Continue to access RSC content when you are not at your institution. Follow our step-by-step guide. Cardenolides and bufadienolides constitute an attractive class of biologically active steroid derivatives which have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy. Due to their application as therapeutic agents and their unique molecular structures, bearing unsaturated 5- or 6-membered lactones or other heterocycles attached to the steroid core, cardio-active steroids have received great attention, which has intensified during the last decade, in the synthetic organic community.
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Plant active metabolites are under intensive examinations around the world to supplement the drugs with minimal side effects. Thus, there is vast potential to explore the possible medicine from the plant sources.
Cardiac glycosides are a unique group of secondary metabolites that they are considered one of the most useful drugs in therapeutics. In this review, cardiac glycosides and their analogues are presented. The structure and distribution in plants, as well as structure elucidations, synthetic routes, and chemical analysis, are shown.
Aromatic and Medicinal Plants - Back to Nature. Many research efforts have been done toward the proofs of the use of plant species in medicinal treatments in recent years. The effect of plants used has been examined traditionally to support treatment of various diseases.
Cardiac glycosides are a group that comprises the most drug-like molecules subjected to several investigations and they were proved to be fruitful in developing potential drugs [ 1 — 5 ]. They are chemical compounds responsible for the poisoning of livestock and the treatment of congestive heart failure. Extracts or latexes of cardiac glycosides plants have been applied to poison arrows in Africa, Asia, and South America for use in hunting and fighting.
It is expected to be evolved as a defense way in plants. Cardiac glycosides are steroids having the ability to exert specific powerful action on the cardiac muscle.
A very small amount can exert a beneficial simulation on diseased heart. These compounds are primarily valuable in the treatment of congestive heart failure. They increase the force of heart contraction without a concomitant increase on oxygen consumption. Consequently, the myocardium becomes more efficient pump and is able to meet the demands of circulatory system [ 6 — 8 ]. Cardiac glycosides are a group comprising two main classes of compounds that differ in the structure of their aglycone as shown in Figure 1.
Cardiac glycosides are either C23 or C24 steroids with a basic nucleus of cyclopentanoperhydro phenanthrene substituted at C Plants can produce both cardenolides and bufadienolides. Another group, isocardenolides, has the double bond of butenolid ring at position 21 or 22 instead of position 20 as shown in Figure 1.
Most clinical attention was directed to the cardenolides owing to their therapeutic use. Digoxin and digitoxin are the two most widely used digitalis inotropes. There are two million patients receiving these cardenolides in the US.
In general, some isocardenolides appeared to be devoid from any cardiac activity [ 9 ]. Cardiac glycosides, cardenolides, and bufadienolides, bear a structure resemblance to the steroid saponins and have the same solubility and foaming characteristics.
They are also distinguished from other steroid glycosides by a hydroxy group and some peculiar sugar incorporated in their skeleton. Other substituent groups may be present, for example, additional hydroxyl groups at C-1, 11, 12, 16, and The sugars are always linked at C Some members have an aldehyde group rather than methyl group at C [ 10 ]. Although cardiac glycosides are more abundant than aglycones, some aglycones of cardiac glycosides are used for congestive heart failure and commercially available like digoxigenin, gitoxigenin, strophanthidin, and ouabagenin as shown in Figure 2.
The most commercially important plant sources of cardiac glycosides are digitalis purpurea, D. Figure 2 shows the structure of some common cardiac aglycones. It may include glucose or rhamnose together with other deoxy sugars whose natural occurrence is, so far, known only in association with cardiac glycosides [ 11 — 15 ].
Figure 3 shows the structures of some examples of sugar residues attached to cardenolides, which occur in the pyranoid form [ 11 ].
To differentiate between sugars with a hydroxyl group at C—2 and 2-deoxy-sugar chemically, hydrolysis is the first choice [ 16 ]. The latter are almost completely hydrolyzed by boiling in 0.
