Site-selective lysine modification of peptides and proteins
in
aqueous solutions or in living cells is still a big challenge today.
Here, we report a novel strategy to selectively quinolylate lysine
residues of peptides and proteins under native conditions without
any catalysts using our newly developed water-soluble zoliniums. The
zoliniums could site-selectively quinolylate K350 of bovine serum
albumin and inactivate SARS-CoV-2 3CLpro
via covalently modifying two highly conserved lysine residues (K5 and
K61). In living HepG2 cells, it was demonstrated that the simple zoliniums
(5b and 5B) could quinolylate protein lysine
residues mainly in the nucleus, cytosol, and cytoplasm, while the
zolinium-fluorophore hybrid (8) showed specific lysosome-imaging
ability. The specific chemoselectivity of the zoliniums for lysine
was validated by a mixture of eight different amino acids, different
peptides bearing potential reactive residues, and quantum chemistry
calculations. This study offers a new way to design and develop lysine-targeted
covalent ligands for specific application.
A new metal-free method for the N-quinolylation of primary amino groups using novel dihydrooxazolo[3,2-a]quinoliniums showing good compatibility with other reactive moieties.
Background: DCZ3301, a novel aryl-guanidino compound previously reported by our group, exerts cytotoxic effects against multiple myeloma (MM), diffused large B cell lymphoma (DLBCL), and T-cell leukemia/lymphoma. However, the underlying mechanism of its action remains unknown. Methods: We generated bortezomib (BTZ)-resistant cell lines, treated them with various concentrations of DCZ3301 over varying periods, and studied its effect on colony formation, cell proliferation, apoptosis, cell cycle, DNA synthesis, and DNA damage response. We validated our results using in vitro and in vivo experimental models. Results: DCZ3301 overcame bortezomib (BTZ) resistance through regulation of the G 2 /M checkpoint in multiple myeloma (MM) in vitro and in vivo. Furthermore, treatment of BTZ-resistant cells with DCZ3301 restored their drug sensitivity. DCZ3301 induced M phase cell cycle arrest in MM mainly via inhibiting DNA repair and enhancing DNA damage. Moreover, DCZ3301 promoted the phosphorylation of ATM, ATR, and their downstream proteins, and these responses were blocked by the ATM specific inhibitor KU55933. Conclusions: Our study provides a proof-of-concept that warrants the clinical evaluation of DCZ3301 as a novel anti-tumor compound against BTZ resistance in MM.
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