RASS-Enabled S/P-C and S-N Bond Formation for DEL Synthesis

Abstract

DNA encoded libraries (DEL) have shown promise as a valuable technology for democratizing the hit discovery process. Although DEL provides relatively inexpensive access to libraries of unprecedented size, their production has been hampered by the idiosyncratic needs of the encoding DNA tag relegating DEL compatible chemistry to dilute aqueous environments. Recently reversible adsorption to solid support (RASS) has been demonstrated as a promising method to expand DEL reactivity using standard organic synthesis protocols. Here we demonstrate a suite of on-DNA chemistries to incorporate medicinally relevant and C-S, C-P and N-S linkages into DELs, which are underrepresented in the canonical methods.

Keywords: DNA encoded library; nickel cross-coupling; reversible adsorption to solid support; sulfonamide; sulfone.

Figure 1:

Sulfur containing bioactive compounds and routes to sulfur containing moiety incorporation into DELs

Figure 2:

On-DNA sulfide and sulfone synthesis: (A) nickel mediated C-S cross coupling, conditions, HPLC chromatogram of reaction, and reaction scope. Deviation from above reaction conditions: ^a alkyl thiol (500 mM), 36 h, ^b none, ^c phosphonic chloride (100 mM), 4,4’ ditertbutyl bipyridine (200 mM). (B) on-DNA sulfone formation reaction conditions and reaction scope. Deviation from stated reaction conditions: ^d none; ^e thiol (500 mM), Cs₂CO₃ (500 mM), DMF, 18 h. ^f Electrochemical oxidation: tetrabutyl ammonium chloride (100 mM), TEMPO (200 mM), +C/−C, 5 mA, 15 min, alternating polarity every 30 sec

Figure 3:

On-DNA sulfonamide and reverse sulfonamide synthesis: (A) on-DNA sulfonamide reaction conditions and reaction scope. ^a aryl sulfonamide formation, aryl sulfinate (500 mM), iodine (500 mM), in EtOH, 18 h. ^b alkyl sulfonamide formation: alkyl sulfinate (1000 mM), NCS (500 mM), in EtOH, 1.5 h sonication. (B) reverse sulfonamide formation reaction conditions and reaction scope. ^c reaction conditions: rongalite (750 mM), DMSO, 18 h. wash with DMSO. amine (500 mM), DCDMH (500 mM), DMSO, 18 hr. (C) proposed RASS enabled workflow for performing multiple encoded diversification steps using a sensitive intermediate.

Figure 4:

DNA binding and elution: (A) DNA adsorption kinetics to strata XAL with various DNA constructs. (B) loading capacity of DNA onto Strata XAL using 40mer dsDNA. (C) DNA elution from strata XAL using various DNA constructs.