Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related deaths worldwide. We recently showed that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of HCC. Synthetic LXRα agonists induce the production of toxic saturated fatty acids in tumor cells. When combined with DFG-out Raf inhibitors, which block fatty acid desaturation by inducing proteasomal degradation of stearoyl-CoA desaturase (SCD1), LXRα activation can trigger lipotoxicity-induced cancer cell death. However, the clinical translation of this therapeutic strategy is limited by the lack of specific LXRα agonists for clinical use. Here, we have developed a series of promising maleimide LXR agonists with increased potency for LXRα and enhanced specificity. Our agonist frontrunner 40 shows high selectivity for LXRα and strong therapeutic efficacy in HCC organoids, therefore illustrating a strong potential for advancing this lipotoxic treatment strategy to clinical application.

• MeSH
• hepatocelulární karcinom * farmakoterapie   metabolismus   patologie   MeSH
• jaterní receptor X * agonisté   metabolismus   MeSH
• lidé MeSH
• maleimidy * farmakologie   chemie   terapeutické užití   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory jater * farmakoterapie   metabolismus   patologie   MeSH
• protinádorové látky * farmakologie   chemie   terapeutické užití   chemická syntéza   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• jaterní receptor X * MeSH
• maleimidy * MeSH
• protinádorové látky * MeSH

Starting from benzyl 30-oxobetulinate and 30-oxobetulin diacetate, substituted dienes were synthesized and subjected to Diels-Alder reaction, yielding a variety of triterpenoid phthalates, phthalimides, and related derivatives. A total of 55 new compounds were prepared and tested for in vitro cytotoxic activity against eight cancer cell lines and two non-cancerous cell lines. Four compounds with IC50 values of 5 μM or lower were selected for further investigation. These compounds induced apoptosis in CCRF-CEM cells in a concentration-dependent manner, accompanied by mitochondrial depolarization and altered expression of key proteins involved in mitochondrial apoptosis. The compounds also disrupted DNA replication and transcriptional activity. Modulation of key proliferation pathways, including PI3K/Akt and STAT3, further supported the antiproliferative potential of these derivatives. Considering their high cytotoxicity and antiproliferative activity in CCRF-CEM cells, compounds 19, 26, 28, and 30 have been identified as promising candidates for further development.

• Klíčová slova
• Apoptosis, Betulin, Betulinic acid, Cancer, Cell cycle regulation, Diels-Alder reaction, Mitochondria, Phthalates, Triterpenoids, Wittig reaction,
• MeSH
• apoptóza * účinky léků   MeSH
• ftalimidy * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• mitochondrie * účinky léků   metabolismus   MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• screeningové testy protinádorových léčiv * MeSH
• triterpeny * farmakologie   chemie   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
• ftalimidy * MeSH
• protinádorové látky * MeSH
• triterpeny * MeSH

Protein cross-linking has assumed an irreplaceable role in structural proteomics. Recently, significant efforts have been made to develop novel mass spectrometry (MS)-cleavable reagents. At present, only water-insoluble MS-cleavable cross-linkers are commercially available. However, to comprehensively analyse the various chemical and structural motifs making up proteins, it is necessary to target different protein sites with varying degrees of hydrophilicity. Here we introduce the new MS-cleavable cross-linker disulfodisuccinimidyl dibutyric urea (DSSBU), which we have developed in-house for this purpose. DSSBU contains an N-hydroxysulfosuccinimide (sulfo-NHS) reactive group, so it can serve as a water-soluble counterpart to the widely used cross-linker disuccinimidyl dibutyric urea (DSBU). To investigate the applicability of DSSBU, we compared the efficacy of four similar cross-linkers: bis[sulfosuccinimidyl] suberate (BS3), disuccinimidyl suberate (DSS), DSBU and DSSBU with bovine serum albumin. In addition, we compared the efficacy of DSBU and DSSBU with human haemoglobin. Our results demonstrate that the sulfo-NHS group ensures the superior water solubility of DSSBU and thus negates the need for organic solvents such as dimethyl sulfoxide while preserving the effectivity of urea-based MS-cleavable crosslinkers such as DSBU. Additionally, it makes it possible to target polar regions in proteins. The data gathered are available via ProteomeXchange under identifier PXD055284. SIGNIFICANCE: We have synthesized the novel protein cross-linker DSSBU, which combines sulfo-NHS ester chemistry with a mass spectrometry-cleavable urea group. This makes DSSBU a water-soluble, MS-cleavable cross-linker that reacts with amino groups. To our knowledge, it is the first cross-linker which combines all three of these characteristics. We have tested the performance of our novel cross-linker on bovine serum albumin, a model widely used by the cross-linking mass spectrometry community, and on human haemoglobin. We have comprehensively assessed the performance of DSSBU and compared its efficacy with that of three other cross-linkers in current use (BS3, DSS and DSBU). We conclude that our novel cross-linker surpasses its MS-non-cleavable analogue BS3 in performance and that its water solubility eliminates the need for organic solvents while its hydrophilicity allows for the targetting of polar regions in proteins. Therefore, it will likely become a significant addition to the portfolio of N-hydroxysuccinimide ester cross-linkers.

