Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1

Zhou, Chao; Wu, Feng; Lu, Lianghao; Wei, Liping; Pai, Eric; Yao, Yuan; Song, Yuanlin

doi:10.1371/journal.pone.0170301

Cited by 12 publications

(9 citation statements)

References 26 publications

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“…Alkylation of 55 with a piperazine moiety followed by Boc deprotection provided derivative 56 (Scheme ). Compound 56 was one of the most potent LSD1 inhibitors of the series (IC 50 =0.064 μ m ) also displaying high selectivity (>280‐fold) towards related enzymes monoamine oxidase (MAO) A and B …”

Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

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The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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The Curtius rearrangement is the thermal decomposition of an acyl azide derived from carboxylic acid to produce an isocyanate as the initial product. The isocyanate can undergo further reactions to provide amines and their derivatives. Due to its tolerance for a large variety of functional groups and complete retention of stereochemistry during rearrangement, the Curtius rearrangement has been used in the synthesis of a wide variety of medicinal agents with amines and amine-derived functional groups such as ureas and urethanes. The current review outlines various applications of the Curtius rearrangement in drug discovery and medicinal chemistry. In particular, the review highlights some widely used rearrangement methods, syntheses of some key agents for popular drug targets and FDA-approved drugs. In addition, the review highlights applications of the Curtius rearrangement in continuous-flow protocols for the scale-up of active pharmaceutical ingredients.

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Section: Application Of the Curtius Rearrangement In Medicinal Chemistrymentioning

confidence: 99%

“…Compound 56 was one of the most potent LSD1 inhibitors of the series (IC 50 = 0.064 mm)a lso displaying high selectivity (> 280-fold) towards relatede nzymes monoamine oxidase (MAO)Aand B. [47]…”

Section: Scheme11 Synthesis Of Podophyllotoxinanalogue 45mentioning

confidence: 99%

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

2018

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“…87 Furthermore, several monocyclopropylhydrazines were reported to be lysine-specific demethylase 1 (LSD1) inhibitors. 88,89 Therefore, in order to achieve the purpose of systematically comparing the N−N BDE change patterns of cycloalkylhydrazine family, the N−N BDEs from cyclopropylhydrazines to cyclohexylhydrazines were all calculated by the M05-2X method. The corresponding results are listed in Table 3, and the BDE value distribution from cyclopropylhydrazines to cyclohexylhydrazines is depicted in Figure 3.…”

Section: Prediction Of N−n Bdes In Cycloalkylhydrazinesmentioning

confidence: 99%

Computational Study on N–N Homolytic Bond Dissociation Enthalpies of Hydrazine Derivatives

Zheng

Wang

et al. 2018

J. Phys. Chem. A

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The hydrazine derivatives have been regarded as the important building blocks in organic chemistry for the synthesis of organic N-containing compounds. It is important to understand the structure-activity relationship of the thermodynamics of N-N bonds, in particular, their strength as measured by using the homolytic bond dissociation enthalpies (BDEs). We calculated the N-N BDEs of 13 organonitrogen compounds by eight composite high-level ab initio methods including G3, G3B3, G4, G4MP2, CBS-QB3, ROCBS-QB3, CBS-Q, and CBS-APNO. Then 25 density functional theory (DFT) methods were selected for calculating the N-N BDEs of 58 organonitrogen compounds. The M05-2X method can provide the most accurate results with the smallest root-mean-square error (RMSE) of 8.9 kJ/mol. Subsequently, the N-N BDE predictions of different hydrazine derivatives including cycloalkylhydrazines, N-heterocyclic hydrazines, arylhydrazines, and hydrazides as well as the substituent effects were investigated in detail by using the M05-2X method. In addition, the analysis including the natural bond orbital (NBO) as well as the energies of frontier orbitals were performed in order to further understand the essence of the N-N BDE change patterns.

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“…Lysine specific demethylase 1 (LSD1) is a histone-modifying enzyme that is a member of the monoamine oxidase family. 5 LSD1 has been shown to suppress gene expression through demethylation of mono and dimethyl groups present on lysine 4 of histone H3. 6 LSD1 is a critical regulator of hematopoiesis, in part, through interaction with the transcription factors GFI-1 and GFI-1b.…”

Section: Introductionmentioning

confidence: 99%

Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes

et al. 2018

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Lysine specific demethylase 1 (LSD1) is a histone modifying enzyme that suppresses gene expression through demethylation of lysine 4 on histone H3. The anti-tumor activity of GSK2879552 and GSK-LSD1, potent, selective irreversible inactivators of LSD1, has previously been described. Inhibition of LSD1 results in a cytostatic growth inhibitory effect in a range of acute myeloid leukemia cell lines. To enhance the therapeutic potential of LSD1 inhibition in this disease setting, a combination of LSD1 inhibition and all- trans retinoic acid was explored. All- trans retinoic acid is currently approved for use in acute promyelocytic leukemia in which it promotes differentiation of abnormal blast cells into normal white blood cells. Combined treatment with all- trans retinoic acid and GSK2879552 results in synergistic effects on cell proliferation, markers of differentiation, and, most importantly, cytotoxicity. Ultimately the combination potential for LSD1 inhibition and ATRA will require validation in acute myeloid leukemia patients, and clinical studies to assess this are currently underway.

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Structure activity relationship and modeling studies of inhibitors of lysine specific demethylase 1

Cited by 12 publications

References 26 publications

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

The Curtius Rearrangement: Applications in Modern Drug Discovery and Medicinal Chemistry

Computational Study on N–N Homolytic Bond Dissociation Enthalpies of Hydrazine Derivatives

Lysine specific demethylase 1 inactivation enhances differentiation and promotes cytotoxic response when combined with all-trans retinoic acid in acute myeloid leukemia across subtypes

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