Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic "thermal tag" with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes: FTO (7; IC =2.6 μm) and ALKBH3 (8; IC =3.7 μm). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.
Curcumin has been transformed to racemic curcuminoids via an azomethine ylide cycloaddition reaction using isatin/acenaphthoquinone and proline as the reagents. The products were characterized by extensive 1D/2D NMR analysis and single-crystal X-ray crystallographic studies. The enantiomers of one racemic product were separated by HPLC on a Chiralcel OD-H column and were indeed confirmed by the CD spectra of the separated enantiomers.
The AlkB family of nucleic acid demethylases
is currently of intense
chemical, biological, and medical interest because of its critical
roles in several key cellular processes, including epigenetic gene
regulation, RNA metabolism, and DNA repair. Emerging evidence suggests
that dysregulation of AlkB demethylases may underlie the pathogenesis
of several human diseases, particularly obesity, diabetes, and cancer.
Hence there is strong interest in developing selective inhibitors
for these enzymes to facilitate their mechanistic and functional studies
and to validate their therapeutic potential. Herein we review the
remarkable advances made over the past 20 years in AlkB demethylase
inhibition research. We discuss the rational design of reported inhibitors,
their mode-of-binding, selectivity, cellular activity, and therapeutic
opportunities. We further discuss unexplored structural elements of
the AlkB subfamilies and propose potential strategies to enable subfamily
selectivity. It is hoped that this perspective will inspire novel
inhibitor design and advance drug discovery research in this field.
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