• Klíčová slova
• Chemical cross-linking, Mass spectrometry, New MS-cleavable cross-linker, Protein conformation, Protein interactions, Water-soluble cross-linker,
• MeSH
• hmotnostní spektrometrie metody   MeSH
• lidé MeSH
• močovina chemie   MeSH
• proteomika metody   MeSH
• reagencia zkříženě vázaná * chemie   MeSH
• sérový albumin hovězí chemie   MeSH
• skot MeSH
• sukcinimidy * chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• skot MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bis(sulfosuccinimidyl)suberate MeSH Prohlížeč
• močovina MeSH
• reagencia zkříženě vázaná * MeSH
• sérový albumin hovězí MeSH
• sukcinimidy * MeSH

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f, and dihydrophthalimide 2h have been selected for further development.

• Klíčová slova
• Apoptosis, Cancer, Cytotoxicity, Heterocycle, Mitochondria, Pharmacology, Phthalate, Phthalimide, Pyrone, Triterpene,
• MeSH
• apoptóza MeSH
• DNA metabolismus   MeSH
• ftalimidy farmakologie   MeSH
• kyseliny ftalové * MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory * farmakoterapie   MeSH
• protinádorové látky * terapeutické užití   MeSH
• pyrony farmakologie   MeSH
• triterpeny * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA MeSH
• ftalimidy MeSH
• kyseliny ftalové * MeSH
• phthalic acid MeSH Prohlížeč
• protinádorové látky * MeSH
• pyrony MeSH
• triterpeny * MeSH

Pharmacophores such as hydroxyethylamine (HEA) and phthalimide (PHT) have been identified as potential synthons for the development of compounds against various parasitic infections. In order to further advance our progress, we conducted an experiment utilising a collection of PHT and HEA derivatives through phenotypic screening against a diverse set of protist parasites. This approach led to the identification of a number of compounds that exhibited significant effects on the survival of Entamoeba histolytica, Trypanosoma brucei, and multiple life-cycle stages of Leishmania spp. The Leishmania hits were pursued due to the pressing necessity to expand our repertoire of reliable, cost-effective, and efficient medications for the treatment of leishmaniases. Antileishmanials must possess the essential capability to efficiently penetrate the host cells and their compartments in the disease context, to effectively eliminate the intracellular parasite. Hence, we performed a study to assess the effectiveness of eradicating L. infantum intracellular amastigotes in a model of macrophage infection. Among eleven L. infantum growth inhibitors with low-micromolar potency, PHT-39, which carries a trifluoromethyl substitution, demonstrated the highest efficacy in the intramacrophage assay, with an EC50 of 1.2 +/- 3.2 μM. Cytotoxicity testing of PHT-39 in HepG2 cells indicated a promising selectivity of over 90-fold. A chemogenomic profiling approach was conducted using an orthology-based method to elucidate the mode of action of PHT-39. This genome-wide RNA interference library of T. brucei identified sensitivity determinants for PHT-39, which included a P-type ATPase that is crucial for the uptake of miltefosine and amphotericin, strongly indicating a shared route for cellular entry. Notwithstanding the favourable properties and demonstrated efficacy in the Plasmodium berghei infection model, PHT-39 was unable to eradicate L. major infection in a murine infection model of cutaneous leishmaniasis. Currently, PHT-39 is undergoing derivatization to optimize its pharmacological characteristics.

