Antioxidant and Anti-inflammatory Effects of α-Lipoic Acid on Lipopolysaccharide-induced Oxidative Stress in Rat Kidney.

α-Lipoic acid (α-LA) is a naturally occurring organosulfur component. Oxidative stress plays an essential role in the pathogenesis of various diseases, such as kidney and cardiovascular diseases, diabetes, neurodegenerative disorders, cancer and aging. Kidneys are especially vulnerable to oxidative stress and damage. The aim of the study was to evaluate the effect of α-LA on lipopolysaccharide (LPS)-induced oxidative stress parameters in rat kidneys. The experimental rats were divided into four groups: I-control (0.9% NaCl i.v.); II-α-LA (60 mg/kg b.w. i.v.); III-LPS (30 mg/kg b.w. i.v.); and IV-LPS + LA (30 mg/kg b.w. i.v. and 60 mg/kg b.w. i.v., respectively). In kidney homogenates the concentration of thiobarbituric acid reactive substances (TBARS), hydrogen peroxide (H2O2), sulfhydryl groups (-SH), total protein, superoxide dismutase (SOD), total glutathione (tGSH), reduced glutathione (GSH), glutathione disulphide (GSSG) and the GSH/GSSG ratio were determined. In addition, the levels of tumour necrosis factor (TNF)-α, and interleukin (IL)-6 were measured to assess inflammation and was estimated kidney oedema. Studies have shown that α-LA administered after LPS administration attenuated kidney oedema and significantly decreased TBARS, H2O2, TNF-α, and IL-6 levels in rat kidneys. α-LA also resulted in increase -SH group, total protein, and SOD levels and ameliorated the GSH redox status when compared to the LPS group. The results suggest that α-LA plays an important role against LPS-induced oxidative stress in kidney tissue as well as downregulating the expression of pro-inflammatory cytokines.

Effect of Alpha-Lipoic Acid on Rat Ventricles and Atria under LPS-Induced Oxidative Stress.

Alpha-lipoic acid (α-LA) is a disulfide compound and one of the most effective antioxidants. Many studies have indicated positive effects of α-LA in the prevention of pathologic conditions mediated by oxidative stress, such as cardiovascular diseases. However, the therapeutic potential of α-LA for the heart has not been explored with regards to the ventricles and atria. The aim of our study was to evaluate the effects of α-LA on oxidative stress parameters and inflammation in the ventricles and atria of the heart in rats under LPS-induced oxidative stress. Wistar rats were divided into 4 groups: I-control (received 2 doses of 0.2 mL of 0.9% NaCl i.v., 0.5 h apart); II-α-LA (received 0.2 mL of 0.9% NaCl and 0.5 h later received α-LA 60 mg/kg b.w. i.v.); III-lipopolysaccharide (LPS) (received 0.2 mL of 0.9% NaCl and 0.5 h later received LPS 30 mg/kg b.w. i.v.); and IV-LPS + LA (received LPS 30 mg/kg b.w. i.v. and 0.5 h later received α-LA 60 mg/kg b.w. i.v.). Five hours later, the rats were euthanized. The hearts were surgically removed and weighed to estimate heart edema. The ventricular and atrium tissue was isolated to measure levels of TNF-α, IL-6, superoxide dismutase (SOD), thiobarbituric acid reactive substances (TBARS), hydrogen peroxide (H2O2), total sulfhydryl groups (-SH), total glutathione (tGSH), reduced glutathione (GSH), glutathione disulfide (GSSG), and the GSH/GSSG ratio. LPS significantly increased TNF-α, IL-6, TBARS, and H2O2 levels and decreased SOD, -SH groups, tGSH, the GSH/GSSG ratio, and GSH levels in rat ventricles and atria while α-LA administered after the injection of LPS significantly decreased TNF-α, IL-6, TBARS, and H2O2 levels. α-LA also increased SOD and -SH group levels and ameliorated the glutathione redox status when compared to the LPS group. Our data suggest that α-LA administration 30 min after LPS infusion may effectively prevent inflammation and oxidative stress in the ventricles and atria.

Hybrid Drugs-A Strategy for Overcoming Anticancer Drug Resistance?

Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers' molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

Characteristic of Cyclodextrins: Their Role and Use in the Pharmaceutical Technology.

