Discovery of 8-sulfonamidoquinolines as anti-proliferative agents against colorectal cancer: design, synthesis, and biological evaluation.

From anti-proliferation to immunomodulation: engineering next-generation cardiovascular biomaterials.

In present work, a new series of modified curcumin analogs of bis(N-arylacetamides) (6-10) was synthesised in good yields. The synthesised compounds were characterised by spectral data and the curcumin hybrids 6-10 were evaluated in vitro by MTT assay for antiproliferative activity against four different human breast carcinoma cell lines. Compounds 10 and 7 show moderate to better IC50 ± SEM (µM) in the range of 66.52 ± 4.53 to 97.79 ± 3.63 and 71.28 ± 4.30 to 99.18 ± 5.99, respectively against MCF-7, MDA MB-231, MDA MB-436 and MDA MB-453 breast cancerous cell lines. Compounds 10 and 7 have shown a significant inhibition against all the cell lines. Cell cycle analysis of compound 10 in MCF-7 cells revealed a pronounced accumulation of the cell population in the S phase (63.67%), indicating effective S-phase arrest. This suggests that the compound interferes with DNA replication processes. Docking studies with EGFR2 have shown higher glide scores, -5.857 and -5.448 kcal/mol, respectively, for compounds 10 and 7. The results indicate that the curcumin-pyrazole bis(N-arylacetamide) hybrid adducts as a promising lead to develop as antiproliferative agents.

New conjugates of natural chlorins with doxorubicin featuring controlled release for combined photodynamic and chemotherapeutic treatment.

Breast and prostate cancer continue with high prevalence inside the top five. According to the global cancer statistics published by the American Cancer Society (2022), with approximately 20 million new cancer cases and almost 10 million related deaths each year, the need for more therapeutic options against cancer is evident. Therefore, proposing or repurposing drugs that can contribute to current treatments will be relevant in the healthcare sector. In recent years, following the COVID-19 pandemic, drug repurposing has increased, further amplified by the use of artificial intelligence (AI). In this way, using AI, we propose the drug Itopride as a potential antiproliferative agent in cancer. This effect was determined through in silico and in vitro assays. Therefore, through AI and drug repurposing, we propose Itopride as a potential adjuvant against prostate and breast cancer. This is justified by the cytotoxic and antiproliferative effects of Itopride observed in vitro cultures. Currently, Itopride is available in several countries and is primarily used as a prokinetic agent and for functional dyspepsia.

In cancer therapy, inhibiting tubulin polymerization is a key approach for modifying microtubule dynamics required for cell survival and proliferation. Microtubule destabilizing agents (MDAs), also known as tubulin polymerization inhibitors, prevent tubulin heterodimers from forming microtubules, resulting in catastrophic cellular collapse. A novel series of thiazole-based compounds 8a-o was developed to inhibit tubulin polymerization and assess for its antiproliferative efficacy against the NCI 60 cell line. The structures of the newly synthesized compounds were confirmed using 1H NMR, 13C NMR, and elemental microanalyses. All 15 compounds (8a-o) were assessed for antiproliferative action at a single dosage (10 μM) and analyzed against the comprehensive 60-cell panel at five concentrations (0.01, 0.1, 1, 10, and 100 μM). The results from the one-dose and five-dose studies demonstrate that 8b, 8c, 8d, 8m, and 8o are the most prominent antiproliferative agents, exhibiting the most favourable low-micromolar GI50 values across various cell lines, frequently advancing to low-micromolar TGI, and, in numerous sensitive cell lines, achieving LC50 values within the single-digit micromolar range. Compounds 8b, 8d and 8m showed significant anti-tubulin activity, with IC50 values ranging from 3.86 to 7.19 μM, compared to the reference CA-4 (IC50 = 2.40 μM). In the MCF-7 breast cancer cell line, compound 8m drove a significant accumulation of cells in the G2/M phase, increasing from 13.74% to 45.35%. G2/M arrest is frequently associated with DNA damage or the inhibition of microtubule dynamics, which aligns with Western blot results demonstrating a decrease in tubulin (50 kDa) expression following treatment with 8m. Apoptotic and necrotic experiments indicate that 8m stimulates a defined programmed cell death pathway rather than inducing non-specific toxic necrosis. Molecular docking corroborated their binding at the colchicine site, while in silico ADMET profiling indicated a promising drug-like profile for compound 8m.

