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Egils Bisenieks  - - - 
Top co-authors See all
Neven Zarkovic

122 shared publications

LabOS, Rudjer Boskovic Institute, Laboratory for Oxidative Stress, 10000 Zagreb, Croatia

G. Duburs

70 shared publications

Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga, LV-1006, Latvia

Aiva Plotniece

37 shared publications

Latvian Institute of Organic Synthesis, Riga, Latvia

Brigita Vīgante

28 shared publications

Latvian Institute of Organic Synthesis, Aizkraukles iela 21, LV-1006 Riga, Latvia

Anatoly Mishnev

26 shared publications

Latvian Institute of Organic Synthesis, Aizkraukles str. 21, Riga, LV-1006, Latvia

Publication Record
Distribution of Articles published per year 
(1997 - 2018)
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Publications See all
PROCEEDINGS-ARTICLE 1 Read 0 Citations Pleiotropic focused anticancer approach by dihydropyridines, dihydropyrimidines and heteroaromatic compounds Gunars Duburs, Brigita Vigante, Egils Bisenieks, Aivars Krau... Published: 14 November 2018
Proceedings of 4th International Electronic Conference on Medicinal Chemistry, doi: 10.3390/ecmc-4-05778
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Complex, focused anticancer therapy approach has been developed in the Latvian Institute of Organic Synthesis by making use of privileged partially hydrogenated nitrogen-containing heterocycles, namely dihydropyridines, dihydropyrimidines, their oxidized heteroaromatic derivatives. Topics of research include: 1. Conventional approach by chemotherapy and synergism of anticancer drugs [1]; 2. Inhibition of multidrug resistance by inhibition of drug efflux pumps [2]; 3. Mitigation of cancer risk factors – e.g., hepatitis B virus chemotherapy for prevention of chronic liver diseases, because chronic hepatitis, in up to 40% of cases, progresses to cyrrhosis and further to hepatocellular carcinoma [3]; 4. Improvement of efficacy of cancer radiotherapy by use of radioprotectors to prevent damage of normal tissues. So, radioprotector diethone (dietone) for skin protection was discovered, elaborated, and developed as ointment. Compounds for protection of eyes, mucous tissues, salivary glands etc have been synthesized. Toxicity of dietone and novel radioprotectors is very low; 5.Amphiphilic compounds have been synthesized, nanoparticles for anticancer drug and gene delivery have been created, pleiotropic properties have been checked, inclusion of magnetic particles for targeted transport performed [4]. Acknowledgements The research was partially supported by the Latvian State Program Biomedicine. References 1.Bisenieks E., Duburs G. et al., Pharmaceutical combination of 5-fluorouracil and derivatives of 1,4-dihydropyridine. US 8492413B2, 2013. 2.Krauze A., Grinberga S. et al., Thieno[2,3-b]pyridines – a new class of multidrug resistance (MDR) modulators. Bioorg.Med.Chem. 2014, 22 (21), 5860-5870. 3.Sipola A., Dubova U., et al., Synthesis and evaluation of 1,4-dihydropyrimidine derivatives – hepatitis B virus capsid self-assembly inhibitors. EFMC International Symposium on Medicinal Chemistry. Ljubljana, Slovenia, 2018, P176. 4.Pajuste K. et al., Gene delivery agents possessing antiradical activity: Self-assembling cationic amphiphilic 1,4-dihydropyridine derivatives. New J.Chem. 2013, 37 (10), 3062-3075.
Article 0 Reads 0 Citations Crystal structure and metabolic activity of 4-(thien-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic ac... Anatoly Mishnev, Egils Bisenieks, Ilona Mandrika, Ramona Pet... Published: 12 October 2018
Acta Crystallographica Section E Crystallographic Communications, doi: 10.1107/s2056989018014251
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In the title compound, C25H25NO5S, which exhibits metabolism-regulating activity, the 1,4-dihydropyridine ring adopts a flattened boat conformation while the cyclohexenone ring is in an envelope conformation. Molecules in the crystal are assembled into C(6) chains along the a-axis direction via N—H...O hydrogen bonds. The thienyl fragment is disordered over two sets of sites in a 0.7220 (19):0.2780 (19) ratio.
Article 1 Read 1 Citation Antioxidative 1,4-Dihydropyridine Derivatives Modulate Oxidative Stress and Growth of Human Osteoblast-Like Cells In Vit... Lidija Milkovic, Tea Vukovic, Neven Zarkovic, Franz Tatzber,... Published: 19 September 2018
Antioxidants, doi: 10.3390/antiox7090123
