Natural and Synthetic Coumarins and Their Pharmacological Activity 169
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European Journal of Clinical and Experimental Medicine Natural and Synthetic Coumarins and their Pharmacological Activity 169 © Wydawnictwo UR 2017 http://www.ejcem.ur.edu.pl/en/ ISSN 2544-1361 (online); ISSN 2544-2406 European Journal of Clinical and Experimental Medicine doi: 10.15584/ejcem.2017.2.12 Eur J Clin Exp Med 2017; 15 (2): 169–175 REVIEW PAPER Tomasz Kubrak 1,2 (ABCDEFGH), Rafał Podgórski 1,2 (ABCDEFGH), Monika Stompor 1,2(ABCDEFGH) Natural and Synthetic Coumarins and their Pharmacological Activity 1 Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszów 2 Department of Biochemistry, Faculty of Medicine, University of Rzeszów ABSTRACT Coumarins are a structurally diverse group of natural substances derives from plants that display a host of bioactivities. In this paper, we will introduce the reader to coumarins and their applications as medicinal substances. The great diversity in courmarin structure will be discussed along with their extensive use as pharmaceutical agents. Coumarins display a wide range of antimicrobial activity and applications of coumarins as antifungal and antiviral agents will be addressed. Other properties of coumarins such as their role in neuroprotection, anticancer, and as antioxidants will also be reviewed. Keywords. coumarins, antimicrobial agents, neuroprotection, natural products in medicine Introduction Structural diversity of coumarins Coumarins form an extensive group of natural substances The structural diversity of natural coumarins is the basis known as secondary metabolites. They are found in over for classifying them into four groups: 150 different speciesof plantsbelonging to almost 30 differ- 1. coumarin derivatives, e.g.simple coumarin, com- ent families.The families containingthe highest content of pounds formed by two rings: benzene and α-pi- coumarinsare: Rutaceae, Clusiaceae, Guttiferae, Caprifolia- ron. Substituents are often hydroxyl, methoxy and ceae, Oleaceae, NyctaginaceaeandApiaceae.1 Coumarin com- aliphatic groups, at the C7, C6 and C3 positions of pounds accumulate in large quantities in fruits (such as cit- benzopyrone (Fig. 1). rus fruits), vegetables (eg. celery), roots, flowers and leaves. In smaller quantities they are isolated from bark and stems.2 Coumarins, in addition to occurring in vascular plants, are also found in bacteria and fungi such as novo- biocin and coumermicin which are known antibiotics synthesized by bacteria. In contrast, Aspergillus flavus is a source of aflatoxin, a highly carcinogenic substance with acoumarin ring in its structure.3 Figure 1. Chemical structure of coumarin Corresponding author: Tomasz Kubrak, e-mail: [email protected] Participation of co-authors: A – Author of the concept and objectives of paper; B – collection of data; C – implementa- tion of research; D – elaborate, analysis and interpretation of data; E – statistical analysis; F – preparation of a manuscript; G – working out the literature; H – obtaining funds Received: 12.02.2017 | Accepted: 06.06.2017 Publication date: June 2017 Kubrak T, Podgórski R, Stompor M. Natural and Synthetic Coumarins and their Pharmacological Activity. Eur J Clin Exp Med. 2017;15(2):169–175. doi: 10.15584/ejcem.2017.2.12 170 European Journal of Clinical and Experimental Medicine 2017; 15 (2): 169–175 2. isocoumarin derivatives,formed by benzene rings and α-isopirone. They have substituents in positions C3, C6, C7 and C8 (Fig. 2). They are isolated mainly from fungi: Artemisia, Aspergilus, Fusarium, Penicil- linium, Stremtomycesand the few plants belonging to families:Compositae, Leguminoseaeand Myriaceae.4 Figure 4. Chemical structure ofpyrancoumarin Figure 2. Chemical structure of isocoumarin 3. furanocoumarin derivatives, (Fig. 3) formed by the coupling of the coumarin ring with the furan ring at Figure 4A. Xanthyletin-type the C6-C7 position (psoralen type, Fig. 3A) or in the C7-C8 position (angelicin type, Fig. 3B). Figure 4B. Seselin-type Pharmacological Activity of Coumarins Figure 3. Chemical structure of furanocoumarin Coumarins are a group of biologically active compounds. They are produced by living organisms (plants, fungi and bacteria) as secondary metabolites. Their activities are, among others, anti-inflammatory, antithrombotic, anti- microbial, antifungal, antiviral (including anti-HIV), anticonvulsant, antioxidant, and antitumor.1 Anti-inflammatory activity of coumarins Figure 3A. Psoralentype Coumarins (1,2-benzopyrone) haveanti-inflammatory properties andhavebeen used to treat oedema, helping wound healing. This removes protein and oedemafluid from injured tissue by stimulating phagocytosis and pro- teolytic enzyme production.5 Esculetin exhibited anti-in- flammatory activityin