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Aivars Krauze  - - - 
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G. Duburs

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

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(1998 - 2018)
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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 5 Citations 1,4-Dihydropyridine Derivatives: Dihydronicotinamide Analogues—Model Compounds Targeting Oxidative Stress Astrīda Velēna, Neven Zarkovic, Koraljka Gall Trošelj, Egils... Published: 01 January 2016
Oxidative Medicine and Cellular Longevity, doi: 10.1155/2016/1892412
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Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry.1. Introduction1,4-Dihydropyridines (DHPs) [1], including Ca2+ antagonist (CA) drugs [2], are large group of structurally diverse compounds. Functionally, they are similar to dihydronicotinamide redox-active synthetic compounds with radical scavenging and antioxidant (AO) properties and may be considered as protectors against oxidative stress (OS) and associated disorders [3].Oxidative stress is extremely important for molecular pathogenesis, especially influencing the redox regulation of cellular signaling pathways [4–7]. Oxidative stress closely relates to presence of oxygen and nitrogen free radicals, known as reactive oxygen species and reactive nitrogen species (ROS and RNS, resp.). They cumulatively increase upon cellular exposure to various endogenous and/or exogenous insults. ROS and RNS have the “two-faced” character and play a dual role as both deleterious and beneficial species [8, 9]. Although explored in many diseases, various phenomena related to OS have been probably best studied in cancer cells in which, depending on various factors, OS may have anticancer-like effects. Its protumorigenic effects are primarily related to induction of oxidative DNA lesions (8-OH-G) and consequential increase of DNA mutations that may, if not repaired, lead to genome instability and an increased rate of cellular proliferation [10]. On the other hand, antitumorigenic actions of OS have been closely linked to cellular processes of senescence and apoptosis, two major molecular mechanisms that counteract tumor development. Which of these two actions will dominate depends on many factors including the metabolic status of the cell, as recently reviewed by Kujundžić et al., 2014 [11].Antioxidants (AOs) are defined as substances that, even when present in low concentrations compared to those of an oxidizable substrate, prevent or significantly delay the oxidation process (Halliwell and Gutteridge, 1995 [12]). Their activity depends on complex factors including the nature of the antioxidants, the condition of oxidation, the properties of substrate oxidized, and the level of oxidation (reviewed in Kancheva and Kasaikina, 2013 [13]). Accordingly, an antioxidative effect may be direct, resulting from direct ROS scavenging, or indirect from the influence on various signaling pathways related to cellular defense, that is, stress responses. In relation to human physiology, antioxidants are traditionally classified as exogenous (supplied mostly through food) and endogenous and are further subclassified as enzymatic (i.e., superoxide dismutase (SOD) and catalase (CAT)) and nonenzymatic (i.e., glutathione, vitamins A, C, and E, etc.) [3].DHPs could be classified as the separate group of synthetic nonenzymatic, however, biomimetic AOs.2. Oxidative Stress and Its Prevention: Wavy Scientific Process Development—Pro et ContraThere are opposite views both towards the role of oxidative stress and about potential applications of exogenous antioxidants in onset of OS [14–16].Herewith, we need to mention that antioxidants have been studied for decades (starting from 1970s) as the tools for the treatment of various disorders. The role of native and synthetic antioxidants (acting on lipid peroxidation (LP) in biological membranes) in radiation damage and malignant growth was seriously evaluated [17]. The overall conclusions point out antioxidants role in decreasing the damage of cells by reducing oxidants before the occurrence of cellular damage [14]. It was elicited and accented (Burlakova et al. [15]) that(i)antioxidants, nontoxic inhibitors of free radical processes, exhibit a wide gamut (pleiotropy) of biological activity (as further will be reported, this phenomenon is also characteristic for the DHP antioxidants group);(ii)the biological effectiveness of AOs correlates with their antioxidant activity (AOA);(iii)depending on dose, AOs may either increase or decrease the AOA;(iv)the efficacy of AO depends on the time of introduction in the course of medical treatment because the development of the disease may be accompanied by stages of changing the AOA. In relation to dose-effect dependence, Burlakova et al. [15] have found the nonlinear pattern: after addition of an AO, there is an initial increase of AOA, followed by returning to normal and finally decreasing drastically below the normal value. Therefore, antioxidants may produce a specific effect by decreasing (at low doses) or increasing (at high doses) the rate of free radical reactions. Hence, the compound may be efficient AO only if it is introduced in a low dose at the stage of reduced AOA or in a high dose at the stage of AOA elevation. The widespread opinion of opponents was that