Developments in Photoredox-Mediated Alkylation for DNA-Encoded Libraries

Photochemical C–H arylation of heteroarenes for DNA-encoded library synthesis

“…10,11 The DNA barcode of the remaining high-affinity ligands are then amplified using polymerase chain reaction (PCR), and the corresponding chemical identities can be decoded through next generation sequencing of the DNA barcode. Using this interrogation technique, combinatorial libraries of remarkable size (>10 6 to 10 12 molecules) are screened against a protein target of interest, 12 while only vanishingly small quantities of the library are used per experiment. [13][14][15][16] Given that DEL technology is currently in its early stages of development relative to traditional HTS, it is remarkable that DEL success stories within medicinal chemistry are already known.…”

“…To address these inherent mechanistic limitations, the rise of photoredox catalysis has provided access to alternative single-electron-transfer (SET) reaction pathways facilitating C-C and C-X bond formation via open shell intermediates under exceptionally mild conditions at room temperature, platforms that continue to render a significant impact in DEL settings. [36][37][38][39][40] As part of a research program centered on the development of novel synthetic methods to expand chemical space in DELs, 12,26,27 herein we report a photochemical strategy for the assembly of C(sp 2 )-C(sp 2 ) linkages using DNA-conjugated (hetero)aryl halides 41 as carbon-based radical precursors (Scheme 2, bottom). This Minisci-type C-H arylation harnesses medicinally-relevant heteroarenes as acceptors, bypassing the need for prefunctionalization of library BBs.…”

“…As part of a research program centered on the development of novel synthetic methods to expand chemical space in DELs, 12,26,27 herein we report a photochemical strategy for the assembly of C(sp 2 )–C(sp 2 ) linkages using DNA-conjugated (hetero)aryl halides 41 as carbon-based radical precursors ( Scheme 2 , bottom). This Minisci-type C–H arylation harnesses medicinally-relevant heteroarenes as acceptors, bypassing the need for prefunctionalization of library BBs.…”

Recent advances in DNA-encoded dynamic libraries

“…[2][3][4][5][6][7][8][9][10][11] For instance, many companies and institutions are offering DEL selection services; premade DEL kits 12 for direct use in selections and reagent kits 13 for custom DEL synthesis are also available to meet the needs of individual researchers. Furthermore, with the recent expansion of DNA-/DEL-compatible reaction toolkit, 2,6,7,[14][15][16] DELs can access much greater chemical space, which has been a major driver for its adoption in the pharmaceutical industry. 3,11,[17][18][19][20] The concept of DEL was proposed by Brenner and Lerner in 1992.…”

PhOxi-Seq: Single-nucleotide resolution sequencing of N2-methylation at guanosine in RNA by photoredox catalysis

“…OG is known to basepair with adenine, resulting in a G→T transversion, while Iz is known to base-pair with guanine, resulting in a G→C transversion (Figure 1b). 18 With these oxidation outcomes in mind and inspired by examples of visible light photoredox chemistry on RNA [19][20] and DNA, 21 we sought to explore the prospect of visible light photoredox catalysis as a means to detect N 2 -methylation at guanosine sites by oxidative mutagenesis (Figure 1c). We first determined the oxidation potential of N 2methylated guanosines compared with unmodified guanosine using cyclic voltammetry (Figure 2a).…”