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Oxidative stress has been implicated in pathophysiology of different human stress- and age-associated disorders, including osteoporosis for which antioxidants could be considered as therapeutic remedies as was suggested recently. The 1,4-dihydropyridine (DHP) derivatives are known for their pleiotropic activity, with some also acting as antioxidants. To find compounds with potential antioxidative activity, a group of 27 structurally diverse DHPs, as well as one pyridine compound, were studied. A group of 11 DHPs with 10-fold higher antioxidative potential than of uric acid, were further tested in cell model of human osteoblast-like cells. Short-term combined effects of DHPs and 50 µM H2O2 (1-h each), revealed better antioxidative potential of DHPs if administered before a stressor. Indirect 24-h effect of DHPs was evaluated in cells further exposed to mild oxidative stress conditions induced either by H2O2 or tert-butyl hydroperoxide (both 50 µM). Cell growth (viability and proliferation), generation of ROS and intracellular glutathione concentration were evaluated. The promotion of cell growth was highly dependent on the concentrations of DHPs used, type of stressor applied and treatment set-up. Thiocarbatone III-1, E2-134-1 III-4, Carbatone II-1, AV-153 IV-1, and Diethone I could be considered as therapeutic agents for osteoporosis although further research is needed to elucidate their bioactivity mechanisms, in particular in respect to signaling pathways involving 4-hydroxynoneal and related second messengers of free radicals.
Article 0 Reads 0 Citations Searching for inhibitors of human H 2 S-synthesizing enzymes by orthogonal methods Karim Zuhra, Pedro M.F. Sousa, Giulia Paulini, Ana Rita Lemo... Published: 01 May 2018
Free Radical Biology and Medicine, doi: 10.1016/j.freeradbiomed.2018.04.509
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Article 0 Reads 2 Citations Modifications of expression of genes and proteins involved in DNA repair and nitric oxide metabolism by carbatonides [di... Kristīne Ošiņa, Elina Leonova, Sergejs Isajevs, Larisa Bauma... Published: 26 September 2017
Archives of Industrial Hygiene and Toxicology, doi: 10.1515/aiht-2017-68-2945
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Studies on the pathogenesis of diabetes mellitus complications indicate that the compounds reducing free radicals and enhancing DNA repair could be prospective as possible remedies. Carbatonides, the disodium-2,6-dimethyl-1,4- dihydropyridine-3,5-bis(carbonyloxyacetate) derivatives, were tested for these properties. EPR spectroscopy showed that metcarbatone was an effective scavenger of hydroxyl radicals produced in the Fenton reaction, etcarbatone, and propcarbatone were less effective, styrylcarbatone was ineffective. UV/VIS spectroscopy revealed that styrylcarbatone manifested a hyperchromic effect when interacting with DNA, while all other carbatonides showeda hypochromic effect. Rats with streptozotocin induced type 1 DM were treated with metcarbatone, etcarbatone or styrylcarbatone (all compounds at doses 0.05 mg kg-1 or 0.5 mg kg-1) nine days after the DM approval. Gene expression levels in kidneys and blood were evaluated by quantitative RT-PCR; protein expression - immunohistochemically in kidneys, heart, sciatic nerve, and eyes; DNA breakage - by comet assay in nucleated blood cells. Induction of DM induced DNA breaks; metcarbatone and styrylcarbatone (low dose) alleviated this effect. Metcarbatone and etcarbatone up-regulated mRNA and protein of eNOS in kidneys of diabetic animals; etcarbatone also in myocardium. Etcarbatone reduced the expression of increased iNOS protein in myocardium, nerve, and kidneys. iNos gene expression was up-regulated in kidneys by etcarbatone and metcarbatone in diabetic animals. In blood, development of DM increased iNos gene expression; etcarbatone and metcarbatone normalised it. Etcarbatone up-regulated the expression of H2AX in kidneys of diabetic animals but decreased the production of c-PARP1. Taken together, our data indicate that carbatonides might have a potential as drugs intended to treat DM complications.
Article 0 Reads 1 Citation Dihydropyridine Derivatives as Cell Growth Modulators In Vitro Imanta Bruvere, Egils Bisenieks, Janis Poikans, Janis Uldrik... Published: 01 January 2017
Oxidative Medicine and Cellular Longevity, doi: 10.1155/2017/4069839
