Bufagin is a toxic

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

C₂₄H₃₄O₅ obtained from toad's milk, the poisonous secretion of a skin gland on the back of the neck of a large toad (''

Rhinella marina The cane toad (''Rhinella marina''), also known as the giant neotropical toad or marine toad, is a large, terrestrial true toad native to South and mainland Central America, but which has been introduced to various islands throughout Oceani ...

'', synonym ''Bufo marinus'', the cane toad). The toad produces this secretion when it is injured, scared or provoked. Bufagin resembles chemical substances from

digitalis ''Digitalis'' ( or ) is a genus of about 20 species of herbaceous perennial plants, shrubs, and Biennial plant, biennials, commonly called foxgloves. ''Digitalis'' is native to Europe, Western Asia, and northwestern Africa. The flowers are ...

in physiological activity and chemical structure. ''Bufagin'' also refers to any of several similar substances found as components of the mixture

bufotoxin Bufotoxins are a family of toxic steroid lactones or substituted Substituted tryptamine, tryptamines of which some are toxic. They occur in the parotoid glands, skin, and poison of many toads (True toad, Bufonidae family) and other amphibians, an ...

in secretions of other toads, as well as plants and mushrooms.

History

The discovery of bufagin has taken place in the fall of 1910, where

John Jacob Abel John Jacob Abel (19 May 1857 – 26 May 1938) was an American biochemist and pharmacologist. He established the pharmacology department at Johns Hopkins University School of Medicine in 1893, and then became America's first full-time professor o ...

and David I. Macht are investigating the property of unknown substances from a tropical toad, ''Bufo agua''. They collected the "milky secretion" squirted out of toad’s

parotid gland The parotid gland is a major salivary gland in many animals. In humans, the two parotid glands are present on either side of the mouth and in front of both ears. They are the largest of the salivary glands. Each parotid is wrapped around the m ...

due to the control of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

while it was strongly irritated. They observed the semifluid substance is quickly dried in the air and formed a yellow and hard scales that shared a similar appearance with dried

snake venom Snake venom is a highly toxic saliva containing zootoxins that facilitates in the immobilization and digestion of prey. This also provides defense against threats. Snake venom is usually injected by unique fangs during a Snakebite, bite, though ...

. After the experiments with the poison, John Jacob Abel and David I. Macht found there are epinephrin and a newly discovered substance exist within the secretion, which they originally gave the name of “bufagin” to this digitalis-like substance. They also quantitatively analyzed the amounts of epinephrin and bufagin in the venom, which showed that 0.734 gram of bufagin with respect to 0.1 gram of epinephrin presented.

Chemistry

Bufagin and bufagins are

bufadienolide 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 ...

derivatives. This means they are steroids with a six-membered

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

(α-

pyrone Pyrones or pyranones are a class of heterocyclic chemical compounds. They contain an unsaturated six-membered ring, which has one oxygen atom and a carbonyl functional group. There are two isomers, denoted as 2-pyrone and 4-pyrone. The 2-pyrone ...

) ring attached to ring D (the five-membered one). The difference to digitalis compounds is that the latter have a fix-membered lactone (α-

furan Furan is a Heterocyclic compound, heterocyclic organic compound, consisting of a five-membered aromatic Ring (chemistry), ring with four carbon Atom, atoms and one oxygen atom. Chemical compounds containing such rings are also referred to as f ...

) ring that has one carbon atom and one double bond less. Bufagin is the category name of a large bufadienolide family, there are at least 86 identified bufagins. Examples of bufagins are: *

Arenobufagin Arenobufagin is a cardiotoxic bufanolide steroid secreted by the Argentine toad ''Bufo arenarum''. It has effects similar to digitalis, blocking the Na+/K+ pump in heart tissue. Sources The compound arenobufagin is one of the major components of ...

, from the Argentine toad (''Chaunus arenarum'', synonym ''Bufo arenarum''); *

Bufotalin Bufotalin is a cardiotoxic bufanolide steroid, cardiac glycoside analogue, secreted by a number of toad species. Bufotalin can be extracted from the skin parotoid glands of several types of toad. Sources '' Rhinella marina'' (Cane toad), '' Rh ...

, from the

cane toad The cane toad (''Rhinella marina''), also known as the giant neotropical toad or marine toad, is a large, Terrestrial animal, terrestrial true toad native to South America, South and mainland Central America, but which has been Introduced spe ...

(''Rhinella marina'', synonym ''Bufo marinus''); *

Cinobufagin Cinobufagin is a cardiotoxic bufanolide steroid secreted by the Asiatic toad ''Bufo gargarizans''. It has similar effects to digitalis and is used in traditional Chinese medicine. Isolation and purification Cinobufagin, as well as other bufadi ...