• MeSH
• amfotericin B terapeutické užití   MeSH
• antiprotozoální látky * farmakologie   terapeutické užití   MeSH
• ftalimidy farmakologie   terapeutické užití   MeSH
• Leishmania infantum * MeSH
• Leishmania * MeSH
• leishmanióza kožní * parazitologie   MeSH
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amfotericin B MeSH
• antiprotozoální látky * MeSH
• ftalimidy MeSH

OBJECTIVES: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among older adults in developed countries. Although many risk factors are known, the pathogenesis of AMD is still unclear. However, oxidative stress probably plays a vital role in the process of AMD. The increasing prevalence of AMD, risk of vision loss, limited treatment of dry form, expensive treatment of wet form, and decreased quality of life are factors that lead to considering modifiable risk factors of AMD, such as nutrition. This is the first study describing the relationship between dietary habits, dietary nutrient intake and AMD in the Czech Republic. METHODS: In this research, a total of 93 cases with AMD and 58 controls without AMD and cataracts participated. All participants were ophthalmologically examined at the Clinic of Eye Treatments at the University Hospital Brno. Data were collected using a pre-tested self-report questionnaire in a face-to-face interview. Food consumption frequency was assessed by an 18-item semiquantitative food-frequency questionnaire (FFQ). Dietary nutrient intakes were calculated from a 24-hour recall. RESULTS: Patients with AMD compared with controls had significantly higher consumption of legumes and lower consumption of meat products, salt and salty products. In men, we found statistically significant differences in alcohol consumption. The case group consumed alcoholic beverages more frequently (median: 2 times a week) than the control group (median: 1-3 times a month). No differences in alcohol consumption were found in women. In comparison to the case group, the control group had a significantly higher dietary intake of energy (5,783.8 vs. 4,849.3 kJ/day; p = 0.002), proteins (65.3 vs. 52.3 g/day; p = 0.002), fats (57.6 vs. 49.4 g/day; p = 0.046), saturated fatty acids (21.7 vs. 18.9 g/day; p = 0.026), carbohydrates (150.4 vs. 127.1 g/day; p = 0.017), dietary fibre (13.2 vs. 11.3 g/day; p = 0.044), vitamin B2 (1.0 vs. 0.9 mg/day; p = 0.029), vitamin B3 (13.9 vs. 10.0 mg/day; p = 0.011), pantothenic acid (3.5 vs. 2.8 mg/day; p = 0.001), vitamin B6 (1.3 vs. 1.0 mg/day; p = 0.001), potassium (1,656.5 vs. 1,418.0 mg/day; p = 0.022), phosphorus (845.4 vs. 718.7 mg/day; p = 0.020), magnesium (176.5 vs. 143.0 mg/day; p = 0.012), copper (1.0 vs. 0.8 mg/day; p = 0.011), and zinc (7.1 vs. 6.1 mg/day; p = 0.012) counted from a 24-hour recall. CONCLUSIONS: According to FFQ, dietary habits in the patients with AMD and controls were similar. In men from the case group, we found statistically significant higher alcohol consumption. According to a 24-hour recall, the controls achieved recommended dietary intakes rather than cases. In comparison to the case group, the control group had a significantly higher dietary intake of energy, proteins, fats, saturated fatty acids, carbohydrates, dietary fibre, vitamin B2, vitamin B3, pantothenic acid, vitamin B6, potassium, phosphorus, magnesium, copper, and zinc.

• Klíčová slova
• age-related macular degeneration, antioxidants, dietary habits, food groups, oxidative stress,
• MeSH
• dieta MeSH
• dietní tuky MeSH
• draslík MeSH
• energetický příjem MeSH
• fosfor MeSH
• hořčík * MeSH
• kvalita života MeSH
• kyselina pantothenová MeSH
• lidé MeSH
• makulární degenerace * epidemiologie   chemicky indukované   MeSH
• mastné kyseliny MeSH
• měď MeSH
• niacinamid MeSH
• potravní vláknina MeSH
• přijímání potravy MeSH
• riboflavin MeSH
• senioři MeSH
• stravovací zvyklosti MeSH
• studie případů a kontrol MeSH
• vitamin B6 MeSH
• zinek MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dietní tuky MeSH
• draslík MeSH
• fosfor MeSH
• hořčík * MeSH
• kyselina pantothenová MeSH
• mastné kyseliny MeSH
• měď MeSH
• niacinamid MeSH
• potravní vláknina MeSH
• riboflavin MeSH
• vitamin B6 MeSH
• zinek MeSH

