Synthesis of New 3‘-, 5-, and N 4-Modified 2‘-O-Methylcytidine Libraries on Solid Support

• Published in: Journal of combinatorial chemistry Vol. 5; no. 6; pp. 851 - 859
• Main Authors: Ding, Yili, Habib, Qazi, Shaw, Stephanie Z, Li, David Y, Abt, Jeffrey W, Hong, Zhi, An, Haoyun
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.11.2003; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Science & Technology; URACIL; ANALOGS; NUCLEOSIDES; CYTOSINE
• ISSN: 1520-4766; 1520-4774
• DOI: 10.1021/cc0300199

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.