About 40% of newly-discovered entities are poorly soluble in water, and this may be an obstacle in the creation of new drugs. To address this problem, the present review article examines the structure and properties of cyclodextrins and the formation and potential uses of drug - cyclodextrin inclusion complexes. Cyclodextrins are cyclic oligosaccharides containing six or more D-(+)- glucopyranose units linked by α-1,4-glycosidic bonds, which are characterized by a favourable toxicological profile, low local toxicity and low mucous and eye irritability; they are virtually non-toxic when administered orally. They can be incorporated in the formulation of new drugs in their natural form (α-, ß-, γ-cyclodextrin) or as chemically-modified derivatives. They may also be used as an excipient in drugs delivered by oral, ocular, dermal, nasal and rectal routes, as described in the present paper. Cyclodextrins are promising compounds with many beneficial properties, and their use may be increasingly profitable for pharmaceutical scientists.

Cinnoline Scaffold-A Molecular Heart of Medicinal Chemistry?

The cinnoline nucleus is a very important bicyclic heterocycle that is used as the structural subunit of many compounds with interesting pharmaceutical properties. Cinnoline derivatives exhibit broad spectrum of pharmacological activities such as antibacterial, antifungal, antimalarial, anti-inflammatory, analgesic, anxiolytic and antitumor activities. Some of them are under evaluation in clinical trials. In the present review, we have compiled studies focused on the biological properties of cinnoline derivatives conducted by many research groups worldwide between 2005 and 2019. Comprehensive and target oriented information clearly indicate that the development of cinnoline based molecules constitute a significant contribution to the identification of lead compounds with optimized pharmacodynamic and pharmacokinetic properties.

Synthesis, Biological Activity and Preliminary in Silico ADMET Screening of Polyamine Conjugates with Bicyclic Systems.

Polyamine conjugates with bicyclic terminal groups including quinazoline, naphthalene, quinoline, coumarine and indole have been obtained and their cytotoxic activity against PC-3, DU-145 and MCF-7 cell lines was evaluated in vitro. Their antiproliferative potential differed markedly and depended on both their chemical structure and the type of cancer cell line. Noncovalent DNA-binding properties of the most active compounds have been examined using ds-DNA thermal melting studies and topo I activity assay. The promising biological activity, DNA intercalative binding mode and favorable drug-like properties of bis(naphthalene-2-carboxamides) make them a good lead for further development of potential anticancer drugs.

Anticancer activity of some polyamine derivatives on human prostate and breast cancer cell lines.

The aim of this study was to expand our knowledge about anticancer activity of some polyamine derivatives with quinoline or chromane as terminal moieties. Tested compounds were evaluated in vitro towards metastatic human prostate adenocarcinoma (PC3), human carcinoma (DU145) and mammary gland adenocarcinoma (MCF7) cell lines. Cell viability was estimated on the basis of mitochondrial metabolic activity using water-soluble tetrazolium WST1 to establish effective concentrations of the tested compounds under experimental conditions. Cytotoxic potential of polyamine derivatives was determined by the measurement of lactate dehydrogenase activity released from damaged cells, changes in mitochondrial membrane potential, the cell cycle distribution analysis and apoptosis assay. It was revealed that the tested polyamine derivatives differed markedly in their antiproliferative activity. Bischromane derivative 5a exhibited a rather cytostatic than cytotoxic effect on the tested cells, whereas quinoline derivative 3a caused changes in cell membrane integrity, inhibited cell cycle progression, as well as induced apoptosis of prostate and breast cancer cells which suggest its potential application in cancer therapy.

DNA Interaction Studies of Selected Polyamine Conjugates.

The interaction of polyamine conjugates with DNA double helix has been studied. Binding properties were examined by ethidium bromide (EtBr) displacement and DNA unwinding/topoisomerase I/II (Topo I/II) activity assays, as well as dsDNA thermal stability studies and circular dichroism spectroscopy. Genotoxicity of the compounds was estimated by a comet assay. It has been shown that only compound 2a can interact with dsDNA via an intercalative binding mode as it displaced EtBr from the dsDNA-dye complex, with Kapp = 4.26 × 106 M-1; caused an increase in melting temperature; changed the circular dichroism spectrum of dsDNA; converted relaxed plasmid DNA into a supercoiled molecule in the presence of Topo I and reduced the amount of short oligonucleotide fragments in the comet tail. Furthermore, preliminary theoretical study has shown that interaction of the discussed compounds with dsDNA depends on molecule linker length and charge distribution over terminal aromatic chromophores.

