Paulina Koczurkiewicz

Anticonvulsant activity, crystal structures, and preliminary safety evaluation of N-trans-cinnamoyl derivatives of selected (un)modified aminoalkanols.

Adequate control of seizures remains an unmet need in epilepsy. In order to identify new anticonvulsant agents, a series of N-trans-cinnamoyl derivatives of selected aminoalkanols was synthetized. The compounds were obtained in the reaction of N-acylation carried out in a two-phase system. The substances were tested in animal models of seizures induced either electrically (maximal electroshock--MES; 6-Hz test) or chemically, by subcutaneous injection of pentetrazol (scPTZ). Neurotoxicity was determined by the rotarod test. Lipophilicity of the active compounds, expressed as RM0, was determined by reversed-phase thin layer chromatography and it ranged from 1.390 to 2.219. From among the tested series of compounds, R,S-(E)-N-(1-hydroxypropan-2-yl)-3-phenylprop-2-enamide (1) and R,S-(E)-N-(2-hydroxypropyl)-3-phenylprop-2-enamide (3) exhibited the best anticonvulsant activity. Compound 1, when administered to mice by intraperitoneal (i.p.) injection, showed the ED50 values of 86.6, 60.9, and 109.6 mg/kg in the MES, 6-Hz, and scPTZ tests, respectively. For compound 3, the ED50 values were found to be 47.1 mg/kg in MES and 77.1 mg/kg in scPTZ (mice, i.p.). The distances measured in crystals of compound 1 were: 7.99 Å--from the phenyl ring to the hydroxyl group in the amide moiety, 5.729 Å--from the phenyl ring to the amide group, and 3.112 Å--from the amide group to the hydroxyl group in the amide moiety. The reported compounds did not exhibit mutagenic potential when assayed in the Ames test. Compounds 1 and 3 did not affect viability and morphology of human hepatocellular carcinoma cells (HepG2).

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

SummaryAnthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (−)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.

Connective tissue growth factor regulates transition of primary bronchial fibroblasts to myofibroblasts in asthmatic subjects

Graphical abstract Figure. No Caption available. HighlightsCTGF contributes to fibroblasts‐to‐myofibroblasts transition in bronchial asthma.TGF‐&bgr;1‐induced FMT in bronchial fibroblasts of asthmatics is enhanced by CTGF.CTGF silencing potently decreases TGF‐&bgr;1‐induced FMT in bronchial fibroblasts. Abstract Fibroblast to myofibroblast transition (FMT) contributes to bronchial wall remodelling in persistent asthma. Among other numerous factors involved, transforming growth factor type &bgr; (TGF‐&bgr;) plays a pivotal role. Recently it has been demonstrated that connective tissue growth factor (CTGF), a matricellular protein, combines with TGF‐&bgr; in the pathomechanism of many fibrotic disorders. However, it is not clear whether this interaction takes place in asthma as well. Primary cultures of human bronchial fibroblasts from asthmatic and non‐asthmatic subjects were used to investigate the impact of CTGF and TGF‐&bgr;1 on the fibroblast to myofibroblast transition. The combined activity of TGF‐&bgr;1 and CTGF resulted in an average of 90% of FMT accomplished in cell lines derived from asthmatics. In this group FMT was highly dependent on the presence of CTGF produced by the cells, as shown by gene silencing experiments with the specific siRNA. Results support the important role of CTGF biosynthesis in the asthmatic bronchi amplifying FMT. This is evidenced by inhibition of TGF‐&bgr;1‐induced FMT following CTGF silencing in asthmatic bronchial fibroblasts. CTGF is produced by fibroblasts and contributes to the FMT phenomenon in positive loop‐back, inducing and boosting TGF‐&bgr;1 triggered FMT. Thus, CTGF is a promising target for pharmacological intervention in secondary prevention of bronchial remodelling in asthma.

Pentoxifylline and its active metabolite lisofylline attenuate transforming growth factor β1-induced asthmatic bronchial fibroblast-to-myofibroblast transition.

