Design and Synthesis of Biaryl DNA-Encoded Libraries

Abstract

DNA-encoded library technology (ELT) is a powerful tool for the discovery of new small-molecule ligands to various protein targets. Here we report the design and synthesis of biaryl DNA-encoded libraries based on the scaffold of 5-formyl 3-iodobenzoic acid. Three reactions on DNA template, acylation, Suzuki-Miyaura coupling and reductive amination, were applied in the library synthesis. The three cycle library of 3.5 million diversity has delivered potent hits for phosphoinositide 3-kinase α (PI3Kα).

Arylation Chemistry for Bioconjugation

“…Theauthors installed aryl halides on dsDNA by coupling aryl halide carboxylic acids to the terminal amines in dsDNA ( Figure 47 A). [246] In 2016, Ding and Clark reported an ew catalyst system using [(t-Bu) 2 P(OH)] 2 PdCl 2 (POPd) as the palladium source and sodium 2'-(dicyclohexylphosphino)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonate (sSPhos) as the ligand for the on-DNASuzuki-Miyaura coupling of challenging phenyl chlorides and pyrimidinyl chlorides (Figure 47 B). This catalyst system was applied to the synthesis of a3 .5-million-member DNA-encoded library from which potent hits for phosphoinositide 3-kinase a (PI3Ka)w ere identified.…”

DNA‐Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On‐DNA Suzuki, Sonogashira, and Buchwald Reactions

“…In a typical affinity-based selection experiment, when non-and low-affinity binders are washed away, the DNA tag of the remaining compounds can be amplified using polymerase chain reaction and the relative frequency of the remaining compounds before and after selection is determined by counting the number of DNA tags in high-throughput DNA sequencing experiments. Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. [14] Several drug candidates derived from their corresponding DEL hits, such as soluble epoxide hydrolase inhibitor GSK2256294, and death domain receptor-associated adaptor kinase RIP1 inhibitor GSK2982772 have progressed to latestage clinical development, [15,16] further emphasizing DEL as a powerful technology for small molecular drug discovery.…”

“…Among various DNA-compatible reactions developed in recent years, transition-metal-promoted reactions such as Suzuki-Miyaura coupling, [17][18][19][20][21][22][23] Sonogashira coupling, and Buchwald-Hartwig amination using DNA-conjugated aryl halides as electrophiles have been elegantly developed (Figure 1), [24][25][26] and some of them have been developed for DEL synthesis. One of the most fundamental challenges is the synthesis of high-quality libraries with more structural diversity, which in turn depends on the development of new and robust DNA-compatible reactions that allow more flexibility in DEL's design and synthesis.…”

Arylierungschemie für die Biokonjugation

“…Dieses Katalysatorsystem wurde fürd ie Synthese einer Bibliothek von 3.5 Millionen DNA-codierten Verbindungen verwendet, von denen die potentesten fürP hosphoinositid-3-Kinase a (PI3Ka)h erausgefiltert wurden. [246] 2016 stellten Ding, Clark und DeLorey ein neues Katalysatorsystem vor,b estehend aus [(t-Bu) 2 P(OH)] 2 PdCl 2 (POPd) als Palladiumquelle und Natrium-2'-(dicyclohexylphosphanyl)-2,6-dimethoxy-[1,1'-biphenyl]-3-sulfonat (sSPhos) als Ligand, das füre ine direkt an der DNAe rfolgende Suzuki-Miyaura-Kupplung anspruchsvoller Phenyl-und Pyrimidinylchloride verwendet wurde (Abbildung 47 B). [247] Mit diesem Katalysatorsystem wurden außerdem erhçhte Konjugationsausbeuten fürv er-schiedene Aryl-und Heteroarylboronsäuren und -ester gefunden.…”