Abstract
A hypodiboric acid system for the reduction of nitro groups on DNA–chemical conjugates has been developed. This transformation provided good to excellent yields of the reduced amine product for a variety of functionalized aromatic, heterocyclic, and aliphatic nitro compounds. DNA tolerance to reaction conditions, extension to decigram scale reductions, successful use in a DNA-encoded chemical library synthesis, and subsequent target selection are also described.
Highlights
DNA-encoded chemical library (DECL) screens are an economic and efficient method for hit discovery.[1]
Nitro-substituted, bifunctional compounds represent a versatile set of building blocks for the synthesis of DECLs as an incorporation of the nitro functional group for select drug− target classes,[7] as a substituent to facilitate other reactions under DNA-compatible conditions, but most importantly as a widely commercially available set of masked, bifunctional anilines that can be unveiled and screened directly or further functionalized in a subsequent build cycle
Satz and co-workers have utilized a Raney-nickel system,5a we have described a sodium dithionite protocol,[11] and recently, Ding et al have developed an iron sulfate condition[12] for use in the on-DNA synthesis of benzimidazoles through an SNAr, o-amino nitro reduction, and aldehyde condensation sequence (Figure 1A)
Summary
DNA-encoded chemical library (DECL) screens are an economic and efficient method for hit discovery.[1]. Application of the reduction conditions efficiently provided the desired aniline, no evidence of DNA decomposition was detected by LC−MS or gel electrophoresis, and the product underwent efficient ligation with an additional DNA tag to form 4 (Scheme 2; see the Supporting Information for full details).
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