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.
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.
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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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.
