In the context of peptide drug development, glycosylation plays a pivotal role. Accordingly, L-type peptides were synthesized predicated upon the PD-1/PD-L1 blocker ^DPPA-1. Subsequent glycosylation resulted in the production of two distinct glycopeptides, D-glu-^LPPA-1 and D-gal-^LPPA-1, by using D-glucose (D-glu) and D-galactose (D-gal), respectively, during glycosylation. Both glycopeptides significantly inhibited the interaction between PD-1 and PD-L1, and the measured half maximal inhibitory concentrations (IC_50s) were 75.5 μM and 101.9 μM for D-glu-LPPA-1 and D-gal-LPPA-1, respectively. Furthermore, D-gal-LPPA-1 displayed a pronounced ability to restore T-cell functionality. In an MC38 tumor-bearing mouse model, D-gal-LPPA-1 demonstrated a significant inhibitory effect. Notably, D-gal-LPPA-1 substantially augmented the abundance and functionality of CD8⁺ T cells in the tumor microenvironment. Additionally, in the lymph nodes and spleens, D-gal-LPPA-1 significantly increased the proportion of CD8⁺ T cells secreting interferon-gamma (IFN-γ). These strong findings position D-gal-LPPA-1 as a potent enhancer of the antitumor immune response in MC38 tumor-bearing mice, underscoring its potential as a formidable PD-1/PD-L1 blocking agent.

Indoleamine 2,3-dioxygenase 1 (IDO1) has received much attention as an immunomodulatory enzyme in the field of cancer immunotherapy. While several IDO1 inhibitors have entered clinical trials, there are currently no IDO1 inhibitor drugs on the market. To explore potential IDO1 inhibitors, we designed a series of compounds with urea and 1,2,3-triazole structures. Organic synthesis and IDO1 enzymatic activity experiments verified the molecular-level activities of the designed compounds, and the IC₅₀ value of compound 3a was 0.75 μM. Molecular docking and quantum mechanical studies further explained the binding mode and reaction potential of compound 3a with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

Indoleamine 2,3-dioxygenase 1 (IDO1) has attracted much attention in the field of cancer immunotherapy as an immunomodulatory enzyme. To identify potential IDO1 inhibitors, a novel series of compounds with N,N-diphenylurea and triazole structures were synthesized. The designed compounds underwent organic synthesis, and subsequent enzymatic activity experiments targeting IDO1 confirmed their activity at the molecular level. These experiments provided validation for the efficacy of the designed compounds in inhibiting IDO1, compound 3g exhibited an IC₅₀ value of 1.73 ± 0.97 μM. Further molecular docking study further explained the binding mode and reaction potential of compound 3g with IDO1. Our research has resulted in a series of novel IDO1 inhibitors, which is beneficial to the development of drugs targeting IDO1 in numerous cancer diseases.

Cervical cancer, a common malignant tumor of the female reproductive system, ranks fourth in incidence and mortality among female cancers globally, which highlights the urgent need for new therapeutic agents to improve treatment outcomes. In this study, 16 new erlotinib-1,2,3-triazole derivatives were synthesized via click chemistry and evaluated for their anti-proliferative activities against HeLa cells using the MTT assay. Compound 3h exhibited the most potent antitumor activity, with a half-maximal inhibitory concentration (IC₅₀) value of 1.35 ± 0.74 µM, significantly lower than that of erlotinib (IC₅₀ = 25.91 ± 1.35 µM). Further assays showed that compound 3h reduced cell viability, inhibited colony formation, and suppressed migration. It arrested the cell cycle at the G2/M phase and induced mitochondrial apoptosis, marked by decreased Bcl-2, increased Bax, and downregulated Caspase-9, Caspase-3, and PARP-1. Additionally, compound 3h promoted ROS accumulation, induced γ-H2AX expression, and regulated the phosphorylation of ERK, JNK, and p38. Molecular docking studies suggested direct binding to these MAPKs. Overall, compound 3h inhibited HeLa cell proliferation by inducing ROS-mediated DNA damage and mitochondrial apoptosis via the MAPK pathway. This study provides evidence for the therapeutic potential of erlotinib-1,2,3-triazole derivatives in cervical cancer treatment, offering new strategies for developing effective and low-toxicity drugs.

We introduced a terminal alkyne into the core structure of dolutegravir, resulting in the synthesis of 34 novel dolutegravir-1,2,3-triazole compounds through click chemistry. These compounds exhibited remarkable inhibitory activities against two hepatocellular carcinoma cell lines, Huh7 and HepG2. Notably, compounds 5e and 5p demonstrated exceptional efficacy, particularly against Huh7 cells, with IC₅₀ values of 2.64 and 5.42 μM. Additionally, both compounds induced apoptosis in Huh7 cells, suppressed tumor cell clone formation, and elevated reactive oxygen species (ROS) levels, further promoting tumor cell apoptosis. Furthermore, compounds 5e and 5p activated the LC3 signaling pathway, inducing autophagy, and triggered the γ-H2AX signaling pathway, resulting in DNA damage in tumor cells. Compound 5e exhibited low toxicity, highlighting its potential as a promising anti-tumor drug.

Cervical cancer ranks as the fourth most common cancer among women. However, the current treatments have significant side effects and limited therapeutic effects on advanced diseases, so it is necessary to discover better treatments for cervical cancer. The current study investigated the potential anticancer effects of a series of gefitinib-1,2,3-triazole derivative on Hela cells. Among the investigated, the target compound c13 showed good anticancer activity against Hela cells (IC₅₀ = 5.66 ± 0.35 μM) compared with gefitinib (IC₅₀ = 14.18 ± 3.19 μM). Moreover, compound c13 significantly inhibited the colony formation ability of Hela cells in a dose-dependent manner, accompanied by morphological changes in HeLa cells. Further investigations demonstrated that compound c13 triggered cell apoptosis and arrested the cell cycle at the G2/M phase in Hela cells. In addition, western blot analysis revealed that compound c13 upregulated the Bax/Bcl-2 ratio, and increased the levels of active caspase 3 and PARP1 cleavage, which suggested the involvement of the mitochondrial pathway in compound c13-induced apoptosis. In brief, these results indicated that compound c13 is a promising compound for the treatment of cervical cancer.