Cardiac glycosides occur in small amounts in the seeds, leaves, stems, roots, and bark of plants of wide geographical distribution. Many species grow in tropical regions and have been employed, in the past, by natives of Africa, Asia, and South America for preparation of arrow poisons [ 17 ]. In plants, cardenolides appear to be confined to the angiosperms.
They are more abundant in families Apocynaceae and Asclepiadaceae now subsumed in Apocynaceae. However, it could be also found in some plants belonging to Liliaceae, Ranunculaceae, Moraceae, Leguminosae, Scrophulariaceae, Cruciferae, Sterculiaceae, Euphorbiaceae, Tiliaceae, and Celastraceae [ 18 ]. The bufadienolides occur in plants of families: Hyacinthaceae Syn. Two genera of Hyacinthaceae are known to produce them Urginea and Bowiea.
Several compounds of bufadienolides had been isolated from Urginea maritima , which is commonly known as Squill. It is worthy to mention that the genus Urginea is an aggregate of six species and it has been used in medicine since ancient times because of its powerful digitalis-like effect.
There are various animal sources for bufadienolides, e. The isolation and identification of pure cardiac glycosides from their crude mixture faced some difficulties in the past due to its low quantity or its presence as a complex mixture.
Then, it is followed by exhaustive extraction with water-alcohol mixture. Fats could then be removed by extraction with petroleum ether and the aqueous syrup of glycosides is diluted with an equal volume of water. Tannic acid and other polyphenolic and acidic products are precipitated with freshly prepared lead hydroxide and the mixture is filtered through Hyflo-Super Gel.
The clear filtrate is adjusted to pH 6, concentrated under vacuum and subjected to fractional extraction: first with ether, then chloroform, and finally with chloroform-alcohol, and For isolation of glycosides of high solubility in water, the residual aqueous phase is half saturated with sodium sulfate and then extracted with chloroform-alcohol [ 20 , 21 ]. The less polar fractions are separated by chromatography on neutral alumina [ 22 ]. The more polar fractions are usually chromatographed after acetylation or benzoylation and the free glycosides recovered by hydrolysis with bicarbonate.
The employment of HPLC techniques also led to the isolation of large number of cardiac glycosides [ 24 — 27 ]. The technique of DCCC has seen rapid expansion over the past few years.
Four strophanthidin glycosides, out of a total of eight isolated compounds, were separated from one another by DCCC. Further application of DCCC has been reported for the isolation of affinosides from Anodendron affine [ 30 , 31 ].
Recently, Kopp et al. Moreover, radial centrifugal chromatography gives a good resolution and ease of operation to isolate cardiac glycosides [ 33 ]. The analytical methods for cardiac glycosides can be divided into two groups, which are classical and sensitive methods. Sensitive methods ng range include pharmacokinetic investigations, which require sophisticated apparatus. Such method affords reliable measurements in the ng range [ 34 ], whereas the classical methods require preliminary purification, usually by chromatography [ 35 ].
For qualitative and quantitative determination of the cardiac glycosides, it must therefore be converted into colored derivatives as shown in Figure 4. It can be converted into colored derivatives by reaction with polynitroaromatic derivatives in alkaline solution, with Keller-Kiliani or xanthydrolin acidic medium [ 34 ] or by treatment with strong acids and these can be measured by conventional photometers or fluorimeter [ 36 , 37 ].
The reaction between cardenolides and polynitroaromatic derivatives in alkaline solution [ 38 — 41 ] are based on the C-C coupling of the unsaturated lactone ring with them to produce dye complexes which can be measured photometrically.
The reagent may also be used as a spray reagent to visualize cardiac glycosides on TLC. The reagents that gained an established place are Baljet reagent picric acid [ 38 ], Kedde reagent 3,5-dinitrobenzoic acid [ 40 ], and Rabitzsch reagent tetranitrobiphenyl [ 41 ]. However, the specificity of Baljet reagent is low because many other substances, e.
