Synthesis of new 3'-, 5-, and N(4)-modified 2'-O-methylcytidine libraries on solid support.
A versatile solid phase combinatorial approach was developed and utilized for the rapid synthesis of new 2'-O-methylcytidine nucleoside libraries 1-7 containing 672 compounds with 3'-deoxy-3'-C-methyl, 3'-deoxy-3'-C-hydroxymethyl, and 5-alkyl/alkynyl modifications. The modified uridine scaffolds 8-10, 23-25, and 31 were loaded onto the 4-methoxytrityl chloride (MMT-Cl) polystyrene resin through the hydroxyl groups at the 5'-position as well as on the substituents at the 3'- and 5-positions. The scaffolds loaded on the resin were orthogonally protected by MMT group on the resin itself and TBDMS or acetyl protecting groups. The 4-position of the uridine derivatives was activated by 2,4,6-triisopropyl benzene sulfonyl chloride for further derivatization. The resins 14-16, 28-30, and 32 loaded with the corresponding activated scaffolds were reacted with the selected and validated amino building blocks in the 96 well format on the semiautomated synthesizer. The high-quality 2'-O-methylcytidine libraries 1-7 were thus generated and characterized by liquid chromatography-mass spectrometry (LC-MS) analysis with 63-99% successful rates.
Ding
Yili
Y
Ribapharm, Inc., 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
Habib
Qazi
Q
Shaw
Stephanie Z
SZ
Li
David Y
DY
Abt
Jeffrey W
JW
Hong
Zhi
Z
An
Haoyun
H
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry / Q000379:methods; D019151:Peptide Library
D019151:Peptide Library; C052203:2'-O-methylcytidine; D003562:Cytidine