Natural Glycosides & therapeutic potential of

Cardiac GlycosidesBy- MANDEEP SINGH

What are Glycosides ?

Glycosides are organic molecules which consist of a sugar residue covalently bound to a different structure called the aglycone. The sugar residue is in its cyclic form and the point of attachment is the hydroxyl group (sugar) of the hemiacetal (aglycone) function. The sugar moiety can be joined to the aglycone in various ways: 1. Oxygen (O-glycoside)2. Sulphur (S-glycoside) 3. Nitrogen (N-glycoside)4. Carbon (C -glycoside) Bitter in taste Used as a defensive mechanism against predators by many plant

species.

Classification of GlycosidesGlycosides can be classified by the glycone, by the type of glycosidic bond, and by the aglycone.

I. By glycone/presence of sugar If the glycone group of a glycoside is glucose, then the molecule is a glucoside; if it is fructose, then the molecule is a fructoside; if it is glucuronic acid, then the molecule is a glucuronide; etc. & so on

II. By type of glycosidic bond Depending on whether the glycosidic bond lies "below" or "above" the plane of the

cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. There are four type of linkages present between glycone and aglycone: C-linkage/glycosidic bond, "nonhydrolysable by acids or enzymes" O-linkage/glycosidic bond N-linkage/glycosidic bond S-linkage/glycosidic bond

BY AGLYCONE Glycosides are also classified according to the chemical nature of the aglycone. For

purposes of biochemistry and pharmacology, this is the most useful classification. Alcoholic glycosides – Eg. Salicin (converted to Salicyclic acid in the body) Responsible for antipyretic & anti-inflammatory effects. Anthraquinone glycosides- Eg. Antron & Anthranol Responsible for laxative effect.

Cyanogenic glycosides – eg. Amygdalin Aglycone part is cyanide. Used as a defensive mechanism by certain plants against predators.

Flavonoid glycosides – Eg. Rutin, naringin Responsible for Antioxidant effect, improves capillary strength.

Others include Saponins, Phenolic glycosides etc.

Major plant sources of Cardiac Glycosides Scrophulariaceae

Digitalis purpurea leaves (foxglove)Digitalis lanata leaves – white flowers

ApocyanaceaeStrophanthus vine seeds – Africa

LiliceaeUrginea bulbs (squill) – Europe, IndiaConvallaria leaves (lily of the valley)

Cardiac glycosides as potential Anticancer agents

In a recent paper published (2013) in Oncogene journal , Tailler et al. Identified the cardiac glycoside ouabain as a potential antileukemic compound.

They observed that ouabain was highly efficient in inhibiting the growth of human acute myeloid leukemia cells xenotransplanted in immunodeficient mice, without exerting significant toxicity on the host.

Mechanism of Action It disrupts the cell sodium-Potassium ion balance.

Increased cellular levels of Na+ & Ca+ causing malfunctioning in cell signalling processes, ultimately forcing the cancerous cell to enter Apoptosis.

The authors concluded that ouabain was a promising antileukemic agent whose activity should be evaluated in prospective clinical studies

Another research group headed by Dr. Jose Manuel reported in 2013 that cardiac glycosides digitoxin & digoxin and induce selective killing of lung cancer cells, and that the cytotoxicity of digitoxin against these cells occurs at concentrations below those observed in the plasma of cardiac patients treated with this drug.

It has been proposed that the inhibition of the Na+/K+-ATPase pump would decrease glycolysis activity via inhibition of the key glycolytic enzyme phosphofructokinase. In addition, inhibition of the Na+/K+-ATPase pump may restrict the activity of sodium glucose transporters (SGLTs), which couple glucose entry into some types of cells with the activity of this pump.

Published paper- Oncogene, 2013. doi: 10.1038/onc.2013.229

Many other glycosidic molecules are being extensively researched as potential therapeutics for various cardiac & cancerous diseases.

References

Rahimtoola, S.H. and Tak, T. The use of digitalis in heart failure Curr. Probl. Cardiol. 1996, 21, 781-853.

Xie, Z. and Askari, A. Na(+)/K(+)-ATPase as a signal transducer Eur. J. Biochem. 2002, 269, 2434-9.

Schoner, W. and Scheiner-Bobis, G. Endogenous and exogenous cardiac glycosides: their roles in hypertension, salt metabolism, and cell growth Am. J. Physiol Cell Physiol. 2007, 293, C509-C536.

Haux, J. Digitoxin is a potential anticancer agent for several types of cancer Med. Hypotheses. 1999, 53, 543-8.

Lopez-Lazaro, M. Digitoxin as an anticancer agent with selectivity for cancer cells: possible mechanisms involved Expert. Opin. Ther. Targets. 2007, 11, 1043-53.

Newman, R.A.; Yang, P.; Pawlus, A.D.; Block, K.I. Cardiac glycosides as novel cancer therapeutic agents Mol. Interv. 2008, 8, 36-49.

Prassas, I. and Diamandis, E.P. Novel therapeutic applications of cardiac glycosides Nat. Rev. Drug Discov. 2008, 7, 926-35.

Thank you