Cardiac Glycosides - Research Paper Example

Table of Contents Abstract 2 1 Introduction 2 Figure 1 3 2Bioactivities 4 2.1 Antiarrhythmic activity 4 Fig. 2CG Mechanism of Action 5 2.2 Anticancer activity 5 2.3 Antiviral activity 6 2.4 Central nervous activity 6 3 Biosynthesis 6 Figure 3. Biosynthesis of Glycoside 7 Scheme 2. Biosynthesis of digitoxigenin 8 4. Chemical synthesis 8 Figure 4 9 Scheme 3. Chemical modification of digitoxin 11 5. Structure-Activity Relationship 11 6Conclusion 13 References 14 Abstract Cardiac glycosides are category of medication that is used to treat heart failure as well as certain asymmetrical heartbeats. since cardiac glycosides are located in the leaf of the digitalis plant (the original foundation of this medication). In other words, Cardiac glycosides (CGs) are organic compounds that occur in nature which possess inotropic effect on heart.CGs are composed of two portions, a sugar (glycoside) and an aglycone (steroid), which attach to an R-group. CGs mostly isolated from plants, there are so much effort to understand thire biosynthetic pathway. These compounds have become important in treating heart-related conditions. This review summarizes the chemical structures, bioactivities, and modern uses of CGs. 1 Introduction Cardiac glycosides (CGs) happens to be a group of organic compounds thathave the ability to induce cardiotonic effects and also, occur naturally in several plants, as well as in a species of toad.1Thenomenclature of CGs usually is derived from the name of the plant they occur in. The species Nerium oleander(Oleandrin), Antiaris toxicaria, Digitalis purpurea(Digitoxin, gitoxin,gitalin), Digitalis lanata(Digoxin, digitoxin, gitoxin), Strophanthus kombe(Strophanthus), and Strophanthus gratus (Ouabain) species are all major plant sources of CGs.William Withering was the first to note the therapeutic benefits caused by an active ingredient in the foxglove (Digitalis purpurea)--- the ingredient being a cardiac glycoside (digoxin)—as early as 1785.2The mechanisms of action for this compound were not fully understood, however, until Schwartzman and colleagues identified the plant compounds as potent Na+/K+-ATPaseinhibitors that disrupt electrophysiological properties of the heart.3The R group at the 17-position defines the class of cardiac glycoside (Figure 1), which as mentioned earlier, designates them as cardenolides or bufadienolides . The bufadienolides have apyrone ring while the cardenolides have an unsaturated butyrolactone ring. Bufadienolides are mostly found in animals, while cardenolides occur mainly in plants. Figure 1 Modern methods have allowed for the manufacture of safe synthesized or purified versions of CGs(with the exception of some stronger variants, namely3) such as 2(drug name: Lanoxin, Digitek, or Lanoxicaps) and digitoxin 1 to be used clinically as cardiotonic drugs to treat congestive heart failure, atrial fibrillation because of their ability to improve the contractile force of the myocardium. Digitoxin 1, digoxin 2, and ouabain 3have been used for the past 200 years in the treatment of congestive heart failure, sometimes for their destructive qualities, such as on tips for poison arrows (Strophanthus) 4. Channelomic roles of CGs in bioactivities relating to the heart, structure activity relationship of CGs, and CG biosynthesis and chemical synthesis will be discussed. 