Constant emergence of drug-resistant Plasmodium falciparum warrants urgent need for effective and inexpensive drugs. Herein, phthalimide (Pht) analogs possessing the bioactive scaffolds, benzimidazole and 1,2,3-triazole, were evaluated for in vitro and in vivo anti-plasmodial activity without any apparent hemolysis, or cytotoxicity. Analogs 4(a-e) inhibited the growth of 3D7 and RKL-9 strains at submicromolar concentrations. Defects were observed during parasite egress from or invasion of the red blood cells. Mitochondrial membrane depolarization was measured as one of the causes of cell death. Phts 4(a-e) in combination with artemisinin exhibited two-to three-fold increased efficacy. Biophysical and biochemical analysis suggest that Pht analogs mediate plasmodial growth inhibition by interacting with tubulin protein of the parasite. Lastly, Phts 4(a-e) significantly decreased parasitemia and extended host survival in murine model Plasmodium berghei ANKA infection. Combined, the data indicate that Pht analogs should be further explored, which could offer novel value to the antimalarial drug development pipeline.

• Klíčová slova
• Antimalarial, Drug discovery, Drug resistance, Phthalimide analogs, Plasmodium falciparum, Tubulin,
• MeSH
• antimalarika * chemie   MeSH
• ftalimidy chemie   farmakologie   MeSH
• malárie * farmakoterapie   parazitologie   MeSH
• myši MeSH
• Plasmodium berghei MeSH
• Plasmodium falciparum MeSH
• tubulin MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimalarika * MeSH
• ftalimidy MeSH
• tubulin MeSH

Optically active linear polyimides and hyperbranched poly (amic acid-imide) were prepared by using procedures varying in particular in the maximum temperature employed in their synthesis. The two types of linear polyimides were based on 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 1,2-diaminocylohexane enantiomers or 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 2,2'-diamino-1,1'-binaphthalene enantiomers. The amine-terminated hyperbranched poly (amic acid-imide) was prepared from 4,4'-(hexafluoroisopropylidene)diphthalic anhydride and 4,4',4″-triaminotriphenylmethane, and its end groups were modified with the chiral selectors N-acetyl-D-phenylalanine or N-acetyl-L-phenylalanine. The final structure of the products was analyzed by IR spectroscopy, and their optical activity was evaluated and confirmed by polarimetry or circular dichroism.

• Klíčová slova
• chiral selector, circular dichroism, optical activity, polarimetry, polyimide,
• MeSH
• anhydridy * chemie   MeSH
• cirkulární dichroismus MeSH
• imidy * chemie   MeSH
• stereoizomerie MeSH
• teplota MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• anhydridy * MeSH
• imidy * MeSH

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Klíčová slova
• fosmetpantotenate, pantothenate kinase-associated neurodegeneration, randomized controlled trial, treatment,
• MeSH
• činnosti denního života MeSH
• dvojitá slepá metoda MeSH
• Hallervordenův-Spatzův syndrom * farmakoterapie   genetika   MeSH
• kyselina pantothenová analogy a deriváty   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• fosmetpantotenate MeSH Prohlížeč
• kyselina pantothenová MeSH

A structure-activity relationship (SAR) study in terms of G-quadruplex binding ability and antiproliferative activity of six fluorescent perylenemonoimide (PMIs) derivatives is reported. A positive charge seems to be the key to target G4. This study also reveals the importance of the element substitution in the potential biological activity of PMIs, being the polyethylene glycol (PEG) chains in the peri position responsible for their antiproliferative activity. Among them, the cationic PMI6 with two PEG chains is the most promising compound since its fluorescence is enhanced in the presence of G-quadruplex structures. Moreover, PMI6 binds to the human telomeric G-quadruplex hTelo with high affinity and displays a high antiproliferative potential towards HeLa (cervical adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian adenocarcinoma) cells. Its fate can be followed inside cells thanks to its fluorescent properties: the compound is found to accumulate in the mitochondria.

• Klíčová slova
• Antiproliferative, DNA binding, G-quadruplexes, Perylenemonoimide,
• MeSH
• G-kvadruplexy účinky léků   MeSH
• imidy chemická syntéza   chemie   farmakologie   MeSH
• kultivované buňky MeSH
• lidé MeSH
• mitochondrie účinky léků   MeSH
• molekulární struktura MeSH
• perylen analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• proliferace 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
• práce podpořená grantem MeSH
• Názvy látek
• imidy MeSH
• perylen MeSH
• perylenemonoimide MeSH Prohlížeč