Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents.

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q2 = 0.606 and r2 = 0.919) and COMSIA (q2 = 0.641 and r2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders.Communicated by Ramaswamy H. Sarma.

Artemisia sieberi Besser essential oil inhibits the growth and migration of breast cancer cells via induction of S-phase arrest, caspase-independent cell death and downregulation of ERK.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia sieberi Besser is a medicinal herb that has been traditionally used across the Middle East for the treatment of cancer. Further pharmacological studies on its extracts revealed that they possess cytotoxic activity against certain cancer cells, however, there were no studies conducted on the anticancer potential of Artemisia sieberi essential oil (ASEO). AIM OF THE STUDY: To evaluate the anticancer potential of ASEO, elucidate the oil's mode of action for the first time and investigate its chemical composition. MATERIALS AND METHODS: Artemisia sieberi was collected from Hail, Saudi Arabia, and its essential oil was obtained via hydrodistillation. The oil's activity against HCT116, HepG2, A549 and MCF-7 cells was assessed using SRB assay, while its anti-metastatic potential was assessed via a migration assay. Cell-cycle analysis and apoptosis assay were conducted via flow cytometry, while protein expression levels were investigated using Western blotting. The oil's chemical constituents were identified using GCMS. RESULTS: ASEO exerted its highest cytotoxic activity against MCF-7 with an IC50 value of 38.7 µg/ml. Further studies showed that the oil inhibited MCF-7 cells' migration, induced S-phase arrest and apoptosis. Western blot analysis showed no change in the expression level of caspase-3 after treatment, indicating the induction of caspase-independent apoptosis-like cell death in MCF-7. Treatment of MCF-7 with the oil resulted in downregulation of the protein expression levels of total ERK and its downstream target, LC3, indicating that any potential activation of the ERK signalling pathway during the cancer cells' growth would be inhibited. Finally, GCMS analysis identified the oil's major components as cis-crysanthenyl acetate (48.56%), davanone (10.28%), 1,8-cineole (6.81%) and caryophyllene diepoxide (5.34%), whereby it is suggested that these compounds might be responsible for the oil's bioactivity. CONCLUSION: ASEO possessed in vitro anticancer activity and modulated the ERK signalling pathway. This is the first study to explore the anticancer potential of ASEO in detail and reflects the significance of investigating essential oils from medicinal plants that have been traditionally used against cancer. This work might pave the way for further in vivo studies that could result in developing the oil into a natural effective anticancer treatment.

Chemical Composition, Antibacterial Activity and In Vitro Anticancer Evaluation of Ochradenus baccatus Methanolic Extract.

Background and Objectives: Ochradenus baccatus belongs to the family Resedaceae. It is widely spread in Saudi Arabia and other countries in Southwest Asia. O. baccatus is extensively used in traditional medicine as an anti-inflammatory and antibacterial agent, in addition to being a vital source of food for certain desert animal species. The aim of the present study was to investigate the chemical composition and antibacterial/anticancer activities of O. baccatus methanolic extracts collected from Hail, Saudi Arabia. Materials and Methods: The O. baccatus extracts were obtained by macerating the crude powder in methanol, followed by filtration and evaporation. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the methanolic extracts' chemical constituents. Broth microdilution assay for minimum inhibitory concentration (MIC) determination was used to assess antimicrobial activity, while the extracts' anticancer potential was assessed by sulforhodamine B Assay (SRB) assay. Results: The results of the antibacterial assay showed that the methanolic extracts from the roots and branches possessed varying degrees of activity against particular bacterial strains, with the highest activity being exerted by the branches' extract against Escherichia coli and Salmonella typhimurium (St), demonstrating MIC values of 15.6 µg/mL and 20 µg/mL, respectively. Furthermore, the SRB cell viability assay revealed that only the branches' extract inhibited the growth of A549 cancer cells, with an IC50 value of 86.19 µg/mL. The LC-MS analysis of the methanolic extracts from the plant's roots and branches was then conducted, resulting in the identification of 8 and 13 major chemical constituents, respectively. Azelaic acid, ß-amyrin, and phytanic acid are some of the bioactive compounds that were detected in the extracts via LC-MS, and they are thought to be responsible for the observed antibacterial/anticancer activity of O. baccatus methanolic extracts. Conclusions: This study confirmed the antibacterial/anticancer potential of O. baccatus methanolic extracts and analyzed their phytochemical constituents. Further isolation and biological screening are warranted to understand the therapeutic potential of O. baccatus.

Metformin Therapy and Breast Cancer Incidence in the Ha'il Region.

BACKGROUND: Metformin is a drug used to treat patients with type 2 diabetes, especially those who suffer from obesity. It is also used in the treatment of women with polycystic ovary syndrome (PCOS). This disease is related to insulin resistance and multiplied blood sugar ranges. Furthermore, it has been established that the use of metformin improves the menstrual cycles and ovulation rates of these women. METHODS: A structured questionnaire was conducted to determine the prevalence of breast cancer among women using metformin in the Ha'il region. RESULT: The incidence of breast cancer among women using metformin in the Ha'il region is very low. Thus, it can be said that breast cancer cases declined among diabetics taking metformin. This means that metformin use is associated with a lower risk of breast cancer in women with type 2 diabetes, even in cases where these women have a family history of breast cancer. CONCLUSIONS: According to previous findings, metformin has been linked to lower breast cancer risk in women with type 2 diabetes. Furthermore, the findings of this study corroborate the literature on this subject by indicating that there is a substantial connection between metformin use and a lower risk of breast cancer in women with type 2 diabetes. However, further in vitro and in vivo experiments are crucial to investigate the protective effect of metformin against breast cancer and to confirm our findings.