Cardiac glycosides (CGs) comprise a large family of naturally derived compounds. They show considerable structural diversity, all members of this family share a common structural motif, its’ core structure consists of a steroidal framework (C23 or C24), which is considered the pharmacophoric moiety responsible for the activity of these compounds. Cardiac glycosides are widely distributed not only among plant kingdom but also within animals and even human tissues.

This review illustrated families/genera used conventionally by native people for cardiac problems, and declare the relation between folkloric and modern authenticated uses. It focuses on cardiac glycosides which are not only important for cardiovascular disorders therapy, but also on their anticancer activity with emphasize on their mechanism of action and their structural features which are accounted for their activity. Moreover, the clinically approved for cancer therapy are also discussed with great spot on the current progress.

Medicinal plants represent the principle source of secondary metabolites ´SMs` (natural drugs) used for centuries for ailments’ therapy for human and veterinary. These SMs can act as phytotoxins ´toxic agents`, phytopharmaceuticals ´medicinal agents` or for both purposes ´phytopharmatoxins`. Moreover, SMs undergo some biochemical modifications within human organs (i.e., liver, heart, pancreas, etc.), through a set of metabolic pathways knowing as drug metabolism [1]. Heart represents one of the important organs involved with drug metabolism. Briefly, it pumps blood rich with O2 to body parts, besides its content of enzymes used for drugs biotransformations [2], these biotransformations in drugs can lead to cardiotoxicity or result in detoxication and cardioprotection. These pharmacological effects ´cardiotoxic and cardioprotective` of plant SMs can be evaluated via in vitro, ex- and in vivo techniques [3]. Medicinal plants in the world and particularly in Africa were attributed to the ethnopharmacological/traditional therapy of different aliments from ancient times, which consider the root for modern medicine. Table 1. Illustrates African plant families/genera (66/142) that were and still used conventionally by native habitats for treatment of cardiac problems, in the form of a maceration, decoction, tea, and/or infusion of its parts (seeds, leaves, bark, roots), or even its edible fruits [4]. The cardio-activities ´cardiotoxic and cardioprotective` of the medicinal plants are attributed to SMs that affect directly or indirectly on heart and blood vessels, with protection or toxic effect depending on their concentration. Different array of SMs have been reported for cardiac failure treatment, including the well-known alkaloids, cardiac glycosides, etc. [3]. This review focuses on cardiac glycosides which are not only important for human poisonings and livestock lethality but also for cardiovascular disorders therapy and cancer treatment. Cardiac glycosides (CGs) comprise a large family of naturally derived compounds. They show considerable structural diversity, but all members of this family share a common structural motif, its’ core structure consists of a steroidal framework (C23 or C24), which is considered the pharmacophoric moiety responsible for the activity of these compounds. This steroid core is double-substituted; with an unsaturated lactone ring at position C-17, and a sugar portion at position C-3 (Fig. 1). The nature of the lactone moiety characterizes the subgroup of the glycosides. Cardenolides (C23) have a five-membered unsaturated butyrolactone ring, whereas bufadienolides (C24) contain a six-membered unsaturated pyrone ring (Fig. 1) [5]. Unlike sex hormones, mineralocorticoids and glycocorticoids, which are all trans-connected, cardiac glycosides, show an A/B and C/D cis-conformation (Fig. 1) [6]. A wide variety of sugars are attached to natural cardiac glycosides; the most common are glucose, galactose, mannose, rhamnose and digitalose. Although sugars themselves have no activity, the addition of sugars to the steroid affects the pharmacodynamic and pharmacokinetic profiles of each glycoside. For example, free aglycones are absorbed more rapidly and are metabolized more easily than their glycosylated counterparts. Moreover, the type of the attached sugar influences the potency of the compound. For instance, the addition of rhamnose was shown to increase potency several times (6–35 times), whereas the addition of mannose had no significant effects [6].

Table 1. African plant families/genera used conventionally for cardiac problems treatment.