Palmoplantar psoriasis is a socially significant form of chronic dermatosis leading to a marked decrease in the quality of life and limitation of work activity. The search for effective and safe treatment methods, especially in the presence of contraindications to systemic therapy, remains relevant. Objective. To evaluate the clinical efficacy and tolerability of pulsed dye laser in patients with palmoplantar psoriasis. Material and methods. Two clinical cases are described. The first patient (61 years old) received a combination of topical therapy (salicylic acid, betamethasone) and a course of pulsed dye laser. The second case (a patient with controlled type 2 diabetes mellitus and intolerance to methotrexate) was treated with pulsed dye laser after discontinuation of the cytostatic agent. Efficacy was assessed by the dynamics of the palmoplantar psoriasis severity index (PPASI). Results. Both patients showed significant positive dynamics. In the first case, the PPASI score decreased from 18 points to 1 point. In the second case, it decreased from 15 points to 0.5 points. There were no side effects from phototherapy. Conclusion. Pulsed dye laser demonstrated high efficacy and good tolerability in the treatment of palmoplantar psoriasis. This method can be considered an optimal treatment option, especially in the presence of comorbid conditions that limit the use of systemic medications.

The conventional triple immunosuppressive regimen administered following heart transplantation typically comprises a calcineurin inhibitor, an antiproliferative agent, and corticosteroids. Everolimus has emerged as a viable alternative to calcineurin inhibitors. This study aims to evaluate the immunosuppressive efficacy and adverse effect profile of everolimus when introduced after the first post-transplant year, in comparison to continued calcineurin inhibitor therapy. A retrospective analysis was conducted on 90 heart transplant recipients under regular follow up. Patients were categorized into two groups: those who maintained calcineurin inhibitor therapy beyond the first year post-transplant (n = 45), and those who transitioned to everolimus after the first year (n = 45). The groups were compared in terms of rejection incidence and side effects. Following the treatment modification, the everolimus group showed a significant improvement in serum urea and creatinine levels (p < 0.05). Rejection rates after the first year were found to be similar between the two groups. Everolimus provides effective immunosuppression with a lower rate of side effects.It demonstrates a favorable impact on renal function without increasing the risk of rejection.The first year may be recommended as the optimal timing, considering both safe wound healing and the risk of rejection.

Halogenated N’-(adamantan-2-ylidene)benzohydrazides as anti-proliferative agents: Supramolecular insights and EGFR-targeted docking and molecular dynamics studies

WCN26-4338 Acute Tubular Injury With Vacuolization After Palbociclib Exposure in a Patient With Advanced Breast Cancer

The use of cytostatic drugs for cancer treatment is currently the main weapon in the fight against cancer; however, prolonged exposure of healthcare personnel can cause adverse toxic effects. Objective: To determine the genotoxicity caused by exposure to cytostatic drugs, using the comet assay, in workers in the oncology department of a tertiary hospital in northern Peru. Methodology: Descriptive, quantitative, correlational, and cross-sectional study. The population consisted of two groups of workers: exposed (n = 40) and unexposed (n = 40). The alkaline lysis comet DNA technique was used on peripheral blood cells; tailing moment and tailing percentage indicators were evaluated. Results: Using nonparametric tests, the percentage and tail moment showed no significant differences, with p values of 0.8928 and 0.4675, respectively. The distribution observed in the group exposed to cytostatic drugs (pharmacists and pharmacy technicians) compared to the control group showed a normal distribution, with a tail moment of 8.29 vs. 3.03 and a percentage of tail of 37.12 vs. 23.24, respectively. Multivariate analysis showed that the tail moment variable was 11.56% greater in the group of pharmacists and pharmacy technicians (p = 0.0119) compared to the other participants. Conclusions: Although no significant difference was found, a trend toward a higher percentage and tail moment was observed in the group exposed to cytostatic drugs. Furthermore, the group of pharmacists and pharmacy technicians, compared to the other professions, showed significantly greater damage.

Bladder neck contracture is considered one of the most common late complications of transurethral treatment of benign prostatic hyperplasia. Its incidence ranges from 0 to 10%–15%, reaching even higher values in the presence of risk factors, the most frequently discussed of which is a small volume of prostatic hyperplasia. The first stage of surgical treatment of benign prostatic hyperplasia involves transurethral incision or resection of the bladder neck; however, during long-term follow-up, the recurrence rate after this procedure may reach 50%–70%. In this context, various minimally invasive approaches to the management of bladder neck contracture have been proposed to improve treatment efficacy and safety. One such approach is balloon dilation of the bladder neck, which involves mechanical expansion of the fibrotic ring to stabilize the process at a urodynamically acceptable level. Balloon dilation may be combined with targeted pharmacological action of a drug directly on the affected tissue in parallel with mechanical expansion of the bladder neck. For this purpose, the balloon surface is coated with antiproliferative and antifibrotic agents. One such agent is the glucocorticoid methylprednisolone. In the present study, we report a clinical case of balloon dilation using a, ultrasound-triggered urethral catheter with a biopolymer drug-eluting coating (methylprednisolone) and provide illustrative visualization. Over a follow-up period of 31 months, the described patient with previously recurrent bladder neck contracture showed no recurrence of the condition.

