DNA-Compatible Cyclization Reaction to Access 1,3,4-Oxadiazoles and 1,2,4-Triazoles.

DNA-encoded chemical library (DECL) technology is a commonly employed screening platform in both the pharmaceutical industry and academia. To expand the chemical space of DECLs, new and robust DNA-compatible reactions are sought after. In particular, DNA-compatible cyclization reactions are highly valued, as these reactions tend to be atom economical and thus may provide lead- and drug-like molecules. Herein, we report two new methodologies employing DNA-conjugated thiosemicarbazides as a common precursor, yielding highly substituted 1,3,4-oxadiazoles and 1,2,4-triazoles. These two novel DNA-compatible reactions feature a high conversion efficiency and broad substrate scope under mild conditions that do not observably degrade DNA.

Camptothecin Nanoprodrug Possessing Dual Responsiveness to Endolysosomal pH and Cytosolic Redox for Amplified Cytotoxic Potency.

Selective activation of prodrug nanomedicine in cell interiors is deemed to be crucial in pursuit of precision anti-tumor therapy. In the present study, we attempted to synthesize an amphiphilic diblock copolymer poly(ethylene glycol)-polylysine (PEG-PLys) based on ring-opening polymerization. The γ terminal amines of lysine units were conjugated with camptothecin (CPT) through redox-responsive disulfide linkage, followed by conversion of the rest of the amines of PLys into carboxyl groups. Core-shell architectural nanoparticles could be achieved by self-assembly of the yielded amphiphiles characterized to possess CPT-linked PLys segments as the internal core and PEG segments as the external shell. Furthermore, attempts were made to precipitate CaPO3 on the yielded core with the aid of the carboxyl groups. Subsequent investigations confirmed uniform nanoscale formation with a hydrodynamic diameter of approximately 63.0 nm and excellent colloidal stabilities. Most importantly, the proposed dually responsive prodrug construct was determined to possess intriguing sequentially intracellular microenvironment-responsive functionalities: (1) the inorganic CaPO3 precipitate could not only exclude the internal payloads from premature reactions but also rapidly dissolve in acidic endosomal compartments, with the induced osmotic pressure thereby facilitating translocation of the prodrug into the cytosol; (2) CPT could be readily metabolized due to disulfide cleavage responsive to the redox potential in cytosolic compartments. Hence, the amalgamated dual-responsiveness eventually contributes to drastic cytotoxic potency, which portends prosperous utilities as precision therapeutics in the treatment of a variety of intractable tumors.