rat colitis.6 Also, esculetin inhibits the cyclooxygenase and lipoxygenase enzymes, which results in an anti-inflammatory effect.7 Anticoagulant activity of coumarins Figure 3B. Angelicintype Vitamin K is a co-catalyst for the carboxylation reac- tion of the glutamic acid residue with γ-carboxyglutamic 4. pyrancoumarin derivatives,coumarine ring is con- acid. The carboxylation process affects the further normal densed with pyran ring (Fig. 4). Ring condensation activity of coagulation factors II, VII, IX and X. Warfa- at the C6-C7 position is defined by the xanthyle- rin interferes with the cycle of vitamin K metabolism, tin-type (Fig. 4A), or in position C7-C8 a seselin-type resulting in liver deposition of partially carboxylated and (Fig. 4B). decarboxylated proteins. These proteins are characterized Natural and Synthetic Coumarins and their Pharmacological Activity 171 by decreased procoagulant activity.8 Coumarins interfere tis cinerea [Pers.], Sclerotiniasclerotiorum [de Bary] and with the carboxylation process of C and S protein, caus- Fusarium graminearum [Patch].13 A number of coumarins ing a procoagulant effect.1 have been tested for antifungal activity, and the three most It has been shown that the warfarin - coumarin deriv- effective ones are psoralen, imperatorin, and ostruthin.14 ative, used as an oral anticoagulant, negatively affects the γ-carboxylation of glutamate residues of bone proteins. Antiviral activity of coumarins As a result of its action in pregnant mothers and those Coumarin derivatives can also have a reverse transcrip- taking warfarin preparation, the fetal skeleton develops tase (RT) inhibitory effectand two isomers (+)-calano- abnormally.8 lide A and (-)-calanolide B isolated fromCalophyllumlan- Warfarin has shown particularly promising results igerum(Clusiaceae), belong to pyranocoumarin, inhibit RT in the treatment of SCCL (Small Cell Carcinoma Lung) activityandcompletely deactivate the replication process a tumour cell type that is characterised by a coagula- of HIV-1.15,16 Others coumarin derivatives – inophyllum tion-associated pathway.9 B i P obtained from an giant African snail Achatinafu- lica[Férussac]significantly inhibit RT activity in HIV-1 Antimicrobial activity of coumarins cell cultures.17 Most coumarins have very low antimicrobial activity, but Aminomethyltrimethyl psoralen (AMT) is usedas a compounds having long chain hydrocarbon substitutions photo-sterilizing agent and is added to blood products such as ammoresinol and ostruthin have a high activity followed by exposure to UVA radiation. AMT has inac- towards gram(+) bacteria andshow antimicrobial activity tivated DNA and RNA viruses.18 Sancho et al. showed on Bacillus megaterium, Micrococcus luteus, Micrococcus that imperatorin also inhibits either vesicular stomatitis lysodeikticusand Staphylococcus auerus. virus or gp-160-enveloped recombinant HIV-1 infection Anthogenol, a coumarin derivative isolated from in several T-cell lines and in HeLa cells.19 green fruits Aegle marmelos (L.),exhibits antimicrobial activity against bacteria of the genus Enterococcus.1 Imper- Antihypertensive activity of coumarins atorinshows high activity towards Shigella dysenteriae.10 Scopoletin, a coumarin isolated from the fruits of Tet- Pyranocoumarins such as grandivittin, agasyllin, rapleuratetraptera (Mimosaceae), in laboratory animals aegelinol benzoate and osthole isolated from the root Feru- shows a smooth muscle relaxant effect onblood vessels lagocampestris(Besser) Grecescu(Apiaceae) show activity resulting in a drop in blood pressure. A similar action towards both gram(+) andgram(-)bacteria, for example wasshown by dihydromammea; a coumarin isolated from on Staphylococcus aureus, Salmonella typhi, Enterobacter the seed of the tree Mammeaafricana [L.] (Guttiferae).1 cloacae, Enterobacter aerogenesand Helicobacter pylori.11 Visnadine – pyranokumarin, an active ingredient Coumarins are mainly isolated from higher plants, but extracted from the fruit of Ammi visnaga, exhibited some of them have been discovered in microorganisms. peripheral and coronary vasodilator activities. It is used Examples include novobiocin, coumermycin, and chartre- adjunctively to treat angina pectoris.20 usin. Novobiocin, a secondary metabolite of Streptomyces niveusand Streptomyces spheroidesexhibit very high activ- Antioxidant activity of coumarins ity towards gram(+) organisms such as Corinebacterium Coumarin antioxidant activity is manifested by the diphtheria, Staphylococcus aureus, Streptomyces pneumo- ability to inhibit reactive oxygen species(ROS) and niae, Streptomyces pyogenesandgram(-) organisms such as to capture them. Studies in rats have shown that the Haemophillusinfluenzae, Neisseria meningitides andPas- inhibition of xanthine oxidase - the enzyme responsi- teurella. Coumermycin,