Abstract Background Drug-eluting stents (DES) have largely solved late thrombosis in most PCI patients. The remaining challenge concerns those at high bleeding risk (HBR, 30–40%), where balancing ischemic and bleeding events remains unresolved. Safely shortening dual antiplatelet therapy (DAPT) is now a key unmet need. For a novel stent to tolerate reduced DAPT, it must resist early thrombogenic triggers and promote rapid endothelial recovery. High-barotrauma implantation (balloon-to-artery ratio &amp;gt;1.3) induces severe vascular injury and delayed healing, forming a stringent preclinical model. A novel CD31 endothelial-mimetic coating based on SP1072, a 16-amino-acid peptide reproducing a key motif of CD31 domain 1 mediating homophilic interactions governing blood homeostasis, provides a biomimetic surface restoring anti-thrombo-inflammatory signaling without drug elution. Purpose To evaluate, by quantitative coronary angiography and OCT, the mechanical and physiological performance of an SP1072-coated cobalt–chromium stent compared with an everolimus-eluting stent (Xience, Abbott Vascular, USA) in a porcine coronary model under deliberate high barotrauma. Methods Twelve CD31-coated and six DES were implanted in the LAD, LCX, and RCA of eight pigs (mean BAR &amp;gt;1.3). Quantitative coronary angiography (QCA), fractional flow ratio (µFR), OCT-derived FFR (OFR), and volumetric OCT analyses were performed at baseline and one month. Results At implantation, BAR averaged 1.33 ± 0.20 (CD31) vs 1.34 ± 0.09 (DES); acute recoil was higher for CD31 (6.0 ± 1.6 % vs 3.2 ± 2.2 %, p = 0.02). After one month, MLD (2.21 ± 0.48 mm vs 2.20 ± 0.47 mm), % diameter stenosis (23.5 ± 12.3 vs 18.6 ± 13.5), µFR (0.94 ± 0.08 vs 0.96 ± 0.03), and OFR (0.94 ± 0.07 vs 0.96 ± 0.03) were comparable. OCT confirmed complete strut coverage and no thrombus or malapposition. Minimum stent area (4.71 ± 1.58 mm² vs 3.57 ± 1.77 mm², p = 0.26) and mean lumen area (5.60 ± 1.45 mm² vs 4.76 ± 1.75 mm², p = 0.38) were numerically higher for CD31, while neointimal volume (37.9 ± 21.3 mm³ vs 28.1 ± 5.6 mm³, p = 0.20) and stent volume (122.3 ± 18.2 mm³ vs 98.5 ± 26.3 mm³, p = 0.12) were greater. Conclusion Even under extreme mechanical stress known to delay endothelial recovery, the CD31-coated stent preserved lumen geometry and flow comparable to a DES while achieving complete endothelial coverage without drug release. Higher minimum stent and mean lumen areas suggest maintained expansion and limited neointimal growth despite the absence of antiproliferative drug. These findings indicate that the CD31 coating preserves mechanical integrity and vascular compatibility even in a stringent injury model, warranting further evaluation under standard implantation (BAR ≈ 1.05) and high-bleeding-risk conditions. By promoting rapid vascular healing without an antiproliferative agent, this biomimetic approach may represent a path toward safer DAPT de-escalation in interventional cardiology.

A series of pyrazolo pyrimidinone derivatives was designed and evaluated as estrogen inhibitors. The newly synthesized compounds were tested for their antiproliferative activity on 60 NCI cell lines. Compound 5a emerged as the most potent antiproliferative agent, with a mean growth inhibition percentage (GI%) of 111.5%, followed by compounds 5b, c, d. The NCI selected compounds 5a and 5b for five-dose assay, yielding GI50 values of 2.57-17.7µM and 11.1-24.1µM, respectively. Furthermore, flowcytometry analysis of the cell cycle on the MCF-7 cell line revealed that compounds 5a-d induced cell cycle arrest at the G1 phase. Moreover, western blot was done for compounds 5a and 5b, showed two-fold greater potency than tamoxifen at 10µM. The cytotoxicity of compounds 5a-d was evaluated against a normal human skin fibroblast cell line (HSF), which exhibited favorable safety profiles. A molecular docking study was conducted to investigate the binding mode and affinity of the new compounds to the estrogen alpha receptor (ERα). Finally, molecular dynamics simulations of compounds 5a and 5b were performed to support the stability of the protein-ligand complexes. Compounds 5a and 5b showed remarkable activity toward tumors which have higher estrogen expression.

