Arsphenamine

Arsphenamine, aka salvarsan, is considered to be the first chemotherapeutic drug. It was developed to combat syphilis and other infectious diseases in the early 1910s by Paul Ehrlich*¹ and co-inventors Alfred Bertheim and Baptist Reuter at Farbwerke vorm. Meister Lucius & Brüning² (Höchst, Germany) and described in US Patents 986,148 (1911) and 1,078,135 (1913). During 1910–13, Ehrlich also published several journal articles on what he initially called “compound 606”.

A word on nomenclature: The dihydrochloride of 4,4’-(1,2-diarsenediyl)bis(2-aminophenol) is conventionally called arsphenamine. The free diamine³ is sometimes also called arsphenamine, but it also goes by arsphenolamine.

Although the structure of arsphenamine is usually depicted with an arsenic–arsenic double bond, in 2005, an electrospray ionization mass spectrometric study by Brian K. Nicholson and co-workers at the University of Waikato (Hamilton, New Zealand) found that no As=As bonds were present. Instead, the chemists observed As–As single bonds that formed rings consisting of three or five arsenic atoms.

Soon after his original discovery, Ehrlich developed a derivative of arsphenamine called neoarsphenamine or neosalvarsan⁴. The new compound had a hydrogen sulfoxylmethyl (HOSOCH₂–) group attached to one of its amino groups and was less toxic and more water-soluble than the parent compound. It was equally effective against syphilis and other diseases, according to dozens of accounts published in 1912–13, although some authors cautioned against toxic overdoses that can result from its high solubility. In a 1912 article, G. Castelli at Georg-Speyer-Haus (Frankfort-am-Main, Germany) reported that neosalvarsan successfully treated rabbits experiencing generalized syphilis and generalized frambesia.

Because all arsenic-containing drugs carry the risk of toxicity, arsphenamine and neoarsphenamine were replaced in the 1940s by penicillin and similar medications. But the breakthrough arsenicals continue to be the subjects of laudatory articles. Examples include Amanda Yarnell’s 2005 story in C&EN and a 2009 account of Ehrlich’s “magic bullet” by British author K. J. Williams.

Because it is no longer an article of commerce, no safety data sheets for arsphenamine are available. The National Library of Medicine’s Pubchem datasheet, however, considers it carcinogenic, as are almost all arsenic compounds. It also lists several other adverse health effects.

For further reading, see ScienceDirect’s extensive topics page on arsphenamine.

1. Ehrlich had previously shared the 1908 Nobel Prize in Physiology or Medicine for his work on the theory of immunity.
2. Forerunner of Hoechst AG.
3. CAS Reg. No. 150-44-7.
4. CAS Reg. No. 457-60-3.