Since the outbreak of SARS-CoV-2 in recent years, our society has become more aware that zoonotic diseases pose a real threat. Therefore, the demand for small molecules that target host proteins, essential for viral entry and replication, has increased as an interesting strategy for the development of antiviral agents, as these agents may be effective against several different pathogens. NAK kinases is one such potential target family because they are involved in a variety of cellular functions, hijacked by viruses to invade host cells, such as clathrin-mediated endocytosis. A large number of different inhibitors have already been reported targeting NAK kinases, but there are still no compounds that selectively target AAK1 over other NAK family members, in particular the closely related family member BIKE. Here, we developed a series of pyrazolo[1,5-a]pyrimidine-based macrocyclic NAK inhibitors, starting from the acyclic AAK1 inhibitor LP-935509. Through a structure-guided activity relationship study within the NAK family, we identified potent AAK1 inhibitors 16, 18 and 27, which show promising selectivity within the NAK family. The inhibitors showed a potent inhibition of the phosphorylation of the AP-2 complex and the antiviral activity of the compounds was evaluated against various RNA viruses.

• Klíčová slova
• AAK1, Antiviral, BIKE, Kinase inhibitors, Macrocycles, NAK,
• MeSH
• antivirové látky * farmakologie   chemie   chemická syntéza   MeSH
• inhibitory proteinkinas * farmakologie   chemie   chemická syntéza   MeSH
• intracelulární signální peptidy a proteiny * antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• makrocyklické sloučeniny * chemie   farmakologie   chemická syntéza   MeSH
• molekulární struktura MeSH
• nukleosidmonofosfátkinasa * antagonisté a inhibitory   metabolismus   MeSH
• protein-serin-threoninkinasy * antagonisté a inhibitory   metabolismus   MeSH
• pyrazoly * chemie   farmakologie   chemická syntéza   MeSH
• pyrimidiny * chemie   farmakologie   chemická syntéza   MeSH
• SARS-CoV-2 účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AAK1 protein, human MeSH Prohlížeč
• antivirové látky * MeSH
• inhibitory proteinkinas * MeSH
• intracelulární signální peptidy a proteiny * MeSH
• makrocyklické sloučeniny * MeSH
• nukleosidmonofosfátkinasa * MeSH
• protein-serin-threoninkinasy * MeSH
• pyrazolo(1,5-a)pyrimidine MeSH Prohlížeč
• pyrazoly * MeSH
• pyrimidiny * MeSH

BACKGROUND: Recent studies indicate a protective role of vitamin D supplementation against sports performance-induced dysregulation of body homeostasis. However, the effects of a single high dose of vitamin D on changes in bone formation and resorption markers due to ultramarathon running have yet to be explored. This study aimed to analyze the effect of a single high-dose vitamin D supplementation on serum levels of bone turnover markers after a mountain ultramarathon run. METHODS: In this clinical trial (reg. number NCT03417700), 35 semiprofessional male ultramarathon runners were assigned into two groups: supplemented group, administered a single high dose of vitamin D3 (cholecalciferol, 150,000 IU) in vegetable oil 24 h before the start of the run (n = 16), and placebo group (n = 19), administered placebo solution 24 h before the start of the run. Blood samples were collected for analysis at three timepoints: 24 h before, immediately after, and 24 h after the run. RESULTS: Serum 25(OH)D3 level significantly increased (p ≤ 0.05.) after the ultramarathon in both groups. The increase was more pronounced in the supplemented population, especially 24 h after the run (147.01% vs 84.71%). According to post-hoc and other analyses, the levels of N-terminal propeptides of type I collagen, a PINP marker, were increased immediately after the run. The increase was significantly higher in the supplemented group than in the control group. CTX, PTH, sclerostin, and procalcitonin levels were significantly higher 24 h after the run in the control group. CONCLUSIONS: The observed attenuation of post-exercise bone resorption and enhancement of bone formation suggest that vitamin D supplementation may modulate bone metabolism in response to extreme physical exertion, potentially through effects on calcium - PTH homeostasis.

• Klíčová slova
• CTX, PINP, Ultramarathon, sclerostin, skeletal muscle damage, vitamin D,
• MeSH
• běh * fyziologie   MeSH
• biologické markery krev   MeSH
• cholekalciferol * aplikace a dávkování   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• kalcifediol krev   MeSH
• kolagen typu I krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• maratonský běh * fyziologie   MeSH
• parathormon krev   MeSH
• peptidové fragmenty MeSH
• peptidy MeSH
• potravní doplňky * MeSH
• prokolagen krev   MeSH
• remodelace kosti * účinky léků   MeSH
• vitamin D aplikace a dávkování   krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• biologické markery MeSH
• cholekalciferol * MeSH
• collagen type I trimeric cross-linked peptide MeSH Prohlížeč
• kalcifediol MeSH
• kolagen typu I MeSH
• parathormon MeSH
• peptidové fragmenty MeSH
• peptidy MeSH
• procollagen Type I N-terminal peptide MeSH Prohlížeč
• prokolagen MeSH
• vitamin D MeSH

Human aldo-keto reductase 1C3 (AKR1C3) is a steroid modifying enzyme involved in cancer progression. Here, A-ring modified 17α-picolyl and 17(E)-picolinylidene androstane derivatives are shown to inhibit AKR1C3 activity in vitro. None of the androstane derivatives have off-target affinity for the androgen receptor, based on a fluorescence assay in yeast cells. The X-ray structure of AKR1C3 in complex with the strongest inhibitor, a 17α-picolyl androstane with a C3-oxime modification, was determined at 1.7 Å resolution. Based on this crystal structure and molecular docking, inhibition of AKR1C3 by the 17α-picolyl or 17(E)-picolinylidene derivatives depends on interactions between the C3 modification and the NADP+ cofactor, while the C17α-picolyl or C17-picolinylidene group anchors the inhibitor to AKR1C3. Because one AKR1C3 inhibitor identified here was also previously reported to inhibit CYP17, it may be possible for future researchers to design dual AKR1C3/CYP17 inhibitors based on a steroid scaffold for potential treatment of advanced prostate cancers.

• Klíčová slova
• AKR1C3, CYP17, molecular docking, prostate cancer, protein X-ray crystallography,
• MeSH
• androstany * chemie   farmakologie   chemická syntéza   MeSH
• inhibitory enzymů * farmakologie   chemie   chemická syntéza   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární struktura MeSH
• protein AKR1C3 * antagonisté a inhibitory   metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AKR1C3 protein, human MeSH Prohlížeč
• androstany * MeSH
• inhibitory enzymů * MeSH
• protein AKR1C3 * MeSH

We designed and synthesised a series of thiazolidinediones and related analogues and evaluated their antiparasitic activity. A structure-activity relationship (SAR) study focused on modifications of specific parts of the molecule revealed derivatives that displayed significant activity against Trypanosoma brucei species. Notably, the analogue 6i exhibited exceptional activity, with an EC50 value of 30 nM and a selectivity index of >2000, against the protozoan Trypanosoma brucei rhodesiense, which causes human African trypanosomiasis. Additionally, compounds 6a, 6k, 7e, and 18 demonstrated antitrypanosomal activities in the less than 5 μM range. Our most active analogue 6i represents a promising candidate for further preclinical development.

• Klíčová slova
• Animal African trypanosomiasis, Antiparasitic agents, Human sleeping sickness, Protozoan diseases, Thiazolidinediones, Trypanosoma brucei, Trypanosomiasis,
• MeSH
• lidé MeSH
• molekulární struktura MeSH
• parazitické testy citlivosti MeSH
• thiazolidindiony * farmakologie   chemie   chemická syntéza   MeSH
• trypanocidální látky * farmakologie   chemie   chemická syntéza   MeSH
• Trypanosoma brucei brucei účinky léků   MeSH
• Trypanosoma brucei rhodesiense * účinky léků   MeSH
• trypanozomóza africká farmakoterapie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• thiazolidindiony * MeSH
• trypanocidální látky * MeSH

A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)-substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η6-pcym)Cl(L)]PF6 (1-4) and [Os(η6-pcym)Cl(L)]PF6 (5-8) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (9-12) and iridium(III) (13-16) [M(η5-Cp∗)Cl(L)]PF6 complexes; L = ethane-1,2-diamine-based Schiff bases (L1-L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), Cp∗ = pentamethylcyclopentadienyl. Biological testing demonstrated that 1-8 possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex 5 showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.

• Klíčová slova
• Antiproliferative activity, Endoplasmic reticulum, Mitochondria, Osmium, Ruthenium, Stress gene expression,
• MeSH
• komplexní sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• organokovové sloučeniny * farmakologie   chemie   chemická syntéza   MeSH
• osmium * chemie   farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• ruthenium * chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• stres endoplazmatického retikula * účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• komplexní sloučeniny * MeSH
• organokovové sloučeniny * MeSH
• osmium * MeSH
• protinádorové látky * MeSH
• reaktivní formy kyslíku MeSH
• ruthenium * MeSH

Coumarins are well-known for their unique chemical structure and a wide range of biological effects. Various substituted coumarin-based compounds have emerged as promising candidates for the development of novel therapeutic agents against numerous diseases. This study was focused on the synthesis of new 4,7-disubstituted coumarin derivatives and investigation of their ability to inhibit the aggregation of Aβ40 peptide, their cytotoxic effect on SH-SY5Y cells, their antioxidant properties, and their ability to penetrate the blood-brain barrier (BBB). The results revealed that the trihydroxy derivatives 5a-c had been the most effective inhibitors of Aβ aggregation, promoting the formation of non-toxic, amorphous aggregates instead. Importantly, no significant decrease in the viability of SH-SY5Y neuroblastoma cells was observed after treatment with the studied coumarins. Among them, coumarin 5a demonstrated the strongest antioxidant activity, while compound 5b also exhibited good antioxidant properties, along with the best inhibition of Aβ aggregation (IC50 = 13.5 μM), and adequate permeability across the blood-brain barrier. These findings suggest that compound 5b is a promising candidate for further investigation in Alzheimer's disease pharmacotherapy.

• Klíčová slova
• Alzheimer's disease, Amyloid aggregation, Antioxidant activity, Aβ peptide, Cell viability assay, Coumarin derivatives,
• MeSH
• amyloidní beta-protein * antagonisté a inhibitory   metabolismus   MeSH
• antioxidancia * farmakologie   chemie   chemická syntéza   MeSH
• hematoencefalická bariéra metabolismus   MeSH
• kumariny * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• peptidové fragmenty * metabolismus   antagonisté a inhibitory   MeSH
• proteinové agregáty účinky léků   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• antioxidancia * MeSH
• coumarin MeSH Prohlížeč
• kumariny * MeSH
• peptidové fragmenty * MeSH
• proteinové agregáty MeSH

Insertion of a heterocyclic ring into the steroid core could enhance bioactivity, improve selectivity and reduce side effects in potential drugs for cancer therapy. The present study describes the synthesis of new thiazoline, thiadiazoline and thiazolidinone steroid compounds combined with lactone, lactam or pyridine moieties. These steroid hybrid molecules may be potential candidates for drug design, with improved biological activity and bioavailability. The starting androstenedione or dehydroepiandrosterone were modified by multiphase synthesis into thiosemicarbazone androstane derivatives, direct precursors for the synthesis of new heterocyclic compounds. Their cytotoxicity was tested against five cancer cell lines: breast adenocarcinoma cells (MCF7), acute lymphoblastic leukemia (CCRF-CEM), cervical carcinoma cells (HeLa), hormone-independent (DU 145) and hormone-sensitive prostate cancer cells (LNCaP), as well as against normal skin fibroblasts (BJ). Compounds 5 and 16 were found to be the most selective, with both inducing apoptosis in HeLa cells. New compounds were also evaluated for their relative binding affinities for the ligand-binding domains (LBDs) of estrogen receptor α (ERα), estrogen receptor β (ERβ), androgen receptor (AR) or glucocorticoid receptor (GR) using a fluorescent assay in yeast cells, where thiazole derivative 13 exhibited the highest binding affinity for ERα, while thiazolidinone 7 showed strong selective affinity for ERβ. Furthermore, inhibition potential against human aldo-keto reductase 1C3 and 1C4 (AKR1C3 and AKR1C4) was evaluated by fluorescence spectroscopy, with acetamido thiadiazoline 21 displaying an IC50 value for AKR1C3 slightly higher than the reference inhibitor ibuprofen. Molecular docking studies were used to propose protein-ligand binding models for compounds showing the strongest affinity toward specific proteins based on in vitro experiments. In summary, our results suggest that the tested heterocyclic derivatives are active against hormone-dependent cancer cells and represent promising leads for the development of novel therapeutics.

• Klíčová slova
• Androstane, Cytotoxic activity, Hormone receptors, Molecular docking, Molecular hybridization, Thiadiazoline, Thiazolidinone, Thiazoline,
• MeSH
• androgenní receptory metabolismus   MeSH
• androstany * farmakologie   chemie   chemická syntéza   MeSH
• apoptóza účinky léků   MeSH
• heterocyklické sloučeniny * chemie   farmakologie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemická syntéza   chemie   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• androgenní receptory MeSH
• androstane MeSH Prohlížeč
• androstany * MeSH
• heterocyklické sloučeniny * MeSH
• protinádorové látky * MeSH

A series of triterpenoids of the lupane, taraxastane, friedelane and baccharane type were oxidized using selenium dioxide (SeO2) and benzeneseleninic anhydride (BSA) under various conditions. Depending on the reaction conditions, different reaction pathways were observed, including dehydrogenation, allylic oxidation, and 1,2-diketone formation. In this way, derivatives functionalized in the triterpene core (especially in rings A, D, and E), difficult to obtain by other methods, can be easily prepared. In some cases, rarely observed α-phenylseleno-ketones were isolated. An unexpected reaction involving the cleavage of the carbon-carbon double bond was observed in the presence of stoichiometric amounts of osmium tetroxide. Further transformations of selected intermediates facilitated the synthesis of new, functionally enriched derivatives. The key reaction pathways were investigated using density functional theory (DFT), focusing on bond length variations and transition states, revealing energetically favored pathways and critical transition structures, including covalent and noncovalent interactions. Solvent and isomerization equilibrium effects were proposed to explain the experimentally observed discrepancies. Cytotoxic activity of selected derivatives was investigated. Derivatives 4 and 38 showed strongest cytotoxicity in cancer cells and fibroblasts (IC50 2.6-26.4 μM); some compounds were selective for G-361 or HeLa cells. These results suggest that they may find application in pharmaceuticals.

