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Activity-based sensing (ABS) probes equipped with a NIR bioluminescence (BL) readout are promising chemical tools to study cancer biomarkers owing to their high sensitivity and deep tissue compatibility. However, the standard approach of installing a responsive trigger at the aniline site through a self-immolative linker is not suitable for NIR substrates because they require N,N-dialkylation at this position to achieve NIR emission. Capping the carboxylate is also unfavorable due to the instability of the resulting ester moiety which would result in high background signals. In this study, we rationally designed a hydrolysis-resistant ester featuring an isopropyl shielding arm. Compared to a benzyl ester analog (proxy for self-immolative linker), the new design is 140.5-fold and 67.8-fold more resistant toward spontaneous and esterase-mediated hydrolysis, respectively. After further in cellulo evaluation of stability, this ester moiety was transformed into a general self-immolative linker for ABS probe development via carboxylate masking. We showcased the utility of this technology by developing the first NIR BL probe for hypoxia sensing (BL660-NTR) and applied it in lung cancer cells and in a murine model of non-small cell lung cancer.

A photoredox-mediated δ-C(sp3)-H fluorination of sulfonyl-protected primary alkylamines with Selectfluor is developed. The reaction can proceed in excellent monofluorination selectivity for amine substrates without α substituent. For α-substituted substrates, a slightly modified reaction conditions with two rounds of operation gives the δ,δ-difluorination products in good yield. Mechanistic studies suggest SET oxidation of sulfonamide group directly generates the key sulfonamide N radical intermediate, which triggers a 1,5-HAT process to form the δ alkyl radical.

A method for the construction of cyclophane-braced peptide macrocycles via Pd-catalyzed aminoquinoline-directed intramolecular C(sp3)–H arylation with aryl iodides is developed. Unlike our previous...

DNA Encoded Libraries 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.