1 2 3 2Bioactivities 2.1 Antiarrhythmic activity GCs act by suppressingthe routine pumps in the cardiac myocytes (cells responsible for controlling heart rate) after phase 3 (at which time full repolarization of heart should occur) so that sodium cannot be released and therefore builds up within the cell—a result that in turn stops another type of exchanger (Na+/Ca2+) in the cell from releasingcalcium, which leads to a calcium buildup as well. As mentioned in the introduction, CGs are potent Na+/K+-ATPase (sodium-potassium pump)inhibitors, thereby leading to a chain of reactions that affectheart excitability( action potential development).3The extra calcium is absorbed by the sarcoplasmic reticulum (SR) 5. When the single transverse tubule (T tubule) signals the SR to release Ca2+,the SRreleases higher amounts of calciumthereby stimulating stronger muscle cell contraction(Figure 2). Fig. 2CG Mechanism of Action 2.2 Anticancer activity Oleandrin (from the species Nerium oleander) is a CG that is already being used for treating colon and lung cancers, leukemia, pancreas cancer, and prostate cancer.6 In addition, it induces cell death, by means of reactive oxygen species (ROS) proliferation. In the past few years, interest in CGs as an anticancer chemotherapy primary or joint treatment has led to include in vivo and in vitro studies with promising findings. The complex cell-signal transduction mechanismsof various CGs could be potentially useful in targeting tumors. Cytotoxicity potential of CGs and their effects are still being studied. 2.3 Antiviral activity The compound, in concentration of 1 μg/ml (IC50=0.86 μg/ml), showed reduction of the virus titre by 69.3% inhibition.8A cardiac glycoside from theAdenium obesumspecies was identified as oleandrigenin-β-D-glucosyl (1→4)-β-D-digitalose in 2011.7 Another study showed that two cardiac glycosides showed moderate activity against herpes simplex virus types 1 and 11 (HSV1 and 11). 2.4 Central nervous activity Cardenolides from the methanolic extract of Nerium oleanderleaves as shown or illustrates clealy the central nervous system slow down activity in mice at a dosage of 50 mg/kg.9 3 Biosynthesis The aglycone portion and the sugar parts are biosynthesized separately and join afterwards.10Due to the difficulty of cardiac glycoside synthesis, CG supply reliance rests on natural sources. This joining occurs after uridine diphosphate sugar (UDP-sugar) is created then reacts with the aglycone to form the glycoside. UDP-sugar is synthesized from a reaction between sugar 1- phosphate(a product of phosphorylation of a sugar ) and uridine triphosphate (UTP) (Figure 3). Figure 3. Biosynthesis of Glycoside The aglycone portion in cardiac glycosides is steroid in nature. The steroid nucleus is biosynthesized via acetate HMG-CoA reductase pathway (polyketide).Our knowledge about biosynthesis of steroid compounds stems from observations of cholesterol biosynthesis pathways.The cholesterol formation may be considered a model for the general mechanisms of steroid biosynthesis. Elucidation regarding digitoxigenin biosynthetic pathways is limited. There is an alternate option midway between pregnenolone and digitoxigenin -- progesterone -- which may be involved in the metabolic saturation of the C-5 double bond.Digitoxigenin would be good example for biosynthesis of a cardiac glycoside. The biosynthetic pathway starts with acetate as is typical for steroid containing compounds.10 Converting pregnenolone (a steroid hormone responsible for synthesizing other steroid hormones) to a cardenolide (a CG with a 5-membered lactone ring in the side chain of the steroid aglycone) involves several reaction steps, including : saturation of the C-5 double bond, hydroxylation and inversion of the asymmetric center at C-14, formation of lactone ring formed by condensation of a C-21 steroid intermediate with a C2 unit(Scheme 2). Scheme 2. Biosynthesis of digitoxigenin 4. Chemical synthesis There are many strategies used to modify the chemical structure of CG. One of them is by chemically modifying the steroid core.16Replacement of glycone moiety-- replacement of natural digioxide with monosaccharidemoiety--is another example. Unprotected sugar can be conjugated to a digitoxigenin-derived methylamine to form N-glycosides. There are several reasons why chemical synthesis or chemical modification of CGs is desirable. For one, it would solve the problem of low therapeutic index of CGs that afflicts patients undergoing digoxin or digitoxin treatment. Also, it would help create new CGs with better biological activity and better pharmacokinetic profiles.Recently, CGs have received renewed attention due to potential activity against cancer. Due to the presence of an axial OH, digitoxin metabolism will form three metabolites 4, 5, and 6 (Figure 1). 