The structure of Arsphenamine has been proposed to be akin to the dimerazobenzene (A), but mass spectral studies published in 2005 suggest[1] it is actually a mixture of the trimer (B) and the pentamer (C).
Salvarsan treatment kit for syphilis, Germany, 1909-1912[3]
Arsphenamine was first synthesized in 1907 in Paul Ehrlich's lab by Alfred Bertheim.[4] The antisyphilitic activity of this compound was discovered by Sahachiro Hata in 1909, during a survey of hundreds of newly synthesized organic arsenical compounds. Ehrlich had theorized that by screening many compounds, a drug could be discovered that would have anti-microbial activity but not kill the human patient. Ehrlich's team began their search for such a "magic bullet" among chemical derivatives of the dangerously toxic drug atoxyl. This project was the first organized team effort to optimize the biological activity of a lead compound 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 under the trade name "Salvarsan" in 1910.[5][6] Salvarsan was the first organic antisyphilitic, and a great improvement over the inorganic mercury compounds that had been used previously. It was distributed as a yellow, crystalline, hygroscopic powder that was highly unstable in air.[7] 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, including rashes, liver damage, and risks of life and limb, were thought to be caused by improper handling and administration.[8] This caused 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." [5]
Ehrlich's laboratory developed a more soluble (but slightly less effective) arsenical compound, Neosalvarsan (neoarsphenamine), which was easier to prepare, and it became available in 1912. Less severe side-effects such as nausea and vomiting were still common. An additional problem was that both Salvarsan and Neosalvarsan had to be stored in sealed vials under a nitrogen atmosphere to prevent oxidation. These arsenical compounds were supplanted as treatments for syphilis in the 1940s by penicillin.[9]
After leaving Ehrlich's laboratory, Hata continued parallel investigation of the new medicines in Japan.[10]
Structure
Salvarsan has long been assumed to have an As=As double bond, akin to the N=N linkage in azobenzene. However, in 2005, in an extensive mass spectrometric analysis Salvarsan was shown to have As–As single bonds, not As=As double bonds. The drug was also found to be a mixture consisting of cyclo-As3 and cyclo-As5 species.[1][5][11]
^ abLloyd NC, Morgan HW, Nicholson BK, Ronimus RS (2005). "The composition of Ehrlich's salvarsan: resolution of a century-old debate". Angew. Chem. Int. Ed. Engl. 44 (6): 941–4. doi:10.1002/anie.200461471. PMID15624113.
^Gibaud, Stéphane; Jaouen, Gérard (2010). Arsenic - based drugs: from Fowler's solution to modern anticancer chemotherapy. Topics in Organometallic Chