Isolation, Structure Determination, and Synthesis of Cyclic Tetraglutamic Acids from Box Jellyfish Species Alatina alata and Chironex yamaguchii

Cubozoan nematocyst venoms contain known cytolytic and hemolytic proteins, but small molecule components have not been previously reported from cubozoan venom. We screened nematocyst extracts of Alatina alata and Chironex yamaguchii by LC-MS for the presence of small molecule metabolites. Three isomeric compounds, cnidarins 4A (1), 4B (2), and 4C (3), were isolated from venom extracts and characterized by NMR and MS, which revealed their planar structure as cyclic γ-linked tetraglutamic acids. The full configurational assignments were established by syntheses of all six possible stereoisomers, comparison of spectral data and optical rotations, and stereochemical analysis of derivatized degradation products. Compounds 1–3 were subsequently detected by LC-MS in tissues of eight other cnidarian species. The most abundant of these compounds, cnidarin 4A (1), showed no mammalian cell toxicity or hemolytic activity, which may suggest a role for these cyclic tetraglutamates in nematocyst discharge.

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Design of Dermaseptin S3 Analogues having Bacterial Cell Selectivity without Mammalian Cell Toxicity

Protein and Peptide Letters ◽

10.2174/0929866013409328 ◽

2001 ◽

Vol 8 (4) ◽

pp. 281-288 ◽

Cited By ~ 1

Author(s):

Song Shin ◽

Sung Yang ◽

Soo Eom ◽

Woo Song ◽

Yangmee Kim ◽

...

Keyword(s):

Mammalian Cell ◽

Bacterial Cell ◽

Cell Toxicity ◽

Cell Selectivity ◽

Mammalian Cell Toxicity

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Discovery of a first-in-class inhibitor of the PRMT5-substrate adaptor interaction

10.1101/2021.02.03.429644 ◽

2021 ◽

Author(s):

David C McKinney ◽

Brian J McMillan ◽

Matthew Ranaghan ◽

Jamie A Moroco ◽

Merissa Brousseau ◽

...

Keyword(s):

Cancer Cells ◽

Small Molecule ◽

Structure Determination ◽

Mode Of Action ◽

Covalent Bond ◽

Adaptor Proteins ◽

Binding Motif ◽

Lead Compound ◽

Synthetic Lethal ◽

Compound Series

AbstractPRMT5 and its substrate adaptor proteins (SAPs), pICln and Riok1, are synthetic lethal dependencies in MTAP-deleted cancer cells. SAPs share a conserved PRMT5 binding motif (PBM) which mediates binding to a surface of PRMT5 distal to the catalytic site. This interaction is required for methylation of several PRMT5 substrates, including histone and spliceosome complexes. We screened for small molecule inhibitors of the PRMT5-PBM interaction and validated a compound series which binds to the PRMT5-PBM interface and directly inhibits binding of SAPs. Mode of action and structure determination studies revealed that these compounds form a covalent bond between a halogenated pyridazinone group and cysteine 278 of PRMT5. Optimization of the starting hit produced a lead compound, BRD0639, which engages the target in cells, disrupts the PRMT5-RIOK1 complex, and reduces substrate methylation. BRD0639 is a first-in-class PBM-competitive small molecule that can support studies of PBM-dependent PRMT5 activities and the development of novel PRMT5 inhibitors that selectively target these functions.

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Faculty Opinions recommendation of The cryoem method microed as a powerful tool for small molecule structure determination.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.734368160.793552626 ◽

2018 ◽

Author(s):

William Gerwick

Keyword(s):

Small Molecule ◽

Structure Determination ◽

Molecule Structure

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Impact of structural changes in heteroleptic bismuth phosphinates on their antibacterial activity in Bi-nanocellulose composites

Dalton Transactions ◽

10.1039/d0dt01226b ◽

2020 ◽

Vol 49 (22) ◽

pp. 7341-7354 ◽

Cited By ~ 1

Author(s):

Megan E. Herdman ◽

Melissa V. Werrett ◽

Rebekah N. Duffin ◽

Liam J. Stephens ◽

Rajini Brammananth ◽

...

Keyword(s):

Antibacterial Activity ◽

Mammalian Cell ◽

Structural Changes ◽

Cell Toxicity ◽

Antibacterial Materials ◽

Mammalian Cell Toxicity

A series of diphenyl mono-phosphinato bismuth complexes were synthesised to study the effect of ligand choice on antibacterial activity, mammalian cell toxicity, and their behaviour in Bi-nanocellulose composites for use as antibacterial materials.

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Studies on dodecyl betainate in combination with its degradation products or with phosphatidyl choline–phase behavior and hemolytic activity

Journal of Colloid and Interface Science ◽

10.1016/j.jcis.2004.06.031 ◽

2004 ◽

Vol 278 (2) ◽

pp. 478-487 ◽

Cited By ~ 21

Author(s):

D. Lundberg ◽

H. Ljusberg-Wahren ◽

A. Norlin ◽

K. Holmberg

Keyword(s):

Phase Behavior ◽

Hemolytic Activity ◽

Phosphatidyl Choline ◽

Degradation Products

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Characterization of Impurities and Degradation Products in Small Molecule Pharmaceuticals and Biologics

Mass Spectrometry for Drug Discovery and Drug Development ◽

10.1002/9781118516157.ch7 ◽

2013 ◽

pp. 191-220

Author(s):

