Design, synthesis and biological evaluation of matrine contains benzimidazole derivatives as dual TOPOI and PARP inhibitors for cancer therapy.

TOPOI inhibitors have long been a focal point in the research and development of antitumor drugs. PARP-1 plays a crucial role in repairing DNA damage induced by TOPOI inhibitors. Thus, concurrent inhibition of TOPOI and PARP-1 has the potential to augment drug activity. Matrine, characterized by low toxicity and good water solubility, offers advantageous properties. In this investigation, a series of benzimidazole matrine derivatives were designed and synthesized using matrine as the lead compound with the aim of developing dual inhibitors targeting both TOPOI and PARP-1. Among these derivatives, Compound B6 exhibited potent inhibitory effects on PARP-1 and TOPOI, effectively suppressing cancer cell proliferation and migration. Mechanistic assessments revealed that B6 induced DNA damage in HGC-27 cells, leading to G0/G1 cell cycle arrest and significant apoptosis. Molecular docking experiments demonstrated that B6 can effectively enter the active pocket of target proteins, where it forms stable hydrogen bonds with amino acid residues. In vivo, experiments demonstrated that B6 exhibited antitumor activity comparable to that of the positive control drug. The tumor growth inhibition rates (TGIs) for irinotecan, B6 and matrine were 87.0%, 75.4% and 9.7%, respectively. Importantly, B6 demonstrated lower toxicity than the positive control drug. Our findings suggest that TOPOI and PARP-1 may represent potential targets for matrine and B6 emerges as a promising candidate for cancer therapy.

Novel chiral matrine derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Since the thalidomide incident, research on chiral drugs has escalated immensely. Differences in drug configuration can lead to significant variations in therapeutic efficacy. Matrine, a natural product esteemed for its low toxicity and high water solubility, has garnered significant attention in research endeavors. Nonetheless, its precise target has proven elusive. In this study, we designed and synthesized a novel chiral matrine derivative. Their cytotoxicity against three types of tumor cells was assessed. Comparing the newly synthesized derivatives to the parent matrine, most compounds exhibited significantly enhanced inhibitory effects on cancer cells. Among them, Q12 exhibited the highest activity, with IC50 values of 8.31 µM against rat glioma cells C6, 6.3 µM against human liver cancer cells HepG2 and 7.14 µM against human gastric cancer cells HGC-27, meanwhile showing low toxicity. Based on IC50 values, we constructed a preliminary structure-activity relationship (SAR). Compound Q12 significantly suppressed the cloning and migration of HepG2 cells. Further mechanistic studies indicated that Q12 inhibited Topo I in HepG2 cells, leading to DNA damage, induction of G0/G1 cell cycle arrest and ultimately causing apoptosis. The molecular docking experiments provided a rational binding mode of Q12 with the Topo I-DNA complex. In vivo, experiments demonstrated that Q12 exhibited a higher tumor growth inhibition rate (TGI) compared to the positive control drug Lenvatinib, while maintaining good safety. In summary, it suggests that Topo I might be a potential target for matrine and Q12 represents a promising candidate for cancer treatment.

ZFP64 transcriptionally activates PD-1 and CTLA-4 and plays an oncogenic role in esophageal cancer.

Anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) are promising therapies for esophageal cancer. Zinc finger protein 64 (ZFP64) is precited as a transcriptional factor for PD-1 and CTLA-4 and presents high expression in esophagus cancer by bioinformatics analysis. The present study was designed to validate these results and to further explore the role of ZFP64 in esophagus cancer tumorigenesis. An orthotopic xenograft mouse model was established. Effects of ZFP64 on tumor growth and weight were assessed. Immunohistochemical staining was performed to reveal the protein expression of ZFP64, PD-1, and CTLA-4. Gain-of-function assays were performed to evaluate the influences of ZFP64 on cancer cell malignant phenotypes. The results revealed that ZFP64 transcriptionally activates PD-1 and CTLA-4 to increase their expression. ZFP64 plays an oncogenic role in esophageal cancer by promoting cancer cell proliferation, migration, invasion, and repressing apoptosis. ZFP64 also promotes esophageal cancer xenograft tumor growth in mice. In conclusion, ZFP64 increases PD-1 and CTLA-4 expression by binding to their promoters and facilitates esophageal cancer tumorigenesis, indicating ZFP64 protein transcription factor as a potential antidrug target in esophageal cancer.

Novel matrinic acid derivatives bearing 2-anilinothiazole structure for non-small cell lung cancer treatment with improved Hsp90 targeting effect.

Involved in mediating the folding and maturation of more than 300 client proteins, many of which are oncoproteins, Hsp90 has emerged as a promising drug target for cancer therapy. In particular, inhibiting Hsp90 plays a vital role in the treatment of non-small cell lung cancer. Owing to undesirable outcomes of Hsp90 inhibitors in clinical trials, a series of matrinic acid compounds bearing 2-anilinothiazole moiety were designed based on the structural features allocation shared among Hsp90 inhibitors within the ATP-binding pocket. Most of the compounds showed potent anticancer activities validated by MTT assay. Among them, the most potent compound C4 (IC50 < 10 µM against four cell lines) was chosen for further mechanism study. Notably, C4 showed a better safety profile than 17AAG with a higher SI value. Thermal shift assay data indicated C4 exhibited a strong binding affinity with Hsp90 (-18.85 ± 0.56°C) comparable to radicicol. Mechanism studies verified that C4 significantly inhibited proliferation and migration activities of A549 cells. Besides, C4 can induce a prolonged G1-phase and cell apoptosis. Western blot analysis results indicated C4 could moderately suppress Hsp90 and upregulate Hsp70 expression. Furthermore, the downregulated trend of the client proteins of Hsp90, such as ß-Catenin and Bcl-2, were consistent with the cellular effect of C4, suggesting that C4 could exert anticancer activity via targeting Hsp90. In the xenograft model in vivo, C4 effectively inhibited lung cancer growth without obvious side effects. Collectively, C4 could be a promising therapeutic agent for lung cancer and the novel scaffold provided new insights into the design of Hsp90 inhibitors.

Degradation kinetics and antioxidant capacity of anthocyanins in air-impingement jet dried purple potato slices.

We investigated the types, degradation kinetics, and antioxidant capacities of anthocyanins in purple potato slices subjected to air-impingement jet drying (AIJD) at different drying temperatures (50, 65, and 80°C). Petunidin-3-p-coumaroylrutinoside-5-glucoside was the predominant anthocyanin in AIJD-treated purple potato and was positively correlated with antioxidant capacity. Anthocyanin concentration decreased with drying time, and anthocyanin degradation followed first-order reaction kinetics. At high drying temperatures, anthocyanin degradation had higher degradation rates and shorter half-life than at low drying temperatures. Thermodynamic results revealed that the degradation of anthocyanins is a non-spontaneous, endothermic reaction and that the transition state has lower structural freedom than the reactant. AIJD at 65°C contributed to the highest anthocyanin content and antioxidant capacity.