the antioxidant function, even that of tocopherol, was a side effect of its activity and important only for in vitro processes and without any role in bioobjects life. This opinion was supported by the fact that the deficiency of natural AO tocopherol (E-avitaminosis) cannot be cured completely by applying synthetic AO. Eventually, it was not certain also that detected lipid peroxides have been generated in vivo in the intact organs and were not artificially formed during the isolation [15]. All these objections and skepticism were rejected in due time.However, some other research directions were suggested.Fang et al. [18] reported two different therapeutic strategies for modulating OS in cancer and inflammation, including (1) antioxidant therapy and (2) “oxidation therapy.”For (1), polymeric superoxide dismutase (e.g., pyran copolymer-SOD), xanthine oxidase (XO) inhibitor, developed water-soluble form of 4-amino-6-hydroxypyrazolo[3,4-d]pyrimidine (AHPP), heme oxygenase-1 (HO-1) inducers (e.g., hemin and its polymeric form), and other antioxidants or radical scavengers (e.g., phenolic compound canolol, 4-vinyl-2,6-dimethoxyphenol) were used.About (2), besides neurodegenerative diseases, cancer may represent yet another very interesting field for exploring antioxidants and prooxidants as therapeutic substances due to their cytotoxic effects (including overproduction of ROS) that, if achieving proper selectivity, may be used for cancer cells destruction (Fang et al. [18]). To achieve this goal, a unique therapeutic strategy was developed, named as “oxidation therapy,” by delivering cytotoxic ROS directly to the solid tumor or alternatively inhibiting the antioxidative enzyme system, such as HO-1 in tumor. This anticancer strategy was examined by use of or H2O2-generating enzymes (i.e., XO and d-amino acid oxidase [DAO], resp.) and by discovering the inhibitor of HO-1 (i.e., zinc protoporphyrin [ZnPP] and its polymeric derivatives).While deleterious when present at high concentrations, low concentrations of ROS exhibit beneficial properties needed for controlling physiological cellular processes (reviewed in Valko et al., 2007 [19]).Jimenez-Del-Rio and Velez-Pardo [20] have discussed oxidative stress as an important etiopathogenic factor for occurrence and development of neurodegenerative diseases (notably Alzheimer’s disease and Parkinson’s disease) and cancer. As an extension, possible preventive and therapeutic values of antioxidants were also discussed. Indeed, if considered within a narrow context of oxidative homeostasis, antioxidants may seem to be ideal weapon in preventing and fighting these diseases. However, the context of human pathology is very broad and, so far, there was little benefit of exogenous antioxidants in human intervention studies or clinical trials. There are numerous reasons for these failures. Maybe, the most important one is the design of the preclinical studies, especially related to concentration of the antioxidant used and time parameters relevant to the clinical setting (Kamat et al., 2008 [21]). The imbalance between uncritical acceptance of antioxidants as powerful “drugs” for various pathological conditions and disappointing results obtained in clinical studies has made a sort of confusion. This issue was addressed by Bast and Haenen [16] through listing ten misconceptions related to commercialized applications of antioxidants: (a) “pros”: (1) antioxidants can cure any disease; (2) the more the better; (3) any AO will do (the trick); (4) AO status measures the level of health; (5) natural AOs are superior (over synthesized ones) and (b) “contras”: (1) AOs increase mortality; (2) when present at high doses, antioxidants become prooxidant; (3) theoretically, antioxidants cannot behave as such; (4) once used, antioxidants are inactive; (5) antioxidant drugs do not work.The first three “pros” clearly cross the line of realistic way of thinking and cannot be considered seriously. The “pro” #4 was very informatively discussed by Pompella et al. [22] who comprehensively presented current problems with the methods (ORAC, oxygen radical absorbance capacity; ferric-reducing abili
Article 0 Reads 0 Citations Synthesis of 6-alkylsulfanyl-1,4-dihydropyridines as potential multidrug resistance modulators Aivars Krauze, Laura Krasnova, Signe Grinberga, Elina Sokolo... Published: 01 January 2016
Heterocyclic Communications, doi: 10.1515/hc-2016-0034
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Article 0 Reads 0 Citations Synthesis of polysubstituted pyridines as potential multidrug resistance modulators Aivars Krauze, Signe Grinberga, Elina Sokolova, Ilona Domrac... Published: 01 January 2015
Heterocyclic Communications, doi: 10.1515/hc-2015-0037
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Article 0 Reads 3 Citations Thieno[2,3-b]pyridines—A new class of multidrug resistance (MDR) modulators Aivars Krauze, Signe Grinberga, Laura Krasnova, Ilze Adlere,... Published: 01 November 2014
Bioorganic & Medicinal Chemistry, doi: 10.1016/j.bmc.2014.09.023
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Article 0 Reads 0 Citations ChemInform Abstract: Effective Method of Lipase-Catalyzed Enantioresolution of 6-Alkylsulfanyl-1,4-dihydropyridines. Zigmars Andzans, Ilze Adlere, Aleksandrs Veršilovskis, Laura... Published: 10 April 2014
ChemInform, doi: 10.1002/chin.201417162
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