, from the Chusan Island toad (''Bufo gargarizans''); * Gamabufagin, from the

Japanese toad The Japanese common toad, Japanese warty toad or Japanese toad (''Bufo japonicus'') is a species of toad in the family Bufonidae. It is endemic to Japan. Its natural habitats are subarctic forests, temperate forests, temperate shrubland, swamps, ...

(''Bufo japonicus''); *

Marinobufagin Marinobufagenin (marinobufagin, MBG) is a cardiotonic bufadienolide steroid. It is secreted by the toad species such as ''Bufo marinus''. It also can be found in the plasma and urine of human subjects with myocardial infarction, kidney failure, h ...

, from ''

Bufo rubescens ''Rhinella rubescens'' is a species of toad in the family Bufonidae. It is endemic to Brazil. Its natural habitats are moist savanna, subtropical or tropical moist shrubland, subtropical or tropical high-altitude shrubland, rivers, freshwater mar ...

'' and the

(''Bufo marinus''); * Quercicobufagin, from the oak toad (''Anaxyrus quercicus'', synonym ''Bufo quercicus''); * Regularobufagin, from the

square-marked toad ''Sclerophrys regularis'', commonly known as the African common toad, square-marked toad, African toad, Egyptian toad, African bouncing toad (due to the bouncing motion) and Reuss's toad, is a species of toad in the family Bufonidae. It is found ...

(''Amietophrynus regularis'', synonym ''Bufo regularis''); * Vallicepobufagin, from the

Gulf Coast toad The Gulf Coast toad (''Incilius valliceps'') is a species of toad native to eastern and southeastern Mexico and Central America as far south as Costa Rica. Description The Gulf Coast toad is a medium-sized toad species, ranging from in leng ...

(''Incilius valliceps'', synonym ''Bufo valliceps''); * Viridibufagin, from the

European green toad The European green toad (''Bufotes viridis'') is a species of true toad found in steppes, mountainous areas, semi-deserts, urban areas and other habitats in mainland Europe, ranging from far eastern France and Denmark to the Balkans, Western Ru ...

(''Bufo viridis'') These bufagins, and especially cinobufagin, have given rise to a large number of derivatives evaluated as potential

anti-tumor Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) in a standard regimen. Chemotherapy may be given with a cu ...

drugs.

Synthesis

Two structurally similar bufagins can be utilized to develop a synthetic method, which is the transformation of bufotalin to cinobufagin. Cinobufagin is known for its potential as the precursor of many anti-tumor drugs and bufotalin is an important venom found within the cane toad. This synthesis method involves 6 steps.

Effects of bufagins

Some bufagins have effects similar to poisoning by

, having effects on the

cardiac muscle Cardiac muscle (also called heart muscle or myocardium) is one of three types of vertebrate muscle tissues, the others being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that constitutes the main tissue of the wall o ...

, causing

ventricular fibrillation Ventricular fibrillation (V-fib or VF) is an abnormal heart rhythm in which the Ventricle (heart), ventricles of the heart Fibrillation, quiver. It is due to disorganized electrical conduction system of the heart, electrical activity. Ventricula ...

. Some also have local anesthetic action. The

analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...

effects have also been proven, by acting as Na+/K+-ATPase

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

s on the binding sites of the

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. The anti-cancer properties in

leukemia Leukemia ( also spelled leukaemia; pronounced ) is a group of blood cancers that usually begin in the bone marrow and produce high numbers of abnormal blood cells. These blood cells are not fully developed and are called ''blasts'' or '' ...

and

melanoma Melanoma is the most dangerous type of skin cancer; it develops from the melanin-producing cells known as melanocytes. It typically occurs in the skin, but may rarely occur in the mouth, intestines, or eye (uveal melanoma). In very rare case ...

cells, and the

inhibition Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransm ...

of the proliferation of

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

cells, have also been investigated in cellular models. Some of the bufagin toxins are used in low doses in

traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medicine, alternative medical practice drawn from traditional medicine in China. A large share of its claims are pseudoscientific, with the majority of treatments having no robust evidence ...

for similar applications as

digoxin Digoxin (better known as digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart disease, heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. ...

is used for in Western medicine (i.e. treatment of heart conditions such as

atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...

). These bufagins, and especially cinobufagin, have given rise to a large number of derivatives evaluated as potential anti-tumor drugs.

References

{{Toxins Antiarrhythmic agents Bufanolides Vertebrate toxins