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The effects of eleven 1,4-dihydropyridine derivatives (DHPs) used alone or together with prooxidant anticancer drug doxorubicin were examined on two cancer (HOS, HeLa) and two nonmalignant cell lines (HMEC, L929). Their effects on the cell growth (3H-thymidine incorporation) were compared with their antiradical activities (DPPH assay), using well-known DHP antioxidant diludine as a reference. Thus, tested DHPs belong to three groups: antioxidant diludine; derivatives with pyridinium moieties at position 4 of the 1,4-DHP ring; DHPs containing cationic methylene onium (pyridinium, trialkylammonium) moieties at positions 2 and 6 of the 1,4-DHP ring. Diludine and DHPs of group 3 exerted antiradical activities, unlike compounds of group 2. However, novel DHPs had cell type and concentration dependent effects on 3H-thymidine incorporation, while diludine did not. Hence, IB-32 (group 2) suppressed the growth of HOS and HeLa, enhancing growth of L929 cells, while K-2-11 (group 3) enhanced growth of every cell line tested, even in the presence of doxorubicin. Therefore, growth regulating and antiradical activity principles of novel DHPs should be further studied to find if DHPs of group 2 could selectively suppress cancer growth and if those of group 3 promote wound healing. 1. IntroductionGrowth modulation, that is, proliferation induction or decline, is fundamental for cellular metabolic processes both in the health and in disease, as well in pharmaceutical interventions. Particularly regenerative medicine needs nontoxic proliferation inducers for cell, tissue, and organ regeneration. On the other side, proliferation inhibitors are necessary for the prevention and inhibition of uncontrolled growth of cancer cells. Recently [1] it was found that same 1-benzyl substituted 1,4-dihydropyridines (1,4-DHPs), activating SIRT1, are proliferation inhibitors in the cancer cells and on the contrary proliferation promoters in the wound healing. Direction of the search of the compounds acting in dual mode seems to be perspective.Cellular redox signaling, including oxidative stress (OS) related events, is connected with genetic and epigenetic regulatory systems. Reactive oxygen species (ROS) and lipid peroxidation products are not only cytotoxic but may also perform and modulate signal transduction in cells. Accordingly, antioxidants (AOs) and radical scavengers may be considered as modifiers of cellular redox signaling, as well as genetic and epigenetic events, and thus 1,4-dihydropyridines being a group of synthetic antioxidants could be used for modulation of cellular redox signaling. Oxidative stress may have at least dual effects on cell proliferation and growth: anticancer-like effects as well as protumorigenic effects. The last ones are primarily related to induction of oxidative DNA lesions (8-OH-G) and consequential increase of DNA mutation frequency. These undesirable changes may, if not repaired, lead to genome instability and an increased rate of cellular proliferation [2]. Antineoplastic (anticarcinogenic, antitumorigenic) effects of OS have been closely linked to cellular processes of senescence and apoptosis, two major molecular mechanisms that counteract tumor development [3]. Which of these two actions will dominate depends on many factors including the metabolic status of the cell, as recently reviewed [4]. Accordingly, many AOs, for instance, curcumin [5], may be antineoplastic and cytotoxic by targeting mitochondria, affecting p53-related signaling and blocking NF-kappa B activation. A number of other curcumin targets include the aryl hydrocarbon receptor, cytochrome P450, glutathione S-transferase, serine/threonine kinases, transcription factors, cyclooxygenase, ornithine decarboxylase, nitric oxide synthase, matrix metalloproteinases, and tyrosine kinases. Some of these targets are characteristic also for DHPs antioxidant action [6].Some of the amphiphilic compounds possessing self-assembling properties and forming nanoparticles in an aqueous medium could form stable liposomes [7–10] which are suitable as gene (pDNA) delivery agents in vitro, while the cytotoxicity and antiradical activity (ARA) of these amphiphilic 1,4-DHP derivatives were determined, too [10].Biological activity of some of these compounds was previously studied (for antioxidant diludine ([11], see as cited in [6]), amphiphilic 1,4-DHP derivative, MDR modifier and suitable gene (plasmid DNA) delivery agent in vitro K-2-11 [10], neuromodulator AP-12 [12, 13], and also close compound Z41-74 [14] (see also Discussion part)). However, physiological activity profile for most of mentioned compounds has not been still determined and published.Presented work includes studies about a set of 11 original 1,4-dihydropyridine derivatives (comprising different substituents at positions 4, 2, and 6 or 3 and 5, containing neutral or cationic moieties, with diverse lipophilic or amphiphilic properties).The studied eleven DHP derivatives could be divided into 3 groups considering structure fragments (see Figure 1, Table 1):(1)1.4-Unsubstituted 1,4-DHP (I, compound in Table 1)(2)1,4-DHPs comprising N-quaternized pyridine moiety at position 4 of the DHP ring (II, compounds (2)–(4) in Table 