Various reaction mechanisms are suggested for the reaction of polynitroaromatic with cardiac glycosides [ 42 ]. According to the studies by Burns et al. The resulting complexes are cyclohexadienate type and known as Meisenheimer compounds [ 34 ], as shown in Figure 5. Both the Keller-Kiliani and xanthydrol convert 2-deoxy-sugars into characteristic colored derivatives. In this way all digitoxose-containing glycosides can be qualitatively and quantitatively determined.
All the acid reagents detect only those digitoxoses, which are easily hydrolyzed under the conditions of the test [ 34 ]. Keller-Kiliani reaction in acetic acid, ferric chloride, and sulfuric acid produces a blue coloration with absorption maxima at and nm.
It is important to note that the color formation is dependent on time and it is affected by moisture content [ 37 ]. However, the reagent is not very stable and decomposed products tend to interfere with the color reaction.
Fluorescence spectroscopy is 10— times more sensitive than absorption photometry [ 46 ], so the reaction between cardiac glycosides and strong acids gives a restricted limit of detection in the ng range.
For digoxin determinations, an activating wavelength of nm is used and the emitted fluorescence is measured at nm [ 47 ]. The method consumed a bigger quantity of the isolated glycoside, and consequently, it was only suitable for structure determination of the major constituents. The great development in the spectroscopic instruments and the analysis of the produced data in the last three decades was accompanied by a great jump in the study of structure and stereochemical behavior of the naturally occurring compounds.
This development led to stabilize a clear relationship between the structure and the data obtained from the spectroscopic experiments. Before developing the recent tools for chemical analysis of organic compounds, it was very difficult to elucidate the cardiac glycosides structures. In the past, it is important to perform acid hydrolysis [ 48 — 51 ] or enzymatic hydrolysis [ 52 , 53 ] to obtain the sugar residues and the aglycone separately. Now, more sophisticated and accurate tools were used for identification the structure of cardiac glycosides with the stereochemistry determination, which give a powerful way to understand the mechanism of action and facilitate the structure activity relationship studies.
No doubt that NMR is the most powerful tool for the structure determination of cardiotonic compounds. The advantage of pulsed Fourier transformation and two-dimensional NMR spectroscopy is that they provide information related to the carbon skeleton of the molecule and the structure environment of each hydrogen and carbon.
Tori et al. Robien et al. Later on, Kopp et al. Cheung and Watson [ 57 ] briefly studied the 1 H and 13 C NMR of the compounds calactin, uscharidin, calotoxin, uscharin, and voruscharin and established their stereochemistry.
The 13 C-chemical shift of C also gives valuable information on the stereochemistry of both cardenolides and bufadienolides at C The number of sugar moieties could be determined from the number of anomeric carbons at the region of 95— ppm in its 13 C-NMR spectrum. Elgamal et al. Some of these compounds are shown in Figure 6. The 1 H and 13 C assignments are shown in Table 2. The stereochemistry of the steroid ring system and all substituents could be determined beyond doubt from the 1 H; 1 H coupling constants, as far as identifiable, and the ROESY cross-peaks.
Cardiac Glycosides in Medicinal Plants
Plant active metabolites are under intensive examinations around the world to supplement the drugs with minimal side effects. Thus, there is vast potential to explore the possible medicine from the plant sources. Cardiac glycosides are a unique group of secondary metabolites that they are considered one of the most useful drugs in therapeutics. In this review, cardiac glycosides and their analogues are presented. The structure and distribution in plants, as well as structure elucidations, synthetic routes, and chemical analysis, are shown. Aromatic and Medicinal Plants - Back to Nature.
Bufadienolide is a chemical compound with steroid structure. Its derivatives are collectively known as bufadienolides , including many in the form of bufadienolide glycosides bufadienolides that contain structural groups derived from sugars. These are a type of cardiac glycoside , the other being the cardenolide glycosides. Both bufadienolides and their glycosides are toxic ; specifically, they can cause an atrioventricular block , bradycardia slow heartbeat , ventricular tachycardia a type of rapid heartbeat , and possibly lethal cardiac arrest.