Family Genera Part Used Acanthaceae Brillantaisia L Justicia L Phaulopsis Wp Adiantaceae Pellaea Wp Agavaceae Dracaena Wp Annonaceae Annona Wp Amaranthaceae Amaranthus L Celosia L Cyathula Wp Amaryllidaceae Agapanthus R Apocynaceae Cyclomorpha B, R Landolphia La Pleiocarpa L Tylophora L Voacanga L Araceae Rhektophyllum L Araliaceae Cussonia W Asparagaceae Dipcadi Bu Protasparagus R Anacardiaceae Schinus B Sclerocarya R Asteraceae Blumea R Conyza Wp Dichrocephala L Elephantopus L Gerbera R Helichrysum Wp Vernonia L Bignoniaceae Newbouldia Rb Boraginaceae Heliotropium R Burseraceae Canarium B Capparaceae Euadenia L Maerua R Caprifoliaceae Valeriana R Celastraceae Catha B Chrysobalanaceae Acioa B Parinari Wp Clusiaceae Symphonia B Combretaceae Combretum B, R Terminalia L Commelinaceae Commelina R Compositae Emilia L 5 Hertia R Connaraceae Rourea L Convolvulaceae Ipomoea R Merremia R Costaceae Costus Wp Cyperaceae Cyperus Rh, L, R Dipterocarpaceae Monotes R Ebenaceae Diospyros R Euclea L, R Euphorbiaceae Alchornea F Erythrococca R Euphorbia L Ricinus L Synadenium L Fabaceae…( Leguminosae) Abrus L Acacia R, Th Albizia R Baphia B Bussea B, S Cajanus L Chamaecrista Wp Desmodium L, R Elephantorrhiza R Erythrophleum B Lablab R Millettia R Rhynchosia L Schotia B Senna S Tamarindus L, R Tephrosia R Tetrapleura F Flacourtiaceae Dovyalis P, Th Hydrostachyaceae Hydrostachys Wp Hypoxidaceae Hypoxis T Icacinaceae Pyrenacantha L Lamiaceae Achyrospermum L Alvesia Wp Ballota L Hoslundia R Plectranthus Wp Lecythidaceae Petersianthus B Malpighiaceae Acridocarpus Rb Malvaceae Abelmoschus L Bombax B Ceiba B 6 Cola S, L Corchorus Tw Desplatzia F Dombeya B, L Melastomataceae Dissotis L Meliaceae Trichilia L Turraea R Melianthaceae Melianthus R, B Mimosaceae Dichrostachys R Menispermaceae Triclisia L, R Moraceae Artocarpus S Ficus R Musaceae Musa F, R Ochnaceae Lophira B Orchidaceae Aerangis R Passifloraceae Tryphostemma L Phyllanthaceae Bridelia R, B Piperaceae Piper L Polygalaceae Securidaca R Polygonaceae Afrobrunnichia Wp Rumex L Ranunculaceae Thalictrum L Rhamnaceae Gouania L Rubiaceae Brenania B Coffea S Corynanthe B Oldenlandia R Pseudomussaenda Wp Psychotria R Spermacoce B Uncaria L Rutaceae Clausena R Ptaeroxylon B, W Ruta L Toddalia R Vepris B, R Santalaceae Osyris B Sapindaceae Allophylus L Chytranthus B Deinbollia L, R Sapotaceae Manilkara B Solanaceae Capsicum L Caralluma St Schwenckia Wp Solanum F, S, Wp Sterculiaceae Sterculia L 7 Urticaceae Musanga R Myrianthus L Verbenaceae Lantana L Verbena R Vitaceae Cayratia Wp Cissus L Leea T Zingiberaceae Aframomum L

B: Bark, Bu: Bulb, L: Leaves, La: Latex, R: Root, Rb: Root bark, Rh: Rhizome, S: Seeds, St: Stems, T: Tuber, Th: Thorn, Tw: Twigs, W: Wood, Wp: Whole plant.

Distribution of cardiac glycosides

CGs are widely distributed over plant kingdom, the most important families and genera (17/53) containing-CGs are itemized in (Table 2). Digitalis purpurea L. (foxglove) is widely distributed all over the world especially in Africa, from which the first cardiac glycosides (Fig. 2a) were reported by William Withering for the treatment of heart disorders in 1785. Moreover, CGs were reported in some genus of Bufo members [7-9]. Furthermore, some CGs were found in human tissues [10, 11] i.e., digoxin, ouabain, bufalin derivatives, etc. (Fig. 2a,b). Moreover, other reports revealed that endogenous CGs are biosynthesized via the substrates cholesterol and progesterone, under the control of hormones i.e., adrenaline, endothelin and renin-angiotensin [12, 13].

Table 2. Cardiac glycosides distribution over plant families/genera.

Family Genera Structure type Ref. Apocynaceae Acokanthera Cardenolides [14] …(subfamily Asclepiadaceae) Adenium [15, 16] Apocyanum [14] Asclepias Cardenolides [17] Beaumontia [18] Calotropis [14] Carissa [14] Cerbera [19] Cryptostegia [20] Gomphocarpus [14] Menabea [14] Nerium Cardenolides [21-23] Pachycarpus [14] Parepigynum [24, 7] Periploca [8, 25, 26] Strophanthus Cardenolides [27-31] Tanghinia [14] Thevetia [34-40] Xysmalobium [14] Brassicaceae Erysimum [39-45] Lepidium [46] Celastraceae Euonymus [47, 48] Lophopetalum [49] Chrysomelidae Chrysolina [50] Convallariaceae Convallaria [51-62] Crassulaceae Cotyledon [63] Tylecodon [64, 65] Cruciferae Cheiranthus [14] Erysimum [66] Hyacinthaceae…(Asparagaceae) Bowiea Bufadienolides [67] Drimia Bufadienolides [68, 69] Schizobasis Bufadienolides [14] Urginea Bufadienolides [14] Fabaceae…(Leguminosae) Coronilla [70, 71] Liliaceae Convallaria Cardenolides [14] Ornithogalum Cardenolides [14] Rohdea [14] Malvaceae Corchorus [72, 73] Mansonia [74, 76] Moraceae Antiaris Cardenolides [77-79] Antiaropsis [14] Castilla [80] Maquira [81, 82] Naucleopsis [83] Ogcodeia [14] Streblus [84] Ranunculaceae Adonis [85-89] Eranthis [90] Helleborus [91] Scrophulariaceae Digitalis Cardenolide [29, 92-109] Solanaceae Nierembergia [110] Sterculiaceae Mansonia [14] Tiliaceae Corchorus [14]