severe side-effects. For this reason, the registration of this drug was suspended for some time when safer alternatives became available. However, mao inhibitors can be very effective in cases where depression has proved to be treatment resistant. Consequently, last year tranylcypromine was re-registered for use in the Netherlands. Since mao inhibitors have been used only sporadically in the Netherlands over the last few years, health professionals have only limited knowledge about the side-effects...
2017: Tijdschrift Voor Psychiatrie
https://www.readbyqxmd.com/read/28579071/tranylcypromine-in-mind-part-ii-review-of-clinical-pharmacology-and-meta-analysis-of-controlled-studies-in-depression
#14
REVIEW
Roland Ricken, Sven Ulrich, Peter Schlattmann, Mazda Adli
It has been over 50 years since a review has focused exclusively on the monoamine oxidase (MAO) inhibitor tranylcypromine (TCP). A new review has therefore been conducted for TCP in two parts which are written to be read preferably in close conjunction: part I - pharmacodynamics, pharmacokinetics, drug interactions, toxicology; and part II - clinical studies with meta-analysis of controlled studies in depression, practice of TCP treatment, place in therapy. The irreversible and nonselective MAO-A/B inhibitor TCP has been confirmed as an efficacious and safe antidepressant drug...
June 1, 2017: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28390942/fluorinated-tranylcypromine-analogues-as-inhibitors-of-lysine-specific-demethylase-1-lsd1-kdm1a
#15
Maria Teresa Borrello, Benjamin Schinor, Katharina Bartels, Hanae Benelkebir, Sara Pereira, Wafa T Al-Jamal, Leon Douglas, Patrick J Duriez, Graham Packham, Günter Haufe, A Ganesan
We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.
May 15, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28237611/abnormal-pregnancy-outcome-associated-with-high-dose-maternal-tranylcypromine-therapy-case-report-and-literature-review
#16
Debra Kennedy, William S Webster, Majella Hill, Helen E Ritchie
BACKGROUND: Tranylcypromine is a non-selective inhibitor of monamine oxidase which also inhibits the reuptake of norepinephrine. Spontaneous hypertensive reactions to the drug have been reported. In sheep tranylcypromine has been shown to cause a dose-dependent reduction in uterine blood flow. A similar effect in a pregnant woman might induce constriction of the uterine arteries and temporary fetal hypoxia. CASES: MotherSafe is a state-based Teratogen Information service and currently provides counselling to around 22,000 consumers and healthcare professionals annually regarding exposures during pregnancy and breastfeeding We report on the outcome of 2 pregnancies in a patient treated with high dose tranylcypromine as well as pimozide, diazepam and alprazolam...
April 2017: Reproductive Toxicology
https://www.readbyqxmd.com/read/27989747/chronic-postnatal-monoamine-oxidase-inhibition-affects-affiliative-behavior-in-rat-pupso
#17
Sofia Blazevic, Mirna Merkler, Dora Persic, Dubravka Hranilovic
Monoamine neurotransmitters serotonin (5-HT), dopamine (DA), and noradrenaline (NA) act as important modulators of mammalian brain development and represent neurobiological substrates of affiliative behavior reflected in rat pups as a tendency to huddle or produce ultrasonic vocalizations (USV) when separated from the nest. Monoamines are metabolized through oxidative deamination catalyzed by the mitochondrial enzyme monoamine oxidase (MAO). In this study, we examined the consequences of postnatal MAO inhibition on affiliative behavior in rat pups...
February 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/27989416/towards-the-development-of-activity-based-probes-for-detection-of-lysine-specific-demethylase-1-activity
#18
Maria E Ourailidou, Alessia Lenoci, Clemens Zwergel, Dante Rotili, Antonello Mai, Frank J Dekker
The implications of lysine-specific demethylase-1 (LSD1) in tumorigenesis have urged scientists to develop diagnostic tools in order to explore the function of this enzyme. In this work, we present our efforts on the development of tranylcypromine (TCP)-based functionalized probes for activity-based protein profiling (ABPP) of LSD1 activity. Biotinylated forms of selected compounds enabled dose-dependent enzyme labeling of recombinant LSD1. However, treatment with LSD1 inhibitors did not clearly reduce the LSD1 labeling efficiency thus indicating that labeling using these probes is not activity dependent...
February 1, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/27893888/potential-neuroprotective-effects-of-an-lsd1-inhibitor-in-retinal-ganglion-cells-via-p38-mapk-activity
#19
Takayuki Tsutsumi, Keiichiro Iwao, Hideki Hayashi, Tomoko Kirihara, Takahiro Kawaji, Toshihiro Inoue, Shinjiro Hino, Mitsuyoshi Nakao, Hidenobu Tanihara
Purpose: The epigenetic mechanisms associated with ocular neurodegenerative diseases remain unclear. The present study aimed to determine the role of lysine-specific demethylase 1 (LSD1), which represses transcription by removing the methyl group from methylated lysine 4 of histone H3, in retinal ganglion cell (RGC) survival, and to investigate the details of the neuroprotective mechanism of tranylcypromine, a major LSD1 inhibitor. Methods: The authors evaluated whether tranylcypromine contributes to neuronal survival following stress-induced damage using primary cultured rat RGCs and in vivo N-methyl-D-aspartate (NMDA)-induced excitotoxicity...
November 1, 2016: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/27885768/gram-scale-synthesis-of-chiral-cyclopropane-containing-drugs-and-drug-precursors-with-engineered-myoglobin-catalysts-featuring-complementary-stereoselectivity
#20
Priyanka Bajaj, Gopeekrishnan Sreenilayam, Vikas Tyagi, Rudi Fasan
Engineered hemoproteins have recently emerged as promising systems for promoting asymmetric cyclopropanations, but variants featuring predictable, complementary stereoselectivity in these reactions have remained elusive. In this study, a rationally driven strategy was implemented and applied to engineer myoglobin variants capable of providing access to 1-carboxy-2-aryl-cyclopropanes with high trans-(1R,2R) selectivity and catalytic activity. The stereoselectivity of these cyclopropanation biocatalysts complements that of trans-(1S,2S)-selective variants developed here and previously...
December 23, 2016: Angewandte Chemie
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