IN SILICO ADME STUDIES OF POLYAMINE CONJUGATES AS POTENTIAL ANTICANCER DRUGS.

The ADME properties and drug-likeness of several polyamine derivatives containing dimeric phthalimide, quinoline, cinnoline and chromone moieties with three different polyamines: 1,4-bis(3-aninopropyl)piperazine, 4,9-dioxa-1,12-dodecanediamine and 3,3-diamino-N-methyldipropylamine as linkers were presented. These compounds are structurally related to DNA bisintercalators, a group of agents with anti-cancer activity. Their biological properties were previously assessed in vitio in a highly aggressive melanoma cell line A375. Current studies evaluate their potential to be qualified as drugs by performing in silico ADME screening. The research is carried out using Discovery Studio 3.0 ADMET protocol obtained from Accelrys and might be useful for further developing and optimization of potential anticancer drugs.

Application of chromatographic data in QSAR Studies of 3-[ω-(4-Arylpiperazin-1-yl)alkyl]pyrimido[5,4-c]quinolin-4(3H)-one derivatives as 5-HT1A receptor ligands.

The activity of several 3-[ω-(4-arylpiperazin-1-yl)alkyl]pyrimido[5,4-c]quinolin-4(3H)-ones (LCAPs) with well-defined serotonin 1A (5-HT1A) receptor affinity was described by using chromatographic and calculated physicochemical parameters in quantitative structure-activity relationship analysis. Normal-phase thin-layer chromatography plates impregnated with solutions of L-aspartic acid, L-serine, L-phenylalanine, L-tryptophan, L-tyrosine, L-asparagine, L-threonine and their mixtures (denoted as S1-S11 biochromatographic models) were used with two mobile phases as a model of the interaction between LCAP and 5-HT1A receptors. Molecular descriptors for the investigated compounds were calculated by using HyperChem and ACD/Labs programs. The significant relationship explains that 82% of the variance was successfully validated by leave-one-out and leave-many-out tests. The results demonstrated that this model has significant predictive ability and can be used for the preliminary screening of newly synthesized potential 5-HT1A receptor ligands.

Synthesis and biological evaluation of new bischromone derivatives with antiproliferative activity.

The synthesis of new bischromone derivatives (4a-c and 5a-c) as potential anticancer drugs is described. The difference in the reactivity between 4-oxo-4H-chromene-3-carboxylic acid 2 (or its methyl ester 3) and 4-oxo-4H-chromene-3-carbonyl chloride 1 with three different polyamines: 3,3'-diamino-N-methyldipropylamine (a), 1,4-bis(3-aminopropyl)piperazine (b), 4,9-dioxa-1,12-dodecanediamine (c) resulted in the formation of two different groups of products, compounds 4a-c and 5a-c, designed in agreement with the bisintercalators' structural requirements. The transformation of 4-oxo-4H-chromene-3-carboxylic acid into 2H-chromene-2,4(3H)-diones (5) was confirmed by the NMR and XRD experiments. Compounds 4a and 5a were evaluated in vitro in the highly aggressive melanoma cell line A375. An enhanced induction of apoptosis and cell cycle arrest clearly revealed that compound 5a was more potent than 4a. Compound 5a was also more active in diminishing the adhesive potential of melanoma cells. Current studies support the notion that small changes in the three-dimensional structure of molecules might have a substantial impact on their biological activity.

Summary of product characteristics (SmPC)--study on utilization of information presented in SmPC by different groups of physicians.

