Design, synthesis and cytotoxic activity of sulfonylated derivatives of camptothecin.

With the intention of advancing our research on diverse C-20 derivatives of camptothecin (CPT), 38 CPT derivatives bearing sulphonamide and sulfonylurea chemical scaffolds and different substituent groups have been designed, synthesised and evaluated in vitro for cytotoxicity against four tumour cell lines, A-549 (lung carcinoma), KB (nasopharyngeal carcinoma), MDA-MB-231 (triple-negative breast cancer) and KBvin (an MDR KB subiline). As a result, all the synthesised compounds showed promising in vitro cytotoxic activity against the four cancer cell lines tested, and were more potent than irinotecan. Importantly, compounds 12b, 12f, 12j and 13 l possessed better antiproliferative activity against all tested tumour cell lines with IC50 values of 0.0118 - 0.5478 µM, and resulted approximately 3 to 4 times more cytotoxic than topotecan against multidrug-resistant KBvin subline. Convincing evidences are achieved that incorporation of sulphonamide and sulfonylurea motifs into position-20 of camptothecin confers markedly enhanced cytotoxic activity against cancer cell lines.

Hydroxylated hierarchical flower-like COF for solid-phase extraction of adrenergic receptor agonists in milk.

A new detection platform based on a hydroxylated covalent organic framework (COF) integrated with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was constructed and used for detecting adrenergic receptor agonists (ARAs) residues in milk. The hydroxylated COF was prepared by polymerization of tris(4-aminophenyl)amine and 1,3,5-tris(4-formyl-3-hydroxyphenyl)benzene and applied to solid-phase extraction (SPE) of ARAs. This hydroxylated COF was featured with hierarchical flower-like morphology, easy preparation, and copious active adsorption sites. The adsorption model fittings and molecular simulation were applied to explore the potential adsorption mechanism. This detection platform was suitable for detecting four α2- and five ß2-ARAs residues in milk. The linear ranges of the ARAs were from 0.25 to 50 µg·kg-1; the intra-day and the inter-day repeatability were in the range 2.9-7.9% and 2.0-10.1%, respectively. This work demonstrates this hydroxylated COF has great potential as SPE cartridge packing, and provides a new way to determine ARAs residues in milk.

Synthesis and antitumor activity of dolutegravir derivatives bearing 1,2,3-triazole moieties.

Modification of marketed drugs is an important way to develop drugs because its safety and clinical applicability. Oxygen-nitrogen heterocycles are a class of important active substances discovered in the process of new drug development. Dolutegravir, an HIV drug with a nitrogen-oxygen heterocycle structure, has the potential ability to inhibit cell survival. In order to find and explore novel anti-tumor drugs, new dolutegravir derivatives bearing different 1,2,3-triazole moieties were prepared via click reactions. In vitro biological experiments performed in several lung cancer cell lines suggested that these novel compounds displayed potent anti-tumor ability. Especially, the compound 9e with a substituent of 2-methyl-3-nitrophenyl and the compound 9p with a substituent of 3-trifluoromethylphenyl were effective against PC-9 cell line with IC50 values of 3.83 and 3.17 µM, respectively. Moreover, compounds 9e and 9p were effective against H460 and A549 cells. Further studies suggested that compounds 9e and 9p could induce cancer cell apoptosis in PC-9 and H460, inhibit cancer cell proliferation, change the cell cycle, and increase the level of reactive oxygen species (ROS) which further induce tumor cell apoptosis. In addition, compounds 9e and 9p increased LC3 protein expression which was the key regulator in autophagy signaling pathway in PC-9 cells. Compound 9e also showed low toxicity against normal cells, and could be regarded as an interesting lead compound for further structure optimization.

Development of Glycosylation-Modified DPPA-1 Compounds as Innovative PD-1/PD-L1 Blockers: Design, Synthesis, and Biological Evaluation.

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 (IC50s) 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.

Decoding the enhanced antioxidant activities of the combined small berry pomaces by widely targeted metabolomics analysis.

Small berry pomaces (SBPs) are poorly utilized as an inexpensive source of bioactive compounds. This study investigated the impact of compounding treatment on nutritional and antioxidant characteristics of combined SBPs, in comparison with single SBP. The results showed that the amounts of protein, minerals, dietary fiber (DF) and anthocyanidins were significantly (p < 0.05) higher in combined SBPs than in combined fruits. Moreover, the combined SBPs were characterized by an elevated abundance of minerals and anthocyanidins (6 kinds, and 5 kinds, respectively), substantiating the effectiveness of compounding treatment on SBP nutrition. A total of 776 secondary phytochemicals were detected in combined SBPs by a widely targeted metabolomics approach. Each SBP contained approximately 100 kinds of unique natural antioxidants. Furthermore, the combined SBPs group had the highest antioxidant activity compared with single SBP. Meanwhile, the antioxidant activities determined in combined SBPs were higher than arithmetic mean value of single SBP. The synergism and interaction of active components in different sources of SBPs play vital role in the high antioxidant capacity of combined SBPs. All the results provide reference for the comprehensive development and utilization of fruit residues. The SBPs should be highly prized for their substantial amount of nutritional and bioactive constituents, including protein, DF, essential minerals and secondary metabolites. These secondary metabolites are positively associated with antioxidant benefits. The present study summarizes the knowledge about bioactive compounds and antioxidant activities of combined SBPs group and discusses the relevant mechanisms. A conclusion can be educed that combined process is an effective way to improve properties of the pomaces.