Arsphenamine
Encyclopedia
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that was used beginning in the 1910s to treat syphilis
Syphilis
Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subspecies pallidum. The primary route of transmission is through sexual contact; however, it may also be transmitted from mother to fetus during pregnancy or at birth, resulting in congenital syphilis...
and trypanosomiasis.
It is an organoarsenic compound
Organoarsenic compound
Organoarsenic chemistry is the chemistry of compounds containing a chemical bond between arsenic and carbon. A few organoarsenic compounds, also called "organoarsenicals," are produced industrially with uses as insecticides, herbicides, and fungicides. In general these applications are declining in...
, and was the first modern chemotherapeutic agent
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
.
History
Sahachiro HataSahachiro Hata
was a Japanese bacteriologist who developed the Arsphenamine drug in 1909 in the laboratory of Paul Ehrlich.Hata was born in Tsumo Village, Mino District, Shimane , and completed his medical education in Kyoto...
discovered the antisyphilitic activity of this compound in 1909 in the laboratory of Paul Ehrlich
Paul Ehrlich
Paul Ehrlich was a German scientist in the fields of hematology, immunology, and chemotherapy, and Nobel laureate. He is noted for curing syphilis and for his research in autoimmunity, calling it "horror autotoxicus"...
, during a survey of hundreds of newly synthesized organic arsenic
Arsenic
Arsenic is a chemical element with the symbol As, atomic number 33 and relative atomic mass 74.92. Arsenic occurs in many minerals, usually in conjunction with sulfur and metals, and also as a pure elemental crystal. It was first documented by Albertus Magnus in 1250.Arsenic is a metalloid...
al compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered with antimicrobial activity. Ehrlich's team began their search for such a "magic bullet
Magic bullet
Magic bullet may refer to:* In the German folk legend Freischütz, an enchanted bullet obtained by a marksman through a contract with the devil....
" among chemical derivatives of the dangerously toxic drug atoxyl
Atoxyl
Arsanilic acid is the organoarsenic compound also called p-aminophenylarsonic acid. This colourless solid was used as a drug in the late 19th and early 20th centuries but is now considered prohibitively toxic. Arsanilic acid is a derivative of phenylarsonic acid with an amine in the 4-position...
. This was the first organized team effort to optimize the biological activity of a lead compound
Lead compound
A lead compound in drug discovery is a chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.Lead compounds are often found in...
through systematic chemical modifications, the basis for nearly all modern pharmaceutical research.
Arsphenamine was originally called "606" because it was the sixth in the sixth group of compounds synthesized for testing; it was marketed by Hoechst AG
Hoechst AG
Hoechst AG was a German chemicals then life-sciences company that became Aventis Deutschland after its merger with France's Rhône-Poulenc S.A. in 1999...
under the trade name
Trade name
A trade name, also known as a trading name or a business name, is the name which a business trades under for commercial purposes, although its registered, legal name, used for contracts and other formal situations, may be another....
Salvarsan in 1910. Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic mercury
Mercury (element)
Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
compounds that had been used previously. It was distributed as a yellow, crystalline, hygroscopic
Hygroscopy
Hygroscopy is the ability of a substance to attract and hold water molecules from the surrounding environment. This is achieved through either absorption or adsorption with the absorbing or adsorbing material becoming physically 'changed,' somewhat, by an increase in volume, stickiness, or other...
powder that was highly unstable in air. This significantly complicated administration, as the drug had to be dissolved in several hundred milliliters of distilled, sterile water with minimal exposure to air to produce a solution suitable for injection. Some of the side effects attributed to Salvarsan were thought to be caused by improper handling and administration, causing Ehrlich, who worked assiduously to standardize practices, to observe, "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger."
Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan
Neosalvarsan
Neosalvarsan is a synthetic chemotherapeutic that is an organoarsenic compound. It became available in 1912 and superseded the more toxic and less water-soluble salvarsan as an effective treatment for syphilis...
(neoarsphenamine), which was easier to prepare, and it became available in 1912. These arsenical compounds came with considerable risk of side effects, and they were supplanted as treatments for syphilis in the 1940s by penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
.
After leaving Erlich's laboratory, Hata continued parallel investigation of the new medicines in Japan
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
.
Mechanism
The bacterium that causes syphilis is a spirochete, Treponema pallidumTreponema pallidum
Treponema pallidum is a species of spirochaete bacterium with subspecies that cause treponemal diseases such as syphilis, bejel, pinta and yaws. The treponemes have a cytoplasmic and outer membrane...
. Arsphenamine is not toxic to spirochetes until it has been converted to an active form by the body.
Structure
From Salvarsan's discovery until recently, it was believed that the structure featured an As=As double bondDouble bond
A double bond in chemistry is a chemical bond between two chemical elements involving four bonding electrons instead of the usual two. The most common double bond, that between two carbon atoms, can be found in alkenes. Many types of double bonds between two different elements exist, for example in...
. However, in 2005, an extensive mass spectral analysis
Mass spectrometry
Mass spectrometry is an analytical technique that measures the mass-to-charge ratio of charged particles.It is used for determining masses of particles, for determining the elemental composition of a sample or molecule, and for elucidating the chemical structures of molecules, such as peptides and...
showed the actual structure is most likely to be a mixture of the cyclic
Cyclic compound
In chemistry, a cyclic compound is a compound in which a series of atoms is connected to form a loop or ring.While the vast majority of cyclic compounds are organic, a few inorganic substances form cyclic compounds as well, including sulfur, silanes, phosphanes, phosphoric acid, and triboric acid. ...
trimer
Trimer (chemistry)
In chemistry, a trimer is a product derived from three identical precursors. Trimers are typically cyclic. Chemical compounds that often trimerise are aliphatic isocyanates and cyanic acids. Often, trimerization competes with polymerization....
and a pentamer
Pentamer
A pentamer is a thing composed out of five sub-units.In chemistry, it applies to molecules made of five monomers.In biochemistry, it applies to macromolecules, in particular to pentameric proteins, made of five proteic sub-units....
. The revised structure features As-As single bonds, not double bonds.