Hui Wei ◽

Guodong Chen ◽

Adrienne A. Tymiak

Keyword(s):

Small Molecule ◽

Degradation Products

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Die oxidative Addition von NickeI(0)-KompIexen an Kohlenstoff-Kohlenstoff-Bindungen im Cyclobutadien. Zur Frage der Überführbarkeit von Cyclobutadien-Nickel(O)-Komplexen in Nickelaringe / Oxidative Addition of Nickel(O) Complexes to Carbon-Carbon Bonds in Cyclobutadiene. The Question of the Interconvertibility of Cyclobutadiene-nickel(O) Complexes and the Nickelaring Systems

Zeitschrift für Naturforschung B ◽

10.1515/znb-1985-0511 ◽

1985 ◽

Vol 40 (5) ◽

pp. 624-635 ◽

Cited By ~ 20

Author(s):

John J. Eisch ◽

Andrzej M. Piotrowski ◽

Allen A. Aradi ◽

Carl Krüger ◽

Maria J. Romão

Keyword(s):

Spectral Data ◽

Structure Determination ◽

Oxidative Addition ◽

Subsequent Treatment ◽

X Ray ◽

X Ray Crystallography ◽

Carbon Carbon Bonds ◽

Elemental Analyses ◽

Carbon Bonds

Abstract Bis(triethylphosphine)(η4-tetraphenylcyclobutadiene)nickel (4) was synthesized by the reduction of (η4-tetraphenylcyclobutadiene)nickel(II)bromide (3) with t-butyllithium in the presence of Et3P, and its structure was determined by X-ray crystallography. Furthermore, its reactivity towards CO, CH3CO2H, PhC≡CPh, LiAlH4 and O2 were investigated. 1,1-Bis(triethylphos-phine)-2,3,4,5-tetraphenylnickelole (14) was synthesized from (E,E)-1,4-dilithio-1,2,3,4-tetraphenyl-1,3-butadiene (15) and bis(triethylphosphine)nickel(II)bromide. Since the resulting crystals of the nickelole were not suitable for X-ray structure determination, the compound was characterized by elemental analyses, spectral data and carbonylation to yield tetraphenylcyclo-pentadienone (6).Analogous reductions of (η4 -tetraphenylcyclobutadiene)nickel(II)bromide (3) in the presence of Ph3P or Ph2PCH2CH2PPh2 , followed by carbonylation, led to 6 in 40% yield, demonstrating that about half of the cyclobutadiene rings in 3 undergo cleavage upon reduction to give the nickelole.Reactions of the dilithium reagent 15 with NiBr2 complexed with Me2PCH2CH2PMe2 ,Ph3P or Et2PCH2CH2PEt2 , led to the formation of thermolabile nickeloles, as demonstrated by carbonylàtion which yielded 6. Warming of the nickeloles and subsequent treatment with CH3CO2H led to the formation of 1,2,3,4,5,6,7,8-octaphenyl-1,3,5,7-octatetraene (8) and, in one case, octaphenyl-cyclooctatetraene (5).The relevance of these findings to the mechanism of the Reppe nickel-catalyzed oligomerization of alkynes is discussed.

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Metallation of Isatin (2,3-Indolinedione). X-Ray Structure and Solution Behavior of Bis(Isatinato)Mercury(II)

Metal-Based Drugs ◽

10.1155/mbd.1995.81 ◽

1995 ◽

Vol 2 (2) ◽

pp. 81-90 ◽

Cited By ~ 4

Author(s):

Angel Garcia-Raso ◽

Juan J. Fiol ◽

Elies Molins ◽

Antonia M. Calafat ◽

Patricia A. Marzilli ◽

...

Keyword(s):

Crystal Structure ◽

Solid State ◽

Metal Complex ◽

Bond Length ◽

Spectral Data ◽

Structure Determination ◽

Monoclinic System ◽

Heterocyclic Nitrogen ◽

X Ray

The first X-ray structure of an isatin (2,3-indolinedione, isaH) metal complex, bis(isatinato)memury(II) (C16H8N2O4Hg) (1), was determined. (1) was obtained from the reaction of isaH with mercury(II) acetate in methanol. Analogously, treatment of sodium saccharinate and mercury(II) acetate in methanol yielded Hg(saccharinato)2•0.5CH3OH (3). (1) crystallizes in the monoclinic system, space group P21/a with a = 7.299(1) Å, b = 8.192(1) Å, c = 11.601(1) Å , β = 105.82(1)°, V = 667.4 Å3, Z = 2, Dcalc = 2.452 g cm−3, MoKα radiation(λ = 0.71073 Å), μ = 115.5 cm-1, F(000) = 460, 21(1) °C. The structure was refined on the basis of 2023 observed reflections to R= 0.044. The two deprotonated, non coplanar isa ligands are trans to each other in a head to tail orientation and bound to the Hg through the nitrogen in a linear N-Hg-N arrangement. The Hg atom is at the center of symmetry of the complex and displaced by 0.62 Å from the two planes of the isa ligands (τ Hg-N1-C2-O2= -16°). The Hg-N bond length is 2.015 Å. Noπ-aryl-memury(ll)-π-aryl stacking interaction was observed either in the solid state or in the solution state. The IR, electronic, and H1 and C13NMR spectral data of (1) and (3) suggest binding of the memury to the heterocyclic nitrogen, in agreement with the crystal structure determination of (1).

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