The tumor suppressor protein p53 orchestrates cellular responses to stress by regulating the transcription of target genes involved in processes such as cell cycle control, DNA damage repair and apoptosis. The protein kinase DYRK1B, known to promote cancer cell survival and contribute to DNA damage repair, is overexpressed in various tumor types. Here, we demonstrate that expression of DYRK1B - but not its closely related paralog DYRK1A - is upregulated by cytostatic drugs (Actinomycin D, Doxorubicin) in multiple cancer cell lines. This induction required functional p53 and was mediated by p53-dependent activation of the transcription factor RFX7. Furthermore, we show that DYRK1B physically interacts with RFX7 and counteracts its activation by p53, thereby establishing a negative feedback loop that attenuates RFX7-dependent gene expression. This inhibitory effect of DYRK1B was strictly dependent on its catalytic activity and could be blocked by using small-molecule DYRK1 inhibitors. In conclusion, our study identifies DYRK1B as an indirect p53 target that suppresses p53-mediated activation of RFX7. These findings suggest that pharmacological inhibition of DYRK1B may represent a therapeutic strategy to enhance RFX7 tumor suppressor function.

The structural and functional features of the endothelium during arteriovenous anastomosis formation in rabbits, and the effect of antiplatelet and antiproliferative agents on endothelial dysfunction over time (on the 10th, 30th, and 90th days after surgery), were studied. The experiment confirmed the pleiotropic properties of platelet P2Y12 receptor inhibitors, including clopidogrel and phosphodiesterase III, as well as the antiplatelet activity of cilostazol, particularly their effect on the synthesis of markers of endothelial dysfunction. It was found that monotherapy with antiplatelet agents is accompanied by a decrease in the content of endothelin-1 (ET-1) and inducible NO synthase (iNOS) in the blood serum by 44–71% and 46–79%, respectively, during observation (most significantly on the 10th and 90th days after anastomosis formation) compared to the control (formation of a connection without pharmacological correction). The effectiveness of topical application of a biodegradable film saturated with the calcineurin inhibitor tacrolimus is most strongly manifested on the 30th day of observation. Local application of tacrolimus in combination with antiplatelet therapy provides optimal indices of the endothelium functional state throughout the observation period. On the 30th day of the examination, the content of ET-1 under conditions of combined therapy decreased by 21 and 28%, and iNOS decreased by 32 and 23%, respectively, compared to the values of similar indexes against the background of using only clopidogrel or cilostazol, respectively. Under the studied conditions, on the 10th day of observation, the NO2- content in the blood serum of the animals in the control group exceeded baseline values (i.e., values before surgery) by 37%. In contrast, against the background of pharmacological correction, the values of the index were 14–33% lower. Morphological examination of the surgical site under the conditions of combined use of antiaggregant and immunosuppressive drugs revealed a decrease in the intensity of smooth muscle cell proliferation and extracellular matrix in the subendothelial layer, confirming the effectiveness of the proposed method for preventing stenotic processes in the vascular anastomosis site. Important aspects include preservation of the structure of the vascular walls with good adventitial vascularization in groups undergoing complex correction. The obtained results are confirmed by the data of ultramicroscopic examination of the vascular wall components' structure. Thus, experiments have proven the effectiveness of combining antiaggregant and topical immunosuppressive therapies in reducing the risk of endothelial dysfunction developing at arteriovenous anastomosis sites.

Azofuranone was transformed into a series of pyrazole-based hydrazones with 71–79% yields through hydrazinolysis using hydrazine hydrate at room temperature followed by condensation with selected aromatic aldehydes in refluxing ethanol. The antiproliferative activity of the obtained derivatives was evaluated against MCF-7 (breast) and HCT-116 (colon) cancer cell lines using the MTT assay. Among the tested compounds, the chlorobenzylidene derivative (3a) exhibited the most pronounced cytotoxic activity (IC50 = 6.33 ± 1.3 µM against HCT-116 and IC50 = 8.61 ± 1.6 µM against MCF-7), while the remaining hydrazones also showed moderate to strong effects in both cell models. Computational target predictions suggested possible involvement of kinase-related pathways. Molecular docking studies were performed using CDK2 (PDB ID: 2 A4L) to explore potential binding modes. Compound 3a displayed a favorable docking score compared with the reference ligands and formed hydrogen-bond interactions with key residues within the active site. Molecular dynamics simulations indicated stable ligand–protein interaction patterns over the simulation period. In addition, in silico ADME analysis revealed acceptable physicochemical and pharmacokinetic characteristics, with compound 3a demonstrating the most balanced profile. Overall, the combined biological and computational findings identify compound 3a as a promising scaffold for further optimization in the development of antiproliferative agents.

