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Six novel proton transfer compounds ( 15–20 ) obtained from 5-sulfosalicylic acid ( 1 ) and 2-aminopyridine derivatives [2-amino-3-benzyloxypyridine ( 2 ), 2-amino-3-hydroxylpyridine ( 3 ), 2-amino-3-methylpyridine ( 4 ), 2-amino-3-nitropyridine ( 5 ), 2-amino-3-nitro-4-methylpyridine ( 6 ) and 2-amino-3-nitro-6-methylpyridine ( 7 )] and their Cu(II) complexes ( 21 – 26 ) along with the Cu(II) complexes of 2–7 ( 9–14 ) have been prepared and characterized by spectroscopic techniques. The in vitro inhibition effects of all compounds on CA IX and CA XII isozymes as well as on hCA I and hCA II were investigated and the results were compared. The inhibition studies showed that the synthesized compounds are more selective to CA XII isozyme. The hydratase IC 50 values of the compounds were determined as in the range of 15.61 ± 2.32 µM–99.02 ± 4.99 µM for hCA I, 22.36 ± 0.75 µM–77.03 ± 4.03 µM for hCA II, 23.90 ± 1.67 µM–138.63 ± 5.45 µM for CA IX, and 9.50 ± 1.16 µM–693.15 ± 8.96 µM for CA XII. The inhibition data have been analyzed using one-way analysis of variance for multiple comparisons ( p  < 0.0001).

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1 H-NMR, 13 C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. K i values of the compounds were in the range of 0.063–3.368 µM for hCA I and 0.007–4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a , 6b and the reference inhibitor, acetazolamide ( AAZ ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ . ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations. Graphical abstract Synthesis, molecular docking, molecular dynamics simulations, drug-likeness, ADMET prediction and biological evaluation of pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors

Surgery is one of the most effective treatment methods for liver metastases developing from primary colorectal cancer (CRC). Despite the widespread application of surgical approaches, recurrence rates remain substantial. Although chemotherapy is frequently employed, the supporting evidence for its efficacy in this context remains inconclusive. In the present study, we aimed to identify potential predictors of post-metastasectomy recurrence by analyzing clinical, pathological, and molecular features of both primary colorectal tumors and their corresponding hepatic metastases. Specifically, we evaluated the expression of epithelial–mesenchymal transition (EMT) markers, cancer stem cell (CSC) markers, and selected oncogenic mRNAs (RAS, mTOR, and CMYC) in tissue samples from 84 patients. RAS and CMYC are well-known proto-oncogenes involved in cell proliferation and survival, while mTOR functions as a central regulator of cell growth and metabolism. Following liver metastasectomy, intra-hepatic recurrence was observed in 40.5% of the cases. Among the molecular markers analyzed, the EMT transcription factor SNAIL—which plays a critical role in cancer cell invasion and metastasis—and mTOR exhibited significantly elevated expression in metastatic lesions from patients who experienced recurrence. While SNAIL expression did not show a clear association with the time to recurrence, increased mTOR expression in metastatic liver tissue was significantly associated with both shorter recurrence-free survival and diminished overall survival (p < 0.001). Results showed that mTOR expression levels could be a clinically relevant predictive indicator of remnant liver recurrence. In patients with liver metastases, the use of mTOR inhibitors may be considered after hepatic metastasectomy.

Purpose Incremental peritoneal dialysis (IPD) could decrease unfavorable glucose exposure results and preserve (RKF). However, there is no standardization of dialysis prescriptions for patients undergoing IPD. We designed a prospective observational multi-center study with a standardized IPD prescription to evaluate the effect of IPD on RKF, metabolic alterations, blood pressure control, and adverse outcomes. Methods All patients used low GDP product (GDP) neutral pH solutions in both the incremental continuous ambulatory peritoneal dialysis (ICAPD) group and the retrospective standard PD (sPD) group. IPD patients started treatment with three daily exchanges five days a week. Control-group patients performed four changes per day, seven days a week. Results A total of 94 patients (47 IPD and 47 sPD) were included in this study. The small-solute clearance and mean blood pressures were similar between both groups during follow-up. The weekly mean glucose exposure was significantly higher in sPD group than IPD during the follow-up ( p  < 0.001). The patients with sPD required more phosphate-binding medications compared to the IPD group ( p  = 0.05). The rates of peritonitis, tunnel infection, and hospitalization frequencies were similar between groups. Patients in the sPD group experienced more episodes of hypervolemia compared to the IPD group ( p  = 0.007). The slope in RKF in the 6th month was significantly higher in the sPD group compared to the IPD group (65% vs. 95%, p  = 0.001). Conclusion IPD could be a rational dialysis method and provide non-inferior dialysis adequacy compared to full-dose PD. This regimen may contribute to preserving RKF for a longer period.