Youlin Zeng

This study successfully constructed and systematically characterised a host-guest complex (Q[7]/BH) based on cucurbit[7]uril (Q[7]) and berberine (BH), which significantly enhanced the antitumor efficacy of BH. Nuclear magnetic resonance, infra-red spectrometry, and fluorescence spectra analysis confirmed the formation of a stable 1:1 inclusion complex (Q[7]/BH) through host-guest interactions. In vitro cell experiments proved that Q[7]/BH had an inhibitory effect on various cancer cells, and in vivo antitumor results showed that Q[7]/BH significantly increased anticancer activity compared with BH. This work provides a supramolecular encapsulation strategy for optimising the activity of natural products.

Herein, we report practical Cu(BF4)2/activated carbon-catalyzed amination of various anilines, isoquinolinone, and naphthyridinone with aryl boronic acids. The ultrasonic and rotary evaporation treatment of the mixture of aq. Cu(BF4)2 and activated carbon in methanol afforded a novel Cu(II)-catalyst, which is air-stable and can be effectively applied in the Chan-Lam coupling reaction. The products of N-arylation were isolated in good to excellent yields at low catalytic loading. And Cu(BF4)2/AC also showed good reusability.

The activation of the stimulating factor of the interferon gene (STING) pathway can enhance the immune response within the tumor. Cyclic diguanylate monophosphate (c-di-GMP) is a negatively charged, hydrophilic STING agonist, however, its effectiveness is limited due to the poor membrane permeability and low bioavailability. Herein, we introduced KL-7 peptide derived from Aβ amyloid fibrils that can self-assemble to form nanotubes to load and deliver c-di-GMP, which significantly enhanced c-di-GMP’s effectiveness and then exhibited a robust “in situ immunity” to kill melanoma cells. KL-7 peptide nanotube, also called PNT, was loaded with negatively charged c-di-GMP via electrostatic interaction, which prepared a nanocomposite named c-di-GMP-PNT. Treatment of RAW 264.7 cells (leukemia cells in mouse macrophage) with c-di-GMP-PNT markedly stimulated the secretion of IL-6 and INF-β along with phospho-STING (Ser365) protein expression, indicating the activation of the STING pathway. In the unilateral flank B16-F10 (murine melanoma cells) tumor-bearing mouse model, compared to PNT and c-di-GMP, c-di-GMP-PNT can promote the expression of INF-β, TNF-α, IL-6, and IL-1β. At the same time, up-regulated CD4 and CD8 active T cells kill tumors and enhance the immune response in tumor tissues, resulting in significant inhibition of tumor growth in tumor-bearing mice. More importantly, in a bilateral flank B16-F10 tumor model, both primary and distant tumor growth can also be significantly inhibited by c-di-GMP-PNT. Moreover, c-di-GMP-PNT demonstrated no obvious biological toxicity on the main organs (heart, liver, spleen, lung, and kidney) and biochemical indexes of mice. In summary, our study provides a strategy to overcome the barriers of free c-di-GMP in the tumor microenvironment and c-di-GMP-PNT may be an attractive nanomaterial for anti-tumor immunity.

Commonly overexpressed in many cancers and associated with tumor growth, metastasis, drug resistance, and poor overall survival, Axl has emerged as a promising target for cancer therapy. However, the availability of new chemical forms for Axl inhibition is limited. Herein, we present the development and characterization of novel Axl inhibitors, including the design, synthesis, and structure–activity relationships (SARs) of a series of diphenylpyrimidine–diamine derivatives. Most of these compounds exhibited remarkable activity against the Axl kinase. In particular, the promising compound m16 showed the highest enzymatic inhibitory potency (IC₅₀ = 5 nM) and blocked multiple tumor cells' proliferation potencies (the CC₅₀ of 4 out of 42 cancer cell lines m16 also possessed preferable pharmacokinetic profiles and liver microsome stability. All these favorable results make m16 a good leading therapeutic candidate for further development.

Spider venom is a valuable resource for the development of novel anticancer drugs. In this study, we focused on novel linear amphipathic α-helical anticancer peptide LVTX-9, which was derived from the cDNA library of the venom gland of the spider Lycosa vittata. The cytotoxicity of LVTX-9 against murine melanoma cells in the range of 1.56–200 μM was tested and found to be significantly lower than those of most anticancer peptides reported. Its IC₅₀ was determined to be 59.2 ± 19.8 μM in a serum or 76.3 ± 12.7 μM in serum-free medium. Fatty acid modification is a promising strategy for improving peptide performance. Therefore, to enhance the cytotoxic activity of LVTX-9, fatty acid modification of this peptide was performed, and five different carbon chain length lipopeptides named LVTX-9-C₁₂-C₂₀ were produced. Among them, the lipopeptide LVTX-9-C₁₈ showed the highest cytotoxic activity in relation to B16-F10 cells, whether in a serum or serum-free medium. Most importantly, the cytotoxic activity of LVTX-9-C₁₈ was improved by about 12.9 times in a serum medium or 19.3 times in a serum-free medium compared to that of LVTX-9. Subsequently, assays including scanning electron microscopy, trypan blue staining, lactate dehydrogenase leakage assay, and hemolytic activity could indicate that the potential direct cell membrane disruption is the main mechanism of LVTX-9-C₁₈ to induce cancer cell death. Furthermore, the LVTX-9-C₁₈ also showed strong cytotoxicity in relation to 3D B16-F10 spheroids, which indicates it might be a promising lead for developing anticancer drugs.