5 and 6 have high binding affinity and strong inhibition activity on Na+,K+-ATPase channel (Figure 4).17Due to their short half-life, 5 and 6are not using clinically. Figure 4 In recent chemical structural modificationsto digitoxin, glycone moiety has been replaced by ethylene glycol.18 It has been observed that etlelyne glycol can partly mimic the protein glycosylation effect. Various digitoxin analogues have been synthesized using different lengths of ethylene glycol to replace the glycone moiety of digitoxin. In the Jones condition, digitoxin 1 converted to digitoxigenon (13) following glycosidic cleavage and alcohol oxidation.18 Ketone 13 treated with sodium borohydride at low temperaturesyields 3-epi-digitoxigenin 14 with very small portion of unwanted digitoxigenin (6). 15 is formed as a result of secondary alcohol 14. 15 is then substituted by potassium thioacetate to form thioacetyl steroid 16. By using NH3 in Meoh/THF(1:1), thodigitoxigenin 17 was obtained. Oxidation of free thiol 17 to disulfide 18 has been easily achieved by column chromatography.The complete process is summarized in scheme 3: Scheme 3. Chemical modification of digitoxin 5. Structure-Activity Relationship A-ring fuses to B- ring in cis configuration. C ring also fuses in cis configuration to a D- ring. B and ring C have a transfusion and those configurations are essential for CG activity. 3-β OH group at C-3 is involved in glycosidic linkage.As stated earlier, all cardiac glycosides are composed of a sugar moiety and an aglycone portion. All aglycones in CGs are steroids and they have typical tetracyclic rings.11 The steroid nucleus is essential for cardiac activity. compounds that bear resemblance to digitoxin have increased interaction to P-gp caused by hydroxyl groups at positions 1β, 12β, and 16β. A deeper understanding of the interactions between CGs and P-gps may result in the synthesis of a new cardiac glycoside with less toxicity. Digitoxin interaction with P-glycoprotein (P-gp) is an important factor in its toxicity.12 It is also found in digoxin-like compounds that contain a δ-lactone ring and a sugar moiety at 3-β of the steroid nucleusand are favorable for its binding to P-gp. The sugar moieties in CGs lie in the β-conformation. The acetyl group of the sugar affects the lipophilic properties and the kinetics of the CG. There is no evidence that the acetyl group plays a key role in biological activity.13Hepatic transporters such as organic anion used in transporting polypeptide (OATP), as well as IBI, OATP1B3, and NNa (+) dependent taurocholate cotransporting polypeptide (NTCP) influence the disposition of a variety of drugs by regulating their absorption into the hepatocytes. The sugar moiety and hydroxyl groups have been known to play important roles in CG interactions with NTCP, OATPAB1, and OATP1B13. Sugar type and length is responsible for anticytomegalovirus (CMV) activity.14CGscontaining a 1-sugar have shown anti-CMV activity and more investigation may lead to better understanding the mechanisms of the anti-CMV activity. It is found that the potency is increased by the presence of C-4.C-6 unsaturation and a C-6 substituent (CH3, Cl, Br).15 C-6 alpha substitution with –CH3,-Cl, or –Br further increased the activity. Substitution with –F,-OCH3, carbonyl, or substituted compounds on C-6 alpha, on the other hand, leads to weak binding. -OC2H5,-OAC,-OCOOCH,or –OH eliminate biding activity.Progesterone derivative compounds and their interaction with the digitalis receptors have been studied by using [3H] ouabain in a radioligand assay. 