Automated solid-phase synthesis of linear nitrogen-linked compounds.
A synthetic library motif has been developed to create linear, nitrogen-linked compounds as screening libraries to target structured RNA for drug discovery. Scaffolds were created in situ from suitably protected bifunctional compounds linked together either by acyl or amine links. Acyl links were created from amino acids, which also introduce one degree of functionality. Amine links from the amino acid nitrogen were created from an N-protected amino alcohol via Fukuyama Mitsunobu alkylation. Each amine site can then be used for introducing functionality or extending the scaffold. This synthetic scheme can be used to create a wide variety of modified-backbone PNA in situ, as shown by the synthesis of a PNA-type monomer. The synthesis steps have been enabled on a 96-well parallel-array synthesizer for high-throughput synthesis. The present study represents a versatile synthetic approach to a wide variety of potential RNA-binding molecules.
Davis
P W
PW
Ibis Therapeutics, a Division of Isis Pharmaceuticals, 2292 Faraday Avenue, Carlsbad, California 92008, USA. pwdavis@home.com
Swayze
E E
EE
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry*; D001331:Automation / Q000379:methods; D001596:Benzylamines; D019992:Databases as Topic; D015195:Drug Design; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D020135:Peptide Nucleic Acids / Q000138:chemical synthesis*; D012313:RNA / Q000737:chemistry*; D012116:Resins, Plant
D000577:Amides; D000588:Amines; D001596:Benzylamines; D007202:Indicators and Reagents; D020135:Peptide Nucleic Acids; D012116:Resins, Plant; D012313:RNA