Bronchial asthma is characterized by persistent airway inflammation and airway wall remodeling. Among many different cells and growth factors triggering changes in bronchi structure, transforming growth factor β1-induced fibroblast to myofibroblast transition is believed to be very important. The aim of this study was to evaluate whether theophylline (used in asthma therapy) and two other methylxanthines (pentoxifylline and its active metabolite lisofylline), may affect transforming growth factor β1-induced fibroblast to myofibroblast transition in bronchial fibroblasts derived from asthmatic patients. We show here for the first time that selected methylxanthines effectively reduce transforming growth factor β1-induced myofibroblast formation in asthmatic bronchial fibroblast populations. PTX was found to be the most effective methylxanthine. The number of differentiated myofibroblasts after PTX, LSF and THEO administration was reduced at least twofold. Studies on the use of methylxanthines opens a new perspective in the development of novel strategies in asthma therapy through their two-pronged, anti-inflammatory and anti-fibrotic action. In the future they can be considered as promising anti-fibrotic drugs.

Cinnamic acid derivatives in cosmetics: current use and future prospects

Cinnamic acid derivatives are widely used in cosmetics and possess various functions. This group of compounds includes both naturally occurring and synthetic substances. On the basis of the Cosmetic Ingredient Database (CosIng) and available literature, this review summarizes their functions in cosmetics, including their physicochemical and biological properties as well as reported adverse effects. A perfuming function is typical of many derivatives of cinnamaldehyde, cinnamyl alcohol, dihydrocinnamyl alcohol and cinnamic acid itself; these substances are commonly used in cosmetics all over the world. Some of them show allergic and photoallergic potential, resulting in restrictions in maximum concentrations and/or a requirement to indicate the presence of some substances in the list of ingredients when their concentrations exceed certain fixed values in a cosmetic product. Another important function of cinnamic acid derivatives in cosmetics is UV protection. Ester derivatives such as ethylhexyl methoxycinnamate (octinoxate), isoamyl p‐methoxycinnamte (amiloxiate), octocrylene and cinoxate are used in cosmetics all over the world as UV filters. However, their maximum concentrations in cosmetic products are restricted due to their adverse effects, which include contact and a photocontact allergies, phototoxic contact dermatitis, contact dermatitis, estrogenic modulation and generation of reactive oxygen species. Other rarely utilized functions of cinnamic acid derivatives are as an antioxidant, in skin conditioning, hair conditioning, as a tonic and in antimicrobial activities. Moreover, some currently investigated natural and synthetic derivatives of cinnamic acid have shown skin lightening and anti‐ageing properties. Some of them may become new cosmetic ingredients in the future. In particular, 4‐hydroxycinnamic acid, which is currently indexed as a skin‐conditioning cosmetics ingredient, has been widely tested in vitro and in vivo as a new drug candidate for the treatment of hyperpigmentation.

Antiallodynic and antihyperalgesic activity of new 3,3-diphenyl-propionamides with anticonvulsant activity in models of pain in mice

Abstract Anticonvulsant drugs are used to treat a wide range of non‐epileptic conditions, including chronic pain. The aim of the present experiments was to examine analgesic activity of three new 3,3‐diphenyl‐propionamides, which had previously demonstrated anticonvulsant activity in the MES (maximal electroshock seizure), scPTZ (subcutaneous pentylenetetrazole) and/or 6 Hz (psychomotor seizure) tests in mice. Antinociceptive activity was examined in mouse models of acute pain (the hot plate test) and tonic pain (the formalin test) in mice. Antiallodynic and antihyperalgesic activity was estimated in the oxaliplatin‐induced neuropathic pain model of chemotherapy‐induced peripheral neuropathy and in the streptozotocin‐induced model of painful diabetic neuropathy in mice. Considering the drug safety evaluation, the influence on locomotor activity was checked. Moreover, using in vitro methods, selected compound was tested for potential hepatotoxicity on human hepatocellular carcinoma cell line and for metabolic stability. To determine the plausible mechanism of anticonvulsant and antinociceptive action, in vitro binding and functional assays were carried out. Among tested molecules two of them JOA 122 (3p) and JOA 123 (3q) revealed significant antinociceptive activity in the model of tonic pain – the formalin test and neuropathic pain models – the oxaliplatin and streptozotocin‐induced peripheral neuropathy. In the binding studies JOA 122 (3p) revealed the high affinity to voltage‐gated sodium channels (Nav1.2), as well as for 5‐HT1A receptors. Metabolism studies in mouse liver microsomes showed a low metabolic stability of this compound.

