The Experts below are selected from a list of 1140 Experts worldwide ranked by ideXlab platform
Maria Teresa Borrello - One of the best experts on this subject based on the ideXlab platform.
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synthesis of carboxamide containing Tranylcypromine analogues as lsd1 kdm1a inhibitors targeting acute myeloid leukemia
ChemMedChem, 2021Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Adam Lee, Chak Hin Tam, Manar S Shafat, Stuart A Rushworth, Kristian M Bowles, Leon Douglas, Sarah G BaileyAbstract:Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of Tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these Tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile Tranylcypromine prodrugs with superior pharmacokinetics.
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fluorinated Tranylcypromine analogues as inhibitors of lysine specific demethylase 1 lsd1 kdm1a
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Graham Packham, Leon Douglas, Benjamin Schinor, Katharina Bartels, Sara Pereira, Wafa T Aljamal, Günter HaufeAbstract: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.
Hanae Benelkebir - One of the best experts on this subject based on the ideXlab platform.
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synthesis of carboxamide containing Tranylcypromine analogues as lsd1 kdm1a inhibitors targeting acute myeloid leukemia
ChemMedChem, 2021Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Adam Lee, Chak Hin Tam, Manar S Shafat, Stuart A Rushworth, Kristian M Bowles, Leon Douglas, Sarah G BaileyAbstract:Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of Tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these Tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile Tranylcypromine prodrugs with superior pharmacokinetics.
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fluorinated Tranylcypromine analogues as inhibitors of lysine specific demethylase 1 lsd1 kdm1a
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Graham Packham, Leon Douglas, Benjamin Schinor, Katharina Bartels, Sara Pereira, Wafa T Aljamal, Günter HaufeAbstract: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.
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enantioselective synthesis of Tranylcypromine analogues as lysine demethylase lsd1 inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Hanae Benelkebir, Christopher Hodgkinson, Patrick J Duriez, Annette Hayden, Rosemary A Bulleid, Simon J Crabb, Graham Packham, A GanesanAbstract:Asymmetric cyclopropanation of styrenes by tert-butyl diazoacetate followed by ester hydrolysis and Curtius rearrangement gave a series of Tranylcypromine analogues as single enantiomers. The o,- m- and p-bromo analogues were all more active than Tranylcypromine in a LSD1 enzyme assay. The m- and p-bromo analogues were micromolar growth inhibitors of the LNCaP prostate cancer cell line as were the corresponding biphenyl analogues prepared from the bromide by Suzuki crosscoupling.
Günter Haufe - One of the best experts on this subject based on the ideXlab platform.
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fluorinated Tranylcypromine analogues as inhibitors of lysine specific demethylase 1 lsd1 kdm1a
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Graham Packham, Leon Douglas, Benjamin Schinor, Katharina Bartels, Sara Pereira, Wafa T Aljamal, Günter HaufeAbstract: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.
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Fluorinated phenylcyclopropylamines. Part 5: Effects of electron-withdrawing or -donating aryl substituents on the inhibition of monoamine oxidases A and B by 2-aryl-2-fluoro-cyclopropylamines
Bioorganic & medicinal chemistry, 2008Co-Authors: Svenja Hruschka, Thomas C. Rosen, Shinichi Yoshida, Kenneth L. Kirk, Roland Fröhlich, Birgit Wibbeling, Günter HaufeAbstract:Abstract A series of racemic, diastereoisomeric aryl cyclopropylamines substituted with fluorine in the 2-position and electron-donating and electron-withdrawing groups on the aromatic ring have been prepared. These represent analogues of the classic MAO inhibitor Tranylcypromine (trans-2-phenylcyclopropylamine, 1). Their activities as inhibitors of recombinant human liver monoamine oxidases A (MAO A) and B (MAO B) were determined. The trans-compounds were low micromolar inhibitors of both MAO A and MAO B with moderate MAO A selectivity while the less active cis-analogues were MAO B selective. In the trans-series, electron-withdrawing para-substituents increased the potency of MAO A inhibition while electron-donating groups such as methyl or methoxy had no influence on this activity. In contrast, aromatic ring substitution in the trans-series had essentially no effect on the inhibition of MAO B. The corresponding cis-compounds were shown to be 10–100 times less active against MAO A, while trans- and cis-compounds were quite similar in terms of inhibition of MAO B. The best MAO A/MAO B selectivity (7:1) in the trans-series was found for trans-2-fluoro-2-(para-trifluoromethylphenyl)cyclopropylamine (7d), while a 1:27 selectivity was found for cis-2-fluoro-2-(para-fluorophenyl)cyclopropylamine (10c). These results are discussed in connection with the pKa and log D values, the mechanism of action of Tranylcypromines, and the geometry of the active site of the enzymes.
Patrick J Duriez - One of the best experts on this subject based on the ideXlab platform.
