2 research outputs found
Synthesis of Cyclic Peptidomimetics via a Pd-Catalyzed Macroamination Reaction
A new method to access cyclic peptidomimetics
via a Pd-catalyzed
macroamination reaction is presented. Natural amino acid amines are
revealed as proficient coupling partners in these transformations.
With a commercially available CPhos G3 catalyst system and substrates
bearing diverse amino acid and aryl halide backbones, the unique head
to side-chain (or side-chain mimic) macrocycles are afforded with
ring sizes from 11 to 23 members in yields up to 84%
Discovery of Selective RNA-Binding Small Molecules by Affinity-Selection Mass Spectrometry
Recent
advances in understanding the relevance of noncoding RNA
(ncRNA) to disease have increased interest in drugging ncRNA with
small molecules. The recent discovery of ribocil, a structurally distinct
synthetic mimic of the natural ligand of the flavin mononucleotide
(FMN) riboswitch, has revealed the potential chemical diversity of
small molecules that target ncRNA. Affinity-selection mass spectrometry
(AS-MS) is theoretically applicable to high-throughput screening (HTS)
of small molecules binding to ncRNA. Here, we report the first application
of the Automated Ligand Detection System (ALIS), an indirect AS-MS
technique, for the selective detection of small molecule–ncRNA
interactions, high-throughput screening against large unbiased small-molecule
libraries, and identification and characterization of novel compounds
(structurally distinct from both FMN and ribocil) that target the
FMN riboswitch. Crystal structures reveal that different compounds
induce various conformations of the FMN riboswitch, leading to different
activity profiles. Our findings validate the ALIS platform for HTS
screening for RNA-binding small molecules and further demonstrate
that ncRNA can be broadly targeted by chemically diverse yet selective
small molecules as therapeutics