Synthesis and anticonvulsant activity of phenoxyacetyl derivatives of amines, including aminoalkanols and amino acids

A series of 17 new phenoxyacetamides has been prepared via multistep chemical synthesis as a continuation of the research carried out by our group on di- and tri-substituted phenoxyalkyl and phenoxyacetyl derivatives of amines. The obtained compounds vary in an amide component, for example aminoalkanol or (un)modified amino acid moieties were introduced. The structures of selected products were confirmed by means of crystallographic methods. All 17 compounds were the subject of preliminary screening for potential anticonvulsant activity (MES, 6 Hz and/or scMET tests) and neurotoxicity (rotarod) in mice after intraperitoneal administration, while several active compounds were subsequently examined in additional models (e.g. MES and rotarod - rats, p.o. or i.p., hippocampal kindling - rats, i.p.). Finally, safety studies (cytotoxicity and cell proliferation assays on astrocytes, metabolic stability assessment, mutagenicity evaluation) were performed for several active compounds, including the most promising one (R-(-)-2-(2,6-dimethylphenoxy)-N-(1-hydroxypropan-2-yl)acetamide, MES ED50 = 12.00 mg per kg b.w., rats, p.o.).

Usnic acid reactive metabolites formation in human, rat, and mice microsomes. Implication for hepatotoxicity

Usnic acid is a lichen compound which is extensively studied due to its cytotoxic, antiproliferative, antimicrobial, antiviral, antiprotozoal, and anti-inflammatory activities. Despite a broad spectrum of biological properties, usnic acid is a hepatotoxic agent, thus its potential use as a drug is limited. Certain hepatotoxic drugs may act by generating reactive metabolites that damage the liver. The aim of the study was to predict the biotransformation of usnic acid enantiomers to reactive products using a trapping assay with glutathione in human, rat, and mice liver microsomes. Our results indicate that each enantiomer forms two reactive metabolites; in turn, these metabolites form adducts with glutathione, which may partially explain the toxicity of usnic acid. In silico analysis indicated structural alerts for the generation of reactive metabolites in usnic acid formula. This study proposes a novel mode of the hepatic toxicity of usnic acid enantiomers; it also provides some useful suggestions for designing safer usnic acid derivatives.

Piperlongumine (piplartine) as a lead compound for anticancer agents – Synthesis and properties of analogues: A mini-review

Piperlongumine, also known as piplartine, is an amide alkaloid of Piper longum L. (long piper), a medical plant known from Ayurvedic medicine. Although was discovered well over fifty years ago, its pharmacological properties have been uncovered in the past decade. In particular, piperlongumine has been most extensively studied as a potential anticancer agent. Piperlongumine has exhibited cytotoxicity against a broad spectrum of human cancer cell lines, as well as demonstrated antitumor activity in rodents. Piperlongumine has also been found to be a proapoptotic, anti-invasive, antiangiogenic agent and synergize with modern chemotherapeutic agents. Because of its clinical potential, several studies were undertaken to obtain piperlongumine analogues, which have exhibited more potent activity or more appropriate drug-like parameters. In this review, the synthesis of piperlongumine analogues and piperlongumine-based hybrid compounds, as well as their anticancer properties and the molecular basis for their activity are explored. General structure-activity relationship conclusions are drawn and directions for the future research are indicated.

The impact of ZnO and TiO2 on the stability of clotrimazole under UVA irradiation: Identification of photocatalytic degradation products and in vitro cytotoxicity assessment

Graphical abstract Figure. No Caption available. HighlightsPhotocatalytic degradation of clotrimazole by TiO2/ZnO under UVA irradiation.UPLC method development for determination of clotrimazole in the presence of its photocatalytic degradation products.Structural characterization of fourteen presumable photodegradation products of clotrimazole using UPLC–MS/MS.In vitro cytotoxic assessment using the Human skin fibroblast cell line. Abstract In order to ensure the safe and effective use of pharmaceutical products especially for topical administration photostability testing is necessary. The current paper presents an in‐depth analysis of the stability of one of the most common antifungal agents, namely clotrimazole. Clotrimazole has proven to be stable under UVA irradiation in applied experimental conditions, but the presence of catalysts such as ZnO and TiO2 has contributed significantly to the degradation of this compound. The findings indicate that its photocatalytic degradation reactions followed the pseudo first‐order kinetics with rate constant depending on the pH and the used solvent. Using LC–MS/MS, 14 presumable degradation products of clotrimazole were identified and the plausible transformation pathways were proposed. The in vitro cytotoxicity risk evaluation based on photostability of clotrimazole was also performed using the Human skin fibroblast cell line (BJ) ATCC™ CRL‐2522. There was no statistically significant difference between cells viability in all analyzed combinations of clotrimazole, TiO2/ZnO, and UVA irradiation (p < 0.05).