Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.

Antagonism of the human adenosine A receptor (hAR) has potential therapeutic application. Alchemical relative binding free energy calculations of and suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hAR affinity. Of the 25 new analogues synthesized, and showed improved hAR affinity compared to (and ).

One-step rapid tracking and isolation of senescent cells in cellular systems, tissues, or animal models via GLF16.

Identification and isolation of senescent cells is challenging, rendering their detailed analysis an unmet need. We describe a precise one-step protocol to fluorescently label senescent cells, for flow cytometry and fluorescence microscopy, implementing a fluorophore-conjugated Sudan Black-B analog, GLF16. Also, a micelle-based approach allows identification of senescent cells in vivo and in vitro, enabling live-cell sorting for downstream analyses and live in vivo tracking.

A fluorophore-conjugated reagent enabling rapid detection, isolation and live tracking of senescent cells.

Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking.

Discovery of a High Affinity Adenosine A/A Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-]pyridazine Scaffold.

Here we describe the design and synthesis of pyrazolo[3,4-]pyridazines as adenosine receptor (AR) ligands. We demonstrate that the introduction of a 3-phenyl group, together with a 7-benzylamino and 1-methyl group at the pyrazolopyridazine scaffold, generated the antagonist compound , which displayed 21 nM affinity and a residence time of ∼60 min, for the human AR, 55 nM affinity and a residence time of ∼73 min, for the human AR and 1.7 μΜ affinity for the human AR while not being toxic.

Novel Substituted Purine Isosteres: Synthesis, Structure-Activity Relationships and Cytotoxic Activity Evaluation.

A number of pyrrolo[2,3-]pyridines, pyrrolo[3,2-]pyrimidines and pyrazolo[4,3-]pyrimidines were designed and synthesized as antiproliferative agents. The target compounds possessed selected substituents in analogous positions on the central scaffold that allowed the extraction of interesting SARs. The cytotoxic activity of the new derivatives was evaluated against prostatic (PC-3) and colon (HCT116) cell lines, and the most potent analogues showed IC values in the nM to low µM range, while they were found to be non-toxic against normal human fibroblasts (WI-38).