Please login first
Brigita Vigante   Dr.  Senior Scientist or Principal Investigator 
Timeline See timeline
Brigita Vigante published an article in November 2018.
Top co-authors See all
Marina Petrova

73 shared publications

Department of Medicinal Chemistry; Latvian Institute of Organic Synthesis; Aizkraukles 21 LV-1006 Riga Latvia

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

Karlis Pajuste

22 shared publications

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

Brigita Cekavicus

20 shared publications

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

28
Publications
16
Reads
3
Downloads
44
Citations
Publication Record
Distribution of Articles published per year 
(1993 - 2018)
Total number of journals
published in
 
20
 
Publications See all
CONFERENCE-ARTICLE 17 Reads 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
DOI See at publisher website ABS Show/hide abstract

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 Synthesis and Comparative Evaluation of Novel Cationic Amphiphile C12-Man-Q as an Efficient DNA Delivery Agent In Vitro Gunita Apsite, Irena Timofejeva, Aleksandra Vezane, Brigita ... Published: 26 June 2018
Molecules, doi: 10.3390/molecules23071540
DOI See at publisher website ABS Show/hide abstract
New amphiphilic 1,4-DHP derivative C12-Man-Q with remoted cationic moieties at positions 2 and 6 was synthesised to study DNA delivery activity. The results were compared with data obtained for cationic 1,4-DHP derivative D19, which is known to be the most efficient one among the previously tested 1,4-DHP amphiphiles. We analysed the effects of C12-Man-Q concentration, complexation media, and complex/cell contact time on the gene delivery effectiveness and cell viability. Transmission electron microscopy data confirms that lipoplexes formed by the compound C12-Man-Q were quite uniform, vesicular-like structures with sizes of about 50 nm, and lipoplexes produced by compound D19 were of irregular shapes, varied in size in the range of 25–80 nm. Additionally, confocal microscopy results revealed that both amphiphiles effectively delivered green fluorescent protein expression plasmid into BHK-21 cells and produced a fluorescent signal with satisfactory efficiency, although compound C12-Man-Q was more cytotoxic to the BHK-21 cells with an increase of concentration. It can be concluded that optimal conditions for C12-Man-Q lipoplexes delivery in BHK-21 cells were the serum free media without 0.15 M NaCl, at an N/P ratio of 0.9. Compound D19 showed higher transfection efficiency to transfect BHK-21 and Cos-7 cell lines, when transfecting active proliferating cells. Although D19 was not able to transfect all studied cell lines we propose that it could be cell type specific. The compound C12-Man-Q showed modest delivery activity in all used cell lines, and higher activity was obtained in the case of H2-35 and B16 cells. The transfection efficiency in cell lines MCF-7, HeLa, and Huh-7 appears to be comparable to the reference compound D19 and minimal in the HepG2 cell line.
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
DOI See at publisher website
CONFERENCE-ARTICLE 10 Reads 0 Citations <strong>Design and Synthesis of Small-molecule Hepatitis B Virus Capsid Self-assembly Inhibitors</strong> Anda Sīpola, Unda Dubova, Brigita Vīgante, Karīna Spunde, Ta... Published: 01 November 2017
3rd International Electronic Conference on Medicinal Chemistry, doi: 10.3390/ecmc-3-04679
DOI See at publisher website ABS Show/hide abstract

An estimated 240 million persons worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B (CHB) in up to 40% of cases progresses to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma, a leading cause of cancer-related morbidity and mortality worldwide [1]. We are focused on original antiviral strategy intended to suppress the self-assembly process of HBV core (HBc) protein as one of the promising ways to cure CHB without induction of drug resistance. Targeting the capsid protein of HBV and thus interrupting normal capsid formation have been an attractive approach to block the replication of HBV.

Heteroaryldihydropyrimidines (HAPs) were shown to bind the HBV core proteins and misdirect the assembly of the capsid in vitro. We carried out structural optimizations based on HAPs analogue Bay 41-4109 and structure-activity relationship studies [2].

Newly synthesized HAPs 1 and 2 were evaluated for their ability to disrupt the capsid assembly in cell culture, and promising candidates were selected for further evaluation of antiviral activity and discovery of mechanisms of compound action.

 

Acknowledgments: The author gratefully acknowledges Gunārs and Renāte Duburi for provided scholarship.

References:

[1] World Health Organization (2016) WHO Hepatitis B Fact Sheet (World Health Organization, Geneva)

[2] Qiu, Z. et.al. (2016), Design and Synthesis of Orally Bioavailable 4-Methyl Heteroaryldihydropyrimidine Based Hepatitis B Virus (HBV) Capsid Inhibitors. J. Med. Chem. 59, 7651-7666

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
DOI See at publisher website ABS Show/hide abstract
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
DOI See at publisher website ABS Show/hide abstract
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
Top