Chemo- and Site-Selective Lysine Modification of Peptides and Proteins under Native Conditions Using the Water-Soluble Zolinium.

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 novel silicone derivative of natural osalmid (DCZ0858) exerts anti-multiple myeloma activity by promoting cell apoptosis and inhibiting cell cycle and mTOR signaling.

Multiple myeloma (MM) is a malignant disease characterized by abnormal proliferation of clonal plasma cells. Based on the organic drug osalmid, the novel small molecule compound DCZ0858 was designed and synthesized for treating MM. DCZ0858 inhibited the proliferation and activity of MM cells and reduced colony formation. It also promoted the apoptosis of primary cells from patients with MM and cultured MM cell lines but had little effect on peripheral blood mononuclear cells in healthy people. Simultaneously, DCZ0858 activated caspase family proteins, blocked MM cells in G0/G1 phase, and reduced the expression of related cyclins CDK4/6 and CyclinD1. Moreover, DCZ0858 overcame the protective effect of the bone marrow microenvironment and effectively inhibited the activity of mTORC1 and mTORC2. Further, xenograft model experiments in mice showed that DCZ0858 significantly inhibited the proliferation and growth of tumors, with low drug toxicity. These results indicate that DCZ0858 has marked anti-MM activity and little effect on normal cells and tissues, making it a new candidate clinical drug for the treatment of MM.

A novel M phase blocker, DCZ3301 enhances the sensitivity of bortezomib in resistant multiple myeloma through DNA damage and mitotic catastrophe.

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 G2/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.

Novel cyclophosphamide of natural products osalmide and pterostilbene induces cytotoxicity and cell cycle arrest in diffuse large B-cell lymphoma cells.

Diffuse large B-cell lymphoma (DLBCL) is the most common category and disease entity of non-Hodgkin lymphoma. Osalmide and pterostilbene are natural products with anticancer activities via different mechanism. In this study, using a new synthetic strategy for the two natural products, we obtained the compound DCZ0801, which was previously found to have anti-multiple myeloma activity. We performed both in vitro and in vivo assays to investigate its bioactivity and explore its underlying mechanism against DLBCL cells. The results showed that DCZ0801 treatment gave rise to a dose- and time-dependent inhibition of cell viability as determined by CCK-8 assay and flow cytometry assay. Western blot analysis results showed that the expression of caspase-3, caspase-8, caspase-9 and Bax was increased, while BCL-2 and BCL-XL levels were decreased, which suggested that DCZ0801 inhibited cell proliferation and promoted intrinsic apoptosis. In addition, DCZ0801 induced G0/G1 phase arrest by downregulating the protein expression levels of CDK4, CDK6 and cyclin D1. Furthermore, DCZ0801 exerted an anti-tumor effect by down-regulating the expressions of p-PI3K and p-AKT. There also existed a trend that the expression of p-JNK and p-P38 was restrained. Intraperitoneal injection of DCZ0801 suppressed tumor development in xenograft mouse models. The preliminary metabolic study showed that DCZ0801 displayed a rapid metabolism within 30 min. These results demonstrated that DCZ0801 may be a new potential anti-DLBCL agent in DLBCL therapy.