Cross-sectional survey study was done, investigating whether information included in SmPC (changing often due to safety reasons) is actually used, properly used or not used at all by cardiologists, GP's (general practitioners), internists and internal diseases physicians. Conducting readability test of Patient Information Leaflet, required by European Commission improved utilization of medical information included in it by European patients. Since there was no such requirement on Summary of Product Characteristics (SmPC), we examined utilization of information presented in Summary of Product Characteristics by physicians. Investigated were six drugs used in antiplatelet therapies, ATC (Anatomical, Therapeutic Chemical classification system) code B01AC. A random sample of 800 physicians took part in the study. They were physicians (300 cardiologists and 300 GP's) chosen from The Polish Chamber of Physicians and Dentists (PCPD) database interviewed using regular mail and 200 physicians interrogated during the XV International Congress of Polish Cardiac Society.Physicians. They were asked to complete a questionnaire consisting of 20 questions (13 concerning active substances, 6 general questions and one open question "Indicate the best way of receiving safety information"). Questions were constructed on the basis on new safety information included in actualized SmPC after submission of Periodic Safety Update Reports (PSURs) for medicinal products concerned. The overall response rate was 16.5% (132 filled in of 800 questionnaires). Of the respondents there were 65 and 67 from group I (cardiologists) and group II (GP's, internists and internal diseases), respectively. Eligible questionnaires (85) were obtained during the Congress (64.4%). Only 47 were received via regular mail (35.6%). Most correct answers were noted for clopidogrel and ASA (acetylsalicylic acid). 72.98% and 72.73%, respectively. The less known substance appeared eptifibatide, only 34.47% of answers were correct. Analyzing both groups (I and II), there were no significant differences regarding percent of correct answers, however, a statistical tendency level has been reached for "drugs for hospital use only" (abciximab, eptifibatide and tirofiban). For the open question, concerning best pipeline for receiving safety information according to respondents, both groups were relatively similar. Most popular were e-mail alerts, web pages/portals and drug compendiums, 44.37 and 24 indications, respectively. Study has limitation of a small sample size. The results are based on small amount of received questionnaires. Due to small sample size, it can be assumed that there are no significant differences between two compared groups (I--cardiologists; II--GP's, internists and internal diseases physicians) with regard to utilization of information from SmPC; however, beside two substances--clopidogrel and ASA, the level of knowledge is below expected. It also should be emphasized that "drugs for hospital use only" pointed out tendency that cardiologists can have better knowledge regarding these substances.

Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT(1A/2A) and 5-HT(7) receptor ligands.

A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT(1A) receptor, and moderate-to-low affinity for 5-HT(2A) and 5-HT(7) receptors. X-ray analysis, two-dimensional NMR, conformational studies and docking into the 5-HT(1A) receptor model were conducted to investigate conformational preferences of selected 5-HT(1A) receptor ligands in different environments. The extended conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form) and as a global energy minimum during conformational analysis in simulated water environment. Ligand geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully extended or with central spacer torsion in synclinal conformation.

Synthesis and in vitro biological evaluation of new polyamine conjugates as potential anticancer drugs.

The synthesis of new polyamine derivatives containing dimeric quinoline (3a-c), cinnoline (4a-c) and phthalimide (7a-c and 8a-c) moieties is described. Three different polyamines: (1,4-bis(3-aminopropyl)piperazine (a), 4,9-dioxa-1,12-dodecanediamine (b), 3,3'-diamino-N-methyldipropylamine (c) were used as linkers. The new compounds were obtained according to known procedures. Their biological activity was assessed in vitro in a highly aggressive melanoma cell line A375. Polyamine diimides containing phthalimide moieties demonstrated no inhibitory activities against melanoma cells. Quinoline diamides were more efficient than cinnoline ones. Mainly cytostatic activity exerted as altered cell cycle profiles was observed at the concentrations causing about 50% reduction of adherent cell proliferation. Based on their structure as well as their biological activity, we assume that some of the newly synthesized compounds may act as DNA bisintercalators. This study might be useful for further designing and developing anticancer drugs with potent activities.

Cinnoline derivatives with biological activity.

Although cinnoline belongs to a family of fairly well known heterocycles, the interest in the study of its derivatives continues. Cinnoline compounds demonstrate interesting bioactivity and many research papers have discussed the biological property, structure-activity relationship, and applications in medicinal science. Attention has been paid to the synthesis of heterocyclic compounds bearing a cinnoline moiety, mainly because of the interest in their broad spectrum of pharmacological activities. This chronological work summarizes almost all synthetic papers and patents concerning the biological properties of 107 cinnoline derivatives published over the last 50 years with 117 references.

Prodrugs and soft drugs.

This review focuses on a new approach to the development of drugs, namely on prodrugs and soft drugs. Nowadays, we try to design drugs that heal sick people having the best acceptance of patients. They must be efficient and selective on their site of action and must be metabolized to non-toxic derivatives. Both, prodrugs and soft drugs should have good distributive properties to enhance their quality. They are designed to maximize the amount of an active drug that reaches its target, through changing the physicochemical, biopharmaceutical or pharmacokinetic properties of drugs. Prodrugs are changed into the active drug within the body through enzymatic or non-enzymatic reactions. Soft drugs are novel and active analogues of already known therapeutic agents. It is expected that continued studies will improve drug properties so as to achieve the best drug delivery system.

Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development.

Determination of metabolic properties of a new chemical entity (NCE) is one of the most important steps during the drug discovery and development process. Nowadays, in vitro methods are used for early estimation and prediction of in vivo metabolism of NCEs. Using in vitro methods, it is possible to determine the metabolic stability of NCEs as well as the risk for drug-drug interactions (DDIs) related to inhibition and induction of drug metabolic enzymes. Metabolic stability is defined as the susceptibility of a chemical compound to biotransformation, and is expressed as in vitro half-life (t(1/2)) and intrinsic clearance (CL(int)). Based on these values, in vivo pharmacokinetic parameters such as bioavailability and in vivo half-life can be calculated. The drug metabolic enzymes possess broad substrate specificity and can metabolize multiple compounds. Therefore, the risk for metabolism-based DDIs is always a potential problem during the drug development process. For this reason, inhibition and induction in vitro screens are used early, before selection of a candidate drug (CD), to estimate the risk for clinically significant DDIs. At present, most pharmaceutical companies perform in vitro drug metabolism studies together with in silico prediction software and automated high-throughput screens (HTS). Available data suggest that in vitro methods are useful tools for identification and elimination of NCEs with unappreciated metabolic properties. However, the quantitative output of the methods has to be improved. The aim of this review is to highlight the practical and theoretical basis of the in vitro metabolic methods and the recent progress in the development of these assays.

Introduction to early in vitro identification of metabolites of new chemical entities in drug discovery and development.

The introduction of combinatorial chemistry and robotics for high throughput screening has changed the way drugs are discovered today compared with 10-15 years ago when fewer compounds were tested in animal or organ models. The introduction of new analytical techniques, especially liquid chromatography/mass spectrometry (LC/MS) has made it possible to characterize the chemical properties, permeability, metabolic stability and metabolic fate of a large number of screening hits for further development in a funnel-like manner. The purpose of this contribution is to discuss principles and recent strategies for metabolite identification and to give an introduction to biotransformation studies. Metabolites are experimentally generated with the use of animal and human recombinant expressed enzymes, and different liver and other tissue fractions like microsomes and slices. For separation and identification of structurally diverse metabolites, LC/MS and tandem mass spectrometry (LC/MS/MS) techniques are commonly used. The LC/MS and LC/MS/MS techniques are rapid, sensitive, easy to automate and robust, and therefore, they are the methods of choice for these studies. The outcome of the metabolite identification studies is detection of metabolites that could be pharmacologically active and contribute to the efficacy of a new chemical entity (NCE), and elimination of compounds that form reactive intermediates and/or toxic metabolites that could cause adverse effects of NCE. If such information is available at an early stage during the drug discovery process, the chemical structure of the compound may be modified to reduce the risk of idiosyncratic and/or adverse drug reactions during clinical development.

Synthesis and cytotoxicity of new potential intercalators based on tricyclic systems of some pyrimido[5,4-c]cinnoline and pyrimido[5,4-c]quinoline derivatives. Part I.

Pyrimido[5,4-c]cinnoline and pyrimido[5,4-c]quinoline derivatives have been tested as potential intercalators. All of them embody stuctural properties alike to afford intercalating activity. Their cytotoxicity was determined on the two human leukemia cell lines, the promyelocytic HL-60 and the lymphoblastic NALM-6. The viability of cells exposed continuously to tested compounds was estimated by the trypan-blue exclusion assay. IC50 data for the NALM-6 cell line are lower than for the HL-60 cell line, what suggested that the HL-60 leukemia cells are more resistant to toxic action of tested compounds. All compounds exerted moderate cytotoxic activity. The compounds were analyzed with the HyperChem/ChemPlus software trying to find basic structure-activity relationships.

Structure and biological activity of some 4-amino-3-cinnolinecarboxylic acid derivatives. QSAR analysis of cinnoline derivatives with antibacterial properties.

QSAR analysis was done in a group of cinnoline-3-carboxylic acid derivatives with antibacterial properties. Several physicochemical parameters, which characterize the variability of the structure of the 15 studied compounds, were compared as to their activity against gram-positive cocci, gram-negative bacilli and gram-positive bacilli strains. The physicochemical parameters with predictive value were found.