• Klíčová slova
• BSA oxidation, Cytotoxic activity, Cytotoxicity of O-Mesylates, DFT calculations, Oxidation of triterpenoids, SeO(2) oxidation, α-phenylseleno-ketone,
• MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• oxidace-redukce MeSH
• pentacyklické triterpeny MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv MeSH
• selen * chemie   MeSH
• teorie funkcionálu hustoty MeSH
• triterpeny * chemie   farmakologie   chemická syntéza   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• lupane MeSH Prohlížeč
• pentacyklické triterpeny MeSH
• protinádorové látky * MeSH
• selen * MeSH
• triterpeny * MeSH

BACKGROUND: Sacituzumab govitecan (SG) is approved for metastatic triple-negative breast cancer in ≥ 2 line setting at 10 mg/kg IV on Days 1 and 8 (21-day cycle). Trials confirmed its superiority over 8 mg/kg with manageable safety. In practice, precautionary dose reductions are used despite no formal guidance. In Poland, fixed 200 mg vials and unreimbursed drug waste lead to early dose adjustments. METHODS: This retrospective study evaluated the impact of initial SG dose reduction on treatment outcomes and tolerability in Polish patients. Medical records provided data on baseline features, treatment, survival, and safety. Kaplan-Meier and chi-square tests were used for survival and group comparisons. A multivariate Cox model assessed the independent effect of dose reduction on overall survival (OS) and progression-free survival (PFS). Significance was set at p < 0.05. RESULTS: Among 83 patients (median age 55, range 30-86), initial dose reductions ≥ 10% were observed in 16 patients (19.3%), including 9 (10.8%) with dose reduced ≥ 20%. Administrative adjustments (reductions > 10% to flat doses of 200 mg multiplications) accounted for 18.1% of the entire cohort. Grade ≥ 2 and ≥ 3 adverse events occurred in 83.1% and 56.6%, respectively. In a multivariate analysis, a ≥ 20% initial dose reduction remained an independent predictor of shorter PFS (HR: 2.6; 95% CI: 1.1-6.6; p = 0.04) and OS (HR: 6; 95% CI: 2-17.5; p = 0.001). Initial dose reduction did not affect toxicity. CONCLUSIONS: In this preliminary report initial dose reduction of SG negatively impacted PFS and OS without reducing toxicity, highlighting the need for further studies and dosing policy adjustments.

• Klíčová slova
• Dose reduction, Metastases, Real world data, Sacituzumab govitecan, Triple negative breast cancer,
• MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   MeSH
• imunokonjugáty MeSH
• kamptothecin * analogy a deriváty   aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• triple-negativní karcinom prsu * farmakoterapie   patologie   mortalita   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Polsko MeSH
• Názvy látek
• humanizované monoklonální protilátky * MeSH
• imunokonjugáty MeSH
• kamptothecin * MeSH
• sacituzumab govitecan MeSH Prohlížeč

Bisphenols are frequently used in the plastic industry. However, there is a need for addressing their safety in in vivo studies based on the observed negative impact of bisphenol A. Bisphenol AP (BPAP) is frequently found in the environment, human food, and biological fluids, but its cardiovascular effects have not yet been tested. For this reason, we administered BPAP in a daily single dose of 2.5 mg.kg-1via oral gavage to eight male Wistar Han rats for a period of 4 weeks. Eight control rats received the solvent, sesame oil. Parent BPAP was detectable in plasma only in 3 animals by a validated LC-MS/MS method, whereas its glucuronide was found in all animals (48.4 ± 25.4 nM). Arterial blood pressure did not change during or at the end of the treatment. Some disturbances in cardiac rhythm were observed (e.g., increased heart rate, prolonged P wave and QTpeak interval, p < 0.05), but there was no increase in serum cardiac troponin T. Vessels isolated from BPAP-treated animals showed impaired vasodilatory response compared to control animals (p < 0.05). BPAP impacted coagulation and caused hemolysis only in hundreds of µM concentrations. These results demonstrate the potential of BPAP to affect cardiac rhythm and impair vessel homeostasis after subacute exposure.

• Klíčová slova
• Bisphenol, Cardiovascular, Endocrine disruptor, Hypertension, Pollutant,
• Publikační typ
• časopisecké články MeSH