Search

Abstract: Variation at the 3’ position of fluorescein via Suzuki–Miyaura cross-coupling with aryl and heteroaryl moieties gave a family of anthofluoresceins whose spectroscopic properties were studied. The 1-methylindole derivative gave the highest quantum yield and was observed to behave as a molecular rotor, displaying marked variations in fluorescent intensities with viscosity and offering possible application in cellular sensing and fluorescent polarisation assays. [Copyright &y& Elsevier]

Abstract: The search for novel, generally applicable and highly efficient delivery tools is a major activity in the biotechnology arena. Using highly optimized microwave based solid-phase chemistry a series of fluorescein-labelled cationic peptoid conjugates were synthesized within 24h and cellular uptake into HeLa, L929 and K562 cells examined via flow cytometry. As expected, analysis revealed that longer oligomers achieved greater cellular penetration (7e (9 mer)> 7d (7 mer)> 7c (5 mer)> 7b (3 mer)> 7a (1 mer)) with the nonamer 7e proving to be a remarkable vehicle for all the cell lines, showing excellent penetrability into K562 and L929 cells and extraordinary cell delivery into HeLa cells. Confocal microscopy showed that the hybrid peptoid-nuclear localizing sequence (PKKKRKV from the simian virus 40 large T antigen) resulted in very high levels of nuclei delivery after 3h, opening up a range of applications such as nuclei staining of living cells with non-DNA-intercalating fluorescent probes. [Copyright &y& Elsevier]

Abstract: The synthesis and characterization of five different 9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxalines is described. Due to the notable electrophilic character of the C-6 position of the [1,2,4]triazolo[3,4-c]-5-azaquinoxaline tricyclic system, SNAr amination was achieved simply by reacting the corresponding 6-chloro derivative with ammonia-saturated acetonitrile (a non-nucleophilic polar solvent) in a sealed reaction vessel, using microwave-mediated or conventional heating. [Copyright &y& Elsevier]

Abstract: A new multicolor pH-dependent fluorophore was synthesized via Pd-mediated cross-coupling chemistry of the mono-triflate of fluorescein with p-hydroxyphenylboronic acid. The novel indicator, named anthofluorescein, is highly sensitive to pH changes between 7 and 10 and displays a green to red fluorescence shift, making it a valuable candidate for biological studies. [Copyright &y& Elsevier]

NXP900 is a selective and potent SRC family kinase (SFK) inhibitor, currently being dosed in a phase 1 clinical trial, that locks SRC in the “closed” conformation, thereby inhibiting both kinase-dependent catalytic activity and kinaseindependent functions. In contrast, several multi-targeted kinase inhibitors that inhibit SRC, including dasatinib and bosutinib, bind their target in the active “open” conformation, allowing SRC and other SFKs to act as a scaffold to promote tumorigenesis through non-catalytic functions. NXP900 exhibits a unique target selectivity profile with sub-nanomolar activity against SFK members over other kinases. This results in highly potent and specific SFK pathway inhibition. Here, we demonstrate that esophageal squamous cell carcinomas and head and neck squamous cell carcinomas are exquisitely sensitive to NXP900 treatment in cell culture and in vivo, and we identify a patient population that could benefit from treatment with NXP900. [ABSTRACT FROM AUTHOR]

The incorporation of abiotic transition metal catalysis into the chemical biology space has significantly expanded the tool kit of bioorthogonal chemistries accessible for cell culture and in vivo applications. A rich variety of homogeneous and heterogeneous catalysts has shown functional compatibility with physiological conditions and biostability in complex environs, enabling their exploitation as extracellular or intracellular factories of bioactive agents. Current trends in the field are focusing on investigating new metals and sophisticated catalytic devices and toward more applied activities, such as the integration of subcellular, cell- and site-targeting capabilities or the exploration of novel biomedical applications. We present herein an overview of the latest advances in the field, highlighting the increasing role of transition metals for the controlled release of therapeutics. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] Heteromeric T andem pore domain A cid S ensitive (TASK)-1/3 channels are critical to oxygen-sensing by carotid body type 1 cells, where hypoxia-induced inhibition of TASK-3 and/or TASK-1/3 potassium currents leads to voltage-gated calcium entry, exocytotic transmitter release and increases in carotid body afferent input responses that initiate corrective changes in breathing patterns. It was proposed that, in response to hypoxia, the AMP–activated protein kinase (AMPK) might directly phosphorylate and inhibit TASK channels, in particular TASK–3, but studies on rat type I cells questioned this view. However, sequence alignment identified a putative AMPK recognition motif in human (h) TASK-3, but not hTASK–1, with Ser55 representing a potential phosphorylation site. We therefore studied the effects of five different AMPK activators on recombinant hTASK–3 potassium channels expressed in human embryonic kidney (HEK)–293 cells. Two structurally unrelated AMPK activators, the thienopyridine A–769662 (100–500 µM) and the benzimidazole 991 (3–30 µM) inhibited hTASK–3 currents in a concentration–dependent manner, while the 4-azabenzimidazole MK–8722 (3–30 µM) partially inhibited hTASK–3 at concentrations above those required for maximal AMPK activation. By contrast, the 4-azabenzimidazole, BI-9774 (10–100 µM; a closely related analogue of MK8722) and the pro-drug AICA-riboside (1 mM; metabolised to ZMP, an AMP-mimetic) had no significant effect on hTASK–3 currents at concentrations sufficient to maximally activate AMPK. Importantly, A–769662 (300 µM) also inhibited hTASK–3 channel currents in HEK–293 cells that stably over-expressed an AMPK–β1 subunit mutant (S108A) that renders AMPK insensitive to activators that bind to the Allosteric Drug and Metabolite site, such as A–769662. We therefore identify A–769662 and 991 as novel hTASK–3 channel inhibitors and provide conclusive evidence that AMPK does not regulate hTASK–3 channel currents. [ABSTRACT FROM AUTHOR]

[Display omitted] The recent incorporation of Au chemistry in the bioorthogonal toolbox has opened up new opportunities to deliver biologically independent reactions in living environments. Herein we report that the O -propargylation of the hydroxamate group of the potent HDAC inhibitor panobinostat leads to a vast reduction of its anticancer properties (>500-fold). We also show that this novel prodrug is converted back into panobinostat in the presence of Au catalysts in vitro and in cell culture. [ABSTRACT FROM AUTHOR]

The search for novel targeted inhibitors active on glioblastoma multiforme is crucial to develop new treatments for this unmet clinical need. Herein, we report the results from a screening campaign against glioma cell lines using a proprietary library of 100 structurally-related pyrazolopyrimidines. Data analysis identified a family of compounds featuring a 2-amino-1,3-benzoxazole moiety (eCF309 to eCF334) for their antiproliferative properties in the nM range. These results were validated in patient-derived glioma cells. Available kinase inhibition profile pointed to blockade of the PI3K/mTOR pathway as being responsible for the potent activity of the hits. Combination studies demonstrated synergistic activity by inhibiting both PI3Ks and mTOR with selective inhibitors. Based on the structure activity relationships identified in this study, five new derivatives were synthesized and tested, which exhibited potent activity against glioma cells but not superior to the dual PI3K/mTOR inhibitor and lead compound of the screening eCF324. [ABSTRACT FROM AUTHOR]