TY - JOUR
T1 - Kinetically guided radical-based synthesis of C(sp3)−C(sp3) linkages on DNA
AU - Wang, Jie
AU - Lundberg, Helena
AU - Asai, Shota
AU - Martín-Acosta, Pedro
AU - Chen, Jason S.
AU - Brown, Stephen
AU - Farrell, William
AU - Dushin, Russell G.
AU - O’Donnell, Christopher J.
AU - Ratnayake, Anokha S.
AU - Richardson, Paul
AU - Liu, Zhiqing
AU - Qin, Tian
AU - Blackmond, Donna G.
AU - Baran, Phil S.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank D.-H. Huang and L. Pasternack for assistance with NMR spectroscopy; Prof. B. Paegel for useful discussions and preliminary tests on DNA stability under DEL-like conditions; M. Hill and E. Costa for DNA analytic method development; Guanda Che, Denghui Bao, and En-Xuan Zhang (Asymchem) for large-scale preparation of HITU (11); and LGC Biosearch Technologies for preparing DNA headpiece. Financial support for this work was provided by Pfizer and NIH (Grant GM-118176). The Swedish Research Council, The Foundation Blanceflor Ludovisi née Bildt, Stiftelsen Olle Engkvist Byggmästare, and The Hans Werthén Fund Scholarship supported research fellowships (to H.L.), Uehara Memorial Foundation supported a research fellowship (to S.A.), and Agencia Canaria de Investigación, Innova-ción y Sociedad de la Información - Unión Europea supported a predoctoral fellowship (to P.M.-A.).
Publisher Copyright:
© 2018 National Academy of Sciences. All rights reserved.
PY - 2018/7/10
Y1 - 2018/7/10
N2 - DNA-encoded libraries (DEL)-based discovery platforms have re cently been widely adopted in the pharmaceutical industry, mainl due to their powerful diversity and incredible number of mole cules. In the two decades since their disclosure, great strides hav been made to expand the toolbox of reaction modes that are com patible with the idiosyncratic aqueous, dilute, and DNA-sensitiv parameters of this system. However, construction of highly impor tant C(sp3)−C(sp3) linkages on DNA through cross-coupling remain unexplored. In this article, we describe a systematic approach t translating standard organic reactions to a DEL setting throug the tactical combination of kinetic analysis and empirical screenin with information captured from data mining. To exemplify thi model, implementation of the Giese addition to forge high valu C–C bonds on DNA was studied, which represents a radical-base synthesis in DEL.
AB - DNA-encoded libraries (DEL)-based discovery platforms have re cently been widely adopted in the pharmaceutical industry, mainl due to their powerful diversity and incredible number of mole cules. In the two decades since their disclosure, great strides hav been made to expand the toolbox of reaction modes that are com patible with the idiosyncratic aqueous, dilute, and DNA-sensitiv parameters of this system. However, construction of highly impor tant C(sp3)−C(sp3) linkages on DNA through cross-coupling remain unexplored. In this article, we describe a systematic approach t translating standard organic reactions to a DEL setting throug the tactical combination of kinetic analysis and empirical screenin with information captured from data mining. To exemplify thi model, implementation of the Giese addition to forge high valu C–C bonds on DNA was studied, which represents a radical-base synthesis in DEL.
KW - Combinatorial chemistr
KW - DNA-encoded libraries
KW - Kinetic analysis
KW - Organic synthesis
KW - Radical reactions
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U2 - 10.1073/pnas.1806900115
DO - 10.1073/pnas.1806900115
M3 - Article
C2 - 29946037
AN - SCOPUS:85049616506
SN - 0027-8424
VL - 115
SP - E6404-E6410
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 28
ER -