2 research outputs found
Ru(II)-Catalyzed Site-Selective Hydroxylation of Flavone and Chromone Derivatives: The Importance of the 5‑Hydroxyl Motif for the Inhibition of Aurora Kinases
An
efficient protocol for RuÂ(II)-catalyzed direct C–H oxygenation
of a broad range of flavone and chromone substrates was developed.
This convenient and powerful synthetic tool allows for the rapid installation
of the hydroxyl group into the flavone, chromone, and other related
scaffolds and opens the way for analog synthesis of highly potent
Aurora kinase inhibitors. The molecular docking simulations indicate
that the formation of bidentate H-bonding patterns in the hinge regions
between the 5-hydroxyflavonoids and Ala213 was the significant binding
force, which is consistent with experimental and computational findings
Identification of β‑Lapachone Analogs as Novel MALT1 Inhibitors To Treat an Aggressive Subtype of Diffuse Large B‑Cell Lymphoma
The
treatment of activated B cell-like DLBCL (ABC-DLBCL) is one of the
urgent unmet medical needs because it is the most resistant DLBCL
subtype to current therapies eagerly awaiting effective therapeutic
strategies. Recently, the paracaspase MALT1 has emerged as a promising
therapeutic target for the treatment of ABC-DLBCL. Herein, we report
a new class of MALT1 inhibitors developed by high-throughput screening
and structure-based drug design. The original hit, 4-amino-1,2-naphthoquinone
series inhibited MALT1 activity but suffered from poor cellular activity.
The extensive pharmacophore search led to the discovery of structurally
similar β-lapachone that is a direct inhibitor of MALT1 and
possesses favorable physicochemical properties. Molecular simulation
studies suggested the possibility of the formation of a covalent bond
between MALT1 and β-lapachone, which was corroborated by experimental
wash-out studies. Inspired by this, we explored the structure–activity
relationships by incorporating electron-withdrawing substituents at
C8 position of β-lapachone. These MALT1 inhibitors exhibited
potent antiproliferative activity to OCI-LY3 cell line and inhibited
the cleavage of CYLD mediated MALT1