6Conclusion Books about CGs and their effects have been in circulation since the 18th century, yet there is still a lot to explore about the varied mechanisms of action of these compounds. Understanding the chemical biosynthetic pathways of cardiac glycosides would allow us to improve the yield of cardiac glycosides synthesis by successfully modifying the plant genes involved in cardiac glycoside biosynthesis. Although CGs, particularly those derived from plant material, have had wide usage since ancient times, more and more CG types are being considered for usage in drugs for an increasing number of applications. There are many potent variants of CGs, many of which greatly disrupt bioactivities in the body and lead to a myriad of reactions and effects-- many of which have yet to be elucidated upon( CG mechanisms of action are still not completely known) -- making this class of compounds of particular pharmacological interest.This may lead to the synthesization of new cardiac glycosides with increased biological activity and decreased toxicity. References 1- Calderón-montaño, JM.; Burgos-morón, E.: Orta, M.; Maldonado-navas, D.; García-domínguez, I.; López-lázaro, M. Evaluating the cancer therapeutic potential of cardiac glycosides. Biomed. Res. Int. 2014, 2014, 794930. 2- Breckenridge, A. William Withering's legacy--for the good of the patient. Clin. Med. 2006, 6, 393-7. 3- Schatzmann, HJ.; Räss, B. Inhibition of the active Na-K-transport and Na-K-activated membrane ATP-ase of erythrocyte stroma by ouabain. Helv. Physiol. Pharmacol. Acta. 1965, 65(1),C47-9. 4- Belcastro, PF. Digitalis: from folklore remedy to valuable drug. J. Am. Pharm. Assoc. 2002, 42(6), 857. 5- Gheorghiade, M.; Van, veldhuisen DJ.; Colucci, WS. Contemporary use of digoxin in the management of cardiovascular disorders. Circulation.2006, 113(21), 2556-64. 6- Arvind, K.; Tanmoy, D.; Amrita M.; Arun K, M. Oleandrin: A cardiac glycosides having the potent cytotoxicity in it. 7.- Kiyohara, H.; Ichino, C.; Kawamura, Y. In vitro anti-influenza virus activity of a cardiotonic glycoside from Adenium obesum (Forssk). Phytomedicine. 2012, 19(2), 111-4. 8- Wangteeraprasert, R,; Lipipun, V.; Gunaratnam, M. Neidle, S.; Gibbons, S.; Likhitwitayawuid, K. Bioactive compounds from Carissa spinarum. Phytother. Res. 2012, 26(10),1496-9. 9- Siddiqui, & Suria, A. Cardenolides from the methanolic extract of Nerium oleander leaves possessing central nervous system depressant activity in mice. J. Nat. Prod. 1997, 60(6), 540-4. 10-Claus, E.; Tyler, Varro.; Brady, Lynn. Pharmacognosy; Henry Kimpton: London, 1970, p 80.11-Lemake, T.; Williams, David. Foye’s Principles of Medicinal Chemistry; Lippincott Whillams & Wilkins, Wolters Kluwer: Philadelphia, 2008, p 699. 12- Gozalpour, E.; Wittgen, H.; Van den, h.; Greupink, R.;Russel, F.; Koenderink, J. Interaction of digitalis-like compounds with p-glycoprotein. Toxicol Sci. 2013, 131(2),502-11. 13—Gozalpour, E.; Greupink, R.; Wortelboer, H. Interaction of digitalis-like compounds with liver uptake transporters NTCP, OATP1B1, and OATP1B3. Mol Pharm. 2014, 11(6),1844-55. 14- Cai, H.;Wang, H.; Venkatadri, R. Digitoxin analogues with improved anticytomegalovirus activity. Med Chem Lett. 2014, 5(4), 395-9. 15- Templeton & Labella, F. Structure-activity relationships of progesterone derivatives that bind to the digitalis receptor: modifications in A and B rings. Steroids. 1987, 49(4-5), 383-96. 16- Beale TM, Taylor MS. Synthesis of cardiac glycoside analogs by catalyst-controlled, regioselective glycosylation of digitoxin. Org Lett. 2013;15(6):1358-61. 17- Graves, P.; Fenster, P., Macfarland, Marcus &Perrier, D. Kinetics of digitoxin and the bis- and monodigitoxosides of digitoxigenin in normal subjects. Clin Pharmacol Ther. 1984, 36(5), 601-6. 18- Jensen, M.; Schmidt, S.; Fedosova, N. Mollenhauer, J.; Jensen, H. Synthesis and evaluation of cardiac glycoside mimics as potential anticancer drugs. Bioorg Med Chem. 2011, 19(7), 2407-17. Read More