201282-04-4Relevant articles and documents
Synthesis and characterisation of folic acid based lanthanide ion probes
Du, Zhangli,Borlace, Glenn N.,Brooks, Robert D.,Butler, Ross N.,Brooks, Doug A.,Plush, Sally E.
, p. 11 - 19 (2014)
As a first step in the process of developing folate based visual probes and contrast agents, we have designed and synthesised a series of first generation lanthanide(III) molecular probes. The molecular probe structure included a lanthanide(III) (Eu(III), Tb(III), Gd(III)) chelate which was linked (2 or 3) to either a folic acid or pteroic acid targeting motif. We have defined the emission properties of the molecular probes at different pHs, the emission lifetimes, and the number of metal bound water molecules. The cellular uptake of the molecular probes was investigated in HeLa cells and the amount of Eu(III) internalisation quantified by inductively coupled plasma mass spectrometry. Our results highlighted several key features of probe design: a shorter linker was more optimal for both Eu(III) ion emission intensity and cellular uptake; the folic acid targeting motif exhibited higher cellular uptake when compared to pteroic acid; the emission intensity of the folic acid based probes was pH insensitive, whereas the pteroic acid based probes were pH sensitive. These first generation folate molecular probes displayed promising chemical and physical properties, suggesting that optical and MRI probes can potentially be developed, to enable the imaging of folate receptors in cancer cells and tissues.
Design and Synthesis of Inhibitors of N8-Acetylspermidine Deacetylase
Dredar, Sasi A.,Blankenship, James W.,Marchant, Pamela E.,Manneh, Victor,Fries, David S.
, p. 984 - 989 (1989)
Analogues of N8-acetylspermidine (1) were synthesized as potential inhibitors of the cytoplasmic enzyme N8-acetylspermidine deacetylase.The compounds were assayed for their ability to inhibit the deacetylation of 1 in a cytosolic fraction from rat liver.The apparent Ki values were determined by Dixon plots.The apparent Km of 1 for this enzyme is 11.0 μM.It was found that compounds which lacked the N1 or the N4 of spermidine were less effective at competing for the enzyme than the substrate.All compounds with acyl substituents larger than acetyl were less potent inhibitors than the corresponding acetylated derivatives.Thus, the enzyme's selectivity as a deacetylase seems to be attributable to steric hindrance which occurs with larger acyl groups.The N8 of the substrate is not essential for its binding to the enzyme.Replacement of N8 with a CH2 group gives the ketone 14, which has an apparent Ki of 0.18 μM, 60-fold lower than the apparent Km of 1.The inhibitory potency of 14 is retained in compounds substituted at the N1 position.The N1,N1-dimethyl and the N1,N1-diethyl analogues (15 and 16) of 14 have apparent Ki values of 0.096 and 0.10 μM, respectively.These agents are the most potent inhibitors of N8-acetylspermidine deacetylase reported, and they are promising tools for use in determining the physiological function of N8-acetylspermidine deacetylase.
Synthesis and biological evaluation of new dipicolylamine zinc chelators as metallo-β-lactamase inhibitors
Prandina, Anthony,Radix, Sylvie,Le Borgne, Marc,Jordheim, Lars Petter,Bousfiha, Zineb,Fr?hlich, Christopher,Leiros, Hanna-Kirsti S.,Samuelsen, ?rjan,Fr?vold, Espen,Rongved, P?l,?strand, Ove Alexander H?gmoen
, p. 1525 - 1540 (2019/02/13)
Antibiotics are key drugs in modern healthcare, especially in hospitals, where multiresistant bacteria resides and is a potential threat to human health. In the present work, a new series of adjuvants working synergistically with the carbapenem meropenem, in which a selective zinc-chelating agent was covalently linked to the small bacterial peptide D-Ala-D-Ala, was synthesized and tested against VIM-2 and NDM-1 metallo-β-lactamases (MBLs). The nature of the linker was modified in a structure-activity relationship study. Compound 1i, having an ethyl piperidine linker, lowered the MIC of meropenem from 32 to 64 mg/L to 2 and 1–2 mg/L against VIM-2- and NDM-1-producing clinical isolates, respectively. The IC50 value of 1i against VIM-2 was 9.8 and 2.2 μM after 5 and 20 min, respectively. Compound 1i also showed intrinsic toxicity against three eukaryotic human tumoral cell lines between 50 and 120 μM.
REGULATING CHIMERIC ANTIGEN RECEPTORS
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Page/Page column 387, (2018/09/08)
This invention is in the area of compositions and methods for regulating chimeric antigen receptor immune effector cell, for example T-cell (CAR-T), therapy to modulate associated adverse inflammatory responses, for example, cytokine release syndrome and tumor lysis syndrome, using targeted protein degradation.
TUNABLE ENDOGENOUS PROTEIN DEGRADATION WITH HETEROBIFUNCTIONAL COMPOUNDS
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Page/Page column 368, (2018/09/08)
The present invention provides a means to modulate gene expression in vivo in a manner that avoids problems associated with CRISPR endogenous protein knock-out or knock-in strategies and strategies that provide for correction, or alteration, of single nucleotides. The invention includes inserting into the genome a nucleotide encoding a heterobifunctional compound targeting protein (dTAG) in-frame with the nucleotide sequence of a gene encoding an endogenously expressed protein of interest which, upon expression, produces an endogenous protein-dTAG hybrid protein. This allows for targeted protein degradation of the dTAG and the fused endogenous protein using a heterobifunctional compound.
METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
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Page/Page column 308; 309, (2017/02/28)
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to nucleic acids, polypeptides, cells, and methods for highly regulated, targeted degradation of proteins through the use of the bifunctional compounds.
METHODS TO INDUCE TARGETED PROTEIN DEGRADATION THROUGH BIFUNCTIONAL MOLECULES
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Paragraph 0711-0713, (2016/07/27)
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
Labeled transition metal complexes
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Page/Page column 33, (2016/01/25)
The invention relates to a labeled transition metal complex comprising a transition metal atom, a reactive moiety for allowing a chemical or biological entity to become attached to the transition metal atom, an inert tridentate moiety as a stabilizing bridge, and a marker. The invention also relates to a labeled chemical or biological entity comprising a chemical or biological entity which is attached to said labeled transition metal complex, to the use of said complex for creating a defined shift in the molecular mass of said entity in order to facilitate mass spectrometric analysis of said entity, to methods for rendering chemical or biological entities distinguishable by mass spectrometry as well as to methods for mass spectrometric analysis of the chemical or biological entities. In addition, the present invention also relates to a set of at least two of said transition metal complexes of different molecular mass, to transition metal complexes comprising different stable isotopes, to chemical or biological entities obtained by a method of the invention and to a kit of parts supporting the use and/or methods of the invention.
COMPOUNDS AND METHODS FOR PURIFICATION OF SERINE PROTEASES
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Paragraph 0146, (2014/07/21)
Disclosed herein are compounds, compositions, methods and kits for purifying a protease and serine proteases purified with the compounds, compositions and methods.