Introducing fluorineinto monosaccharides, or their incompleteacylation that leaves the anomeric group unprotected, can impart antitumorproperties to the resulting glycomimetics. This property could beexploited in the development of new antiproliferative agents. Herein,we report the synthesis and antiproliferative activity of a completeseries of deoxyfluorinated analogs of acylated N-acetylmannosamine(ManNAc) hemiacetals, which combine both aforementioned structuralfeatures. In addition, retentive deoxyfluorination at C4 of a 1,6-anhydro-β-d-mannopyranose derivative provided access to 3,4-difluoro and3,4,6-trifluoro talosazides (TalN3). Attempted conversionof the fluorinated talosazides to fluorinated N-acetyltalosamine(TalNAc) analogs was prevented by unwanted reactions, partly arisingfrom an elimination-addition mechanism. The in vitro antitumor activity of the fluoroanalogs against MDA-MB-231 breastcancer cells was investigated using an MTT proliferation assay, acolony forming assay, a wound healing assay, and cell cycle analysis.The trifluorinated ManNAc analog showed the most pronounced antiproliferativeactivity. In addition, Western blot analysis indicated the inductionof programmed cell death in MDA-MB-231 cells.

Objective: Pancreatic cancer remains one of the most aggressive malignancies with limited therapeutic options, emphasizing the need to identify novel antiproliferative agents. Empagliflozin, a sodium–glucose co transporter-2 (SGLT2) inhibitor widely used in the treatment of type 2 diabetes, has recently gained attention due to its potential anticancer and metabolic regulatory properties. The present study aimed to investigate the antiproliferative effects of empagliflozin on the human pancreatic cancer cell line Mia PaCa-2. Methods: Mia PaCa-2 cells were cultured under standard conditions and treated with increasing concentrations of empagliflozin (0.1–20 µM). Cell viability was assessed at 24, 48, and 72 hours using the MTT assay. Morphological alterations in treated cells were evaluated by phase-contrast microscopy. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. Results: Empagliflozin significantly reduced cell viability in a time- and concentration-dependent manner. At 24 hours, significant inhibition was observed at 2–20 µM. At 48 hours, significant reductions occurred at 0.5–20 µM. The strongest inhibitory effect was observed at 72 hours, where all tested concentrations significantly decreased cell viability compared with control. The highest concentration (20 µM) reduced viability to approximately 37.4%. Morphological analysis confirmed decreased cell density, cell rounding, and detachment. Conclusion: These findings demonstrate that empagliflozin exerts a significant antiproliferative effect on Mia PaCa-2 cells in a time- and dose-dependent manner, suggesting that empagliflozin may represent a promising candidate for further investigation as a potential therapeutic agent against pancreatic cancer.

The advanced stages of hepatocellular carcinoma (HCC) are challenging to treat because of the invasion of blood vessels by malignant cells, as well as underlying cirrhosis in most patients. Current chemotherapeutic approaches are hindered by limited efficacy, systemic toxicity, and drug resistance. Therefore, developing new chemotherapeutic agents that can be used alone or as part of a cocktail regimen could aid in the treatment of HCC patients. This study primarily focuses on a cathepsin inhibitor and its antiproliferative effects on HCC cell lines in vitro and in HCC tumor xenografts in mouse models. The results show that the inhibitor has significant antiproliferative effects on the Hep G2 and Hep 3B cell lines, with low micromolar CC50 values. Furthermore, the compound inhibits both recombinant and endogenous cathepsin L and cathepsin S in a time-dependent manner. In mice, significant reductions in the growth of subcutaneous tumors relative to controls were observed, and it is well-tolerated when compared to Doxorubicin and Sorafenib. Transcriptomics analysis using RNA-Seq revealed that genes involved in regulating cell death, cell proliferation, and cellular processes were enriched in a time- and dose-dependent manner. Overall, the cathepsin inhibitor appears to be a promising starting point for further investigation as an antiproliferative agent.