scholarly journals A Mechanism Based Probe for Visualising Chromatinmodifying Enzyme Lysine-Specific Histone Demethylase 1

2021 ◽  
Author(s):  
◽  
Philip Edward Lane
Keyword(s):  
Chiral Separation ◽  
Nuclear Overhauser Effect ◽  
Histone Demethylase ◽  
X Ray Diffraction ◽  
Rate Determining Step ◽  
Histone 3 ◽  
Phase Ii Clinical Trials ◽  
Lysine Specific Demethylase ◽  
Experimental Activation Energy ◽  
Nuclear Overhauser

Lysine-specific demethylase 1 (LSD1), the first histone demethylase to be identified, catalyses specifically the demethylation of the mono and dimethyl groups of histone 3 (H3) lysine 4 (K4), and its dysregulation is thought to contribute to the development of cancer. GlaxoSmithKline (GSK) and Oryzon Genomics (ORY) have submitted numerous N-alkylated phenylcyclopropylamine (PCPA) molecules to phase II clinical trials against several different cancers. Eight probes have been designed and synthesised with alkyne and azide tags from PCPA. Their inhibitory values have been investigated towards Monoamine Oxidase (MAO) and LSD1, showing over two times the increase in selectivity towards LSD1. Probe 1 has been subject to cell treatment and its ability to inhibit LSD1 confirmed using NTERA2 cells. Furthermore, these synthesised probes are conjugated to a peptide to successfully guide the probes into the cell. The addition of the peptide causes an increase in the inhibitory values towards LSD1 by on average seven fold. Chiral separation was undertaken on probe 7 to explore the potential inhibition differences of the two enantiomers. Single Crystal X-Ray Diffraction analysis and 1H NMR Nuclear Overhauser effect (nOe) confirmed the chiral separation, with inhibitory data showing (1 R – 2 S)-probe 7 is a more potent inhibitor of LSD1 than its enantiomer. In addition to this, N-alkylation of probe 4 achieved a successfully increase of potency towards LSD1 over PCPA. The mechanistic inhibition pathway for PCPA inhibiting LSD1 is currently unknown. Here, DFT is used on cluster models of Flavin Adenine Dinucleotide (FAD) and the active site of LSD1 (135 atoms and 218 atoms) to investigate the mechanistic inhibition pathway for PCPA inhibiting the FAD cofactor. The calculated energy of the potential rate determining step was 45.3 kcal mol-1 which is 23.5 kcal mol-1 greater than the experimental activation energy for the inhibition of LSD1.

Aggregation of Donor Base Stabilized 2-Thienyllithium in a Single Crystal and in Solution: Distances from X-ray Diffraction and the Nuclear Overhauser Effect

2011 ◽  
Vol 134 (2) ◽  
pp. 1344-1351 ◽  
Author(s):  
Markus Granitzka ◽  
Ann-Christin Pöppler ◽  
Eike K. Schwarze ◽  
Daniel Stern ◽  
Thomas Schulz ◽  
...  
Keyword(s):  
Single Crystal ◽  
Nuclear Overhauser Effect ◽  
X Ray Diffraction ◽  
X Ray ◽  
Overhauser Effect ◽  
Nuclear Overhauser

1H NMR studies of [N-MeAib1, Tyr(Me)4]ANGII and [N-MeAib1, Tyr(Me)4, Ile8]ANGII in dimethylsulfoxide by nuclear Overhauser effect (NOE) enhancement spectroscopy: cis-trans Isomerism of the His-Pro bond

1990 ◽  
Vol 55 (4) ◽  
pp. 1106-1111 ◽  
Author(s):  
John Matsoukas ◽  
Paul Cordopatis ◽  
Raghav Yamdagni ◽  
Graham J. Moore
Keyword(s):  
1H Nmr ◽  
Nuclear Overhauser Effect ◽  
Nmr Studies ◽  
Restricted Rotation ◽  
Overhauser Effect ◽  
Major Isomer ◽  
Conformational Properties ◽  
Nuclear Overhauser

The conformational properties of the Sarmesin analogues [N-MeAib1, Tyr(Me)4]ANGII and [N-MeAib1, Tyr(Me)4, Ile8]ANGII in hexadeutero-dimethysulfoxide were investigated by Nuclear Overhauser Effect (NOE) Enhancement Studies. Cis-trans isomers (ratio 1 : 6) due to restricted rotation of the His-Pro bond were observed. Interresidue interactions between the His Cα proton and the two Pro Cδ protons revealed that the major isomer was the trans.

scholarly journals Cylindromicin from Arctic-Derived Fungus Tolypocladium sp. SCSIO 40433

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1080
Author(s):  
Imran Khan ◽  
Jing Peng ◽  
Zhuangjie Fang ◽  
Wei Liu ◽  
Wenjun Zhang ◽  
...  
Keyword(s):  
Secondary Metabolites ◽  
Nuclear Overhauser Effect ◽  
Inhibition Activity ◽  
Tyrosinase Inhibition ◽  
Bioactive Natural Products ◽  
Chemical Structures ◽  
Overhauser Effect ◽  
Spectroscopic Analyses ◽  
Potential Resource ◽  
Nuclear Overhauser

The fungus strain SCSIO 40433 was isolated from an Arctic-derived glacier sediment sample and characterized as Tolypocladium cylindrosporum. A new compound, cylindromicin (1), and seven known secondary metabolites (2–8) were isolated from this strain. The chemical structures of these compounds were elucidated by comprehensive spectroscopic analyses. Cylindromicin (1) featured a 3,4-dihydro-2H-pyran skeleton. The absolute configuration of compound 1 was assigned via interpretation of key Nuclear Overhauser Effect Spectroscopy (NOESY) correlations and Electronic Circular Dichroism (ECD) calculation. Cylindromicin (1) exhibited significant tyrosinase inhibition activity. This study highlights Polar fungi as a potential resource for new bioactive natural products.

The isolation, structure, and stereochemistry of traversiadiene. The precursor hydrocarbon of traversianal biosynthesis

1989 ◽  
Vol 67 (8) ◽  
pp. 1302-1304 ◽  
Author(s):  
Albert Stoessl ◽  
G. L. Rock ◽  
J. B. Stothers
Keyword(s):  
Magnetic Resonance ◽  
Biosynthetic Pathway ◽  
Nuclear Overhauser Effect ◽  
Difference Spectra ◽  
Heteronuclear Correlation ◽  
Magnetic Resonance Studies ◽  
Overhauser Effect ◽  
Effect Difference ◽  
Nuclear Overhauser ◽  
Magnetic Resonance Spectra

A tricyclic diene, traversiadiene, isolated from cultures of Cercosporatraversiana has been shown to have the structure and stereochemistry of the previously postulated hydrocarbon intermediate on the biosynthetic pathway to traversianal (1). Detailed:1H and 13C magnetic resonance studies, including homo- and heteronuclear correlation spectra, led to the gross structure, and the stereochemistry was established through a series of nuclear Overhauser effect difference spectra. Keywords: diterpene, traversiadiene, 1H and 13C magnetic resonance spectra.

scholarly journals Contribution of blood to nuclear Overhauser effect at −1.6 ppm

2021 ◽  
Author(s):  
Jing Cui ◽  
Yu Zhao ◽  
Feng Wang ◽  
Daniel F. Gochberg ◽  
Zhongliang Zu
Keyword(s):  
Nuclear Overhauser Effect ◽  
Overhauser Effect ◽  
Nuclear Overhauser
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