1)(3)1,4-DHPs containing cationic onium methylene moieties at positions 2 and 6 of the DHP cycle (III, compounds (5)–(11) in Table 1) (in this set previously reported compound (12) (Z41-74) was included for more detailed analysis of relationships)Table 1: Studied 1,4-dihydropyridine derivatives, their chemical structures, molecular weight () values, LD50 values (on NIH 3T3, normal mice embryonal fibroblast cells), and antiradical activity (ARA) determined by DPPH assay. The untreated level of the DPPH radical is designated as 100%. Data are presented as mean ± SD.Figure 1: Core structures of studied 1,4-DHP derivatives (for details see Table 1).These DHPs were studied as potential cell proliferation modulators in two normal (human mammary epithelial cells HMEC and murine fibroblasts L929) and in two malignant cell lines (human osteosarcoma HOS and human cervical carcinoma HeLa). The effects of tested DHPs occurred if they were used alone or together with the well-known anticancer, prooxidant drug doxorubicin. Namely, doxorubicin causes long-lasting stimulation of ROS generation and OS in cancer cells and in cardiomyocytes [15]. Therefore, it is assumed that certain antioxidants (including DHPs) may influence the undesired side effects of doxorubicin, like cardiotoxicity. Some suggestions about DHP structure-activity relationships and selectivity on the above-mentioned cell lines are proposed.2. Materials and MethodsAll DHP derivatives (see further as listed in Table 1 and given in the Results and Discussion part) provided for the cell proliferation evaluation and used in this study have been synthesized in the Laboratory of Membrane active compounds of the Latvian Institute of Organic Synthesis (Latvian IOS).Compound AP-12 was obtained following an already reported method [16]; A2-15 was obtained according to procedure described by Makarova et al. [17]; compounds K-2-11, IOS-10003, D-3-59-1, and K2-71 were obtained following an already reported method [10]; compound IOS-10004 was obtained based on analogy by reported method [10]; compounds V-1-32 and V-1-41 were obtained according to procedure described by [18]; compound IB-32 was obtained according to procedure described by [19].2.1. Antiradical (Free Radical Scavenging) Activity (ARA)ARA data were obtained spectrophotometrically using decoloration reaction ability with 1,1-diphenyl-2-picrylhydrazyl (DPPH) as a free radical scavenger [20], adapted for DHPs [10, 16]. An aliquot (0.5 mL) of the tested 1,4-DHP derivative solution in EtOH was added to 3 mL of freshly prepared DPPH solution in EtOH (0.1 mM). The final concentration of the tested compounds was 0.086 mM and the ratio of the tested compound and DPPH was equimolar. The solution was incubated for 30 min in the dark and changes in the optical density of solution were measured at 517 nm using a UV/Vis Camspec M501 spectrometer (UK). Each assay was performed in triplicate.The scavenging activity was defined as the decrease in sample absorbance versus absorbance of DPPH standard solutions. Results were expressed as a percentage (%) of the DPPH free radical scavenging, which is defined by the following formula:where is the absorbance of the standard solution of DPPH and is the absorbance value for the sample.2.2. Basal Cytotoxicity TestThe Neutral Red Uptake (NRU) Assay was performed according to the standard protocol of [21] modified by NICEATM-ECVAM (Committee on the Validation of Alternative Methods (ICCVAM) of National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Methods (NICEATM)) validation study [22]. The NRU cytotoxicity assay procedure is based on the ability of viable cells to incorporate and bind neutral red, a supravital dye. 3T3 (Mouse Swiss Albino embryo fibroblast) cells (purchased from ATCC®) (9000 cells/well) were placed into 96-well plates for 24 h in Dulbecco’s modified Eagle’s medium (DMEM) containing 5% fetal bovine serum and then exposed to the test compound over a range of eight concentrations (1000, 316, 100, 31, 10, 3, and 1 μg/mL) for 24 h. Untreated cells were used as a control. After 24 h, the medium was removed from all plates. Then, 250 μL of neutral red solution was added (0.05 mg/mL NR in DMEM, 24 h, preincubated at 37°C and then filtered before use through 0.22 μm syringe filter). Plates were incubated for 3 h and then cells were washed three times with PBS. The dye within viable cells was released by extraction with a mixture of acetic acid, ethanol, and water (1 : 50 : 49). Absorbance of neutral red was measured using spectrophotometer multiplate reader (TECAN, Infinite M1000) at 540 nm. The optical density (OD) was calculated using the formula: OD (treated cells) 100/OD (control cells). The values were c