Synthesis of Coumarin-Conjugated Oligonucleotides via Knoevenagel Condensation to Prepare an Oligonucleotide Library

• Published in: Chemical & pharmaceutical bulletin Vol. 72; no. 2; pp. 143 - 148
• Main Authors: Osawa, Takashi, Obika, Satoshi
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.02.2024; Japan Science and Technology Agency
• Subjects: Chemical synthesis; conjugated oligonucleotide; Coumarin; DNA damage; DNA-encoded library; Drug development; Drug discovery; Knoevenagel condensation; Libraries; Oligonucleotides; DNA-encoded library; conjugated oligonucleotide; Knoevenagel condensation; coumarin
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.c23-00295

DNA-encoded libraries (DELs) are attracting attention as a screening tool in the early stages of drug discovery. In the development of DELs, drug candidate compounds are chemically synthesized on barcode DNA. Therefore, it is important to perform the synthesis under mild conditions so as to not damage the DNA. On the other hand, coumarins are gaining increasing research focus not only because they possess excellent fluorescence properties, but also because many medicines contain a coumarin skeleton. Among the various reactions developed for the synthesis of coumarins thus far, Knoevenagel condensation followed by intramolecular cyclization under mild conditions can yield coumarins. In this study, we developed a new synthetic method for preparing a coumarin-conjugated oligonucleotide library via Knoevenagel condensation. The results showed that coumarins substituted at the 5-, 6-, 7-, or 8-positions could be constructed on DNA to afford a total of 26 coumarin-conjugated DNAs. Moreover, this method was compatible with enzymatic ligation, demonstrating its utility in DEL synthesis. The developed strategy for the construction of coumarin scaffolds based on Knoevenagel condensation may contribute to the use of DELs in drug discovery and medicinal chemistry.