title: What is a "DNA-Compatible" Reaction?
abstract: DNA-encoded synthesis can generate vastly diverse screening libraries of arbitrarily complex molecules as long as chemical reaction conditions do not compromise DNA's informational integrity, a fundamental constraint that "DNA-compatible" reaction development does not presently address. We devised DNA-encoded reaction rehearsal, an integrated analysis of reaction yield and impact on DNA, to acquire these key missing data. Magnetic DNA-functionalized sensor beads quantitatively report the % DNA template molecules remaining viable for PCR amplification after exposure to test reaction conditions. Analysis of solid-phase bond forming (e.g., Suzuki-Miyaura cross-coupling, reductive amination) and deprotection reactions (e.g., allyl esters, silyl ethers) guided the definition and optimization of DNA-compatible reaction conditions (>90% yield, >30% viable DNA molecules), most notably in cases that involved known (H(+), Pd) and more obscure (Δ, DMF) hazards to DNA integrity. The data provide an empirical yet mechanistically consistent and predictive framework for designing successful DNA-encoded reaction sequences for combinatorial library synthesis.
authors.affiliation: Department of Chemistry and ‡Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute 130 Scripps Way Jupiter, Florida 33458, United States.
authors.forename: Marie L
authors.initials: ML
authors.lastname: Malone
authors.affiliation: Department of Chemistry and ‡Doctoral Program in Chemical and Biological Sciences, The Scripps Research Institute 130 Scripps Way Jupiter, Florida 33458, United States.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Paegel
mesh_terms: D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry* / Q000235:genetics; D016133:Polymerase Chain Reaction
chemical_list: D004247:DNA
keywords: encoded synthesis; one-bead-one-compound (OBOC); split-and-pool