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synthesis of carboxamide containing Tranylcypromine analogues as lsd1 kdm1a inhibitors targeting acute myeloid leukemia
ChemMedChem, 2021Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Adam Lee, Chak Hin Tam, Manar S Shafat, Stuart A Rushworth, Kristian M Bowles, Leon Douglas, Sarah G BaileyAbstract:Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of Tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these Tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile Tranylcypromine prodrugs with superior pharmacokinetics.
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fluorinated Tranylcypromine analogues as inhibitors of lysine specific demethylase 1 lsd1 kdm1a
Bioorganic & Medicinal Chemistry Letters, 2017Co-Authors: Maria Teresa Borrello, Hanae Benelkebir, Patrick J Duriez, Graham Packham, Leon Douglas, Benjamin Schinor, Katharina Bartels, Sara Pereira, Wafa T Aljamal, Günter HaufeAbstract: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.
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enantioselective synthesis of Tranylcypromine analogues as lysine demethylase lsd1 inhibitors
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Hanae Benelkebir, Christopher Hodgkinson, Patrick J Duriez, Annette Hayden, Rosemary A Bulleid, Simon J Crabb, Graham Packham, A GanesanAbstract:Asymmetric cyclopropanation of styrenes by tert-butyl diazoacetate followed by ester hydrolysis and Curtius rearrangement gave a series of Tranylcypromine analogues as single enantiomers. The o,- m- and p-bromo analogues were all more active than Tranylcypromine in a LSD1 enzyme assay. The m- and p-bromo analogues were micromolar growth inhibitors of the LNCaP prostate cancer cell line as were the corresponding biphenyl analogues prepared from the bromide by Suzuki crosscoupling.
Shigeyuki Yokoyama - One of the best experts on this subject based on the ideXlab platform.
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structurally designed trans 2 phenylcyclopropylamine derivatives potently inhibit histone demethylase lsd1 kdm1
Biochemistry, 2010Co-Authors: Shinya Mimasu, Naoki Umezawa, Shin Sato, Tsunehiko Higuchi, Takashi Umehara, Shigeyuki YokoyamaAbstract:Lysine-specific demethylase 1 (LSD1/KDM1) demethylates histone H3, in addition to tumor suppressor p53 and DNA methyltransferase 1 (Dnmt1), thus regulating eukaryotic gene expression by altering chromatin structure. Specific inhibitors of LSD1 are desired as anticancer agents, because LSD1 aberrations are associated with several cancers, and LSD1 inhibition restores the expression of abnormally silenced genes in cancerous cells. In this study, we designed and synthesized several candidate compounds to inhibit LSD1, based on the structures of LSD1 and monoamine oxidase B (MAO-B), in complex with an antidepressant Tranylcypromine (2-PCPA) derivative. Compound S2101 exhibited stronger LSD1 inhibition than Tranylcypromine and the known small LSD1 inhibitors in LSD1 demethylation assays, with a k(inact)/K(I) value of 4560 M(-1) s(-1). In comparison with Tranylcypromine, the compound displayed weaker inhibition to the monoamine oxidases. The inhibition modes of the two 2-PCPA derivatives, 2-PFPA and S1201, were identified by determination of the inhibitor-bound LSD1 structures, which revealed the enhanced stability of the inhibitor-FAD adducts by their interactions with the surrounding LSD1 residues. These molecules are potential pharmaceutical candidates for cancer or latent virus infection, as well as research tools for LSD1-related biological investigations.
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Crystal structure of histone demethylase LSD1 and Tranylcypromine at 2.25 A.
Biochemical and biophysical research communications, 2007Co-Authors: Shinya Mimasu, Takashi Umehara, Toru Sengoku, Seketsu Fukuzawa, Shigeyuki YokoyamaAbstract:Transcriptional activity and chromatin structure accessibility are correlated with the methylation of specific histone residues. Lysine-specific demethylase 1 (LSD1) is the first discovered histone demethylase, which demethylates Lys4 or Lys9 of histone H3, using FAD. Among the known monoamine oxidase inhibitors, Tranylcypromine (Parnate) showed the most potent inhibitory effect on LSD1. Recently, the crystal structure of LSD1 and Tranylcypromine was solved at 2.75 A, revealing a five-membered ring fused to the flavin of LSD1. In this study, we refined the crystal structure of the LSD1-Tranylcypromine complex to 2.25 A. The five-membered ring model did not fit completely with the electron density, giving R(work)/R(free) values of 0.226/0.254. On the other hand, the N(5) adduct gave the lowest R(work)/R(free) values of 0.218/0.248, among the tested models. These results imply that the LSD1-Tranylcypromine complex is not completely composed of the five-membered adduct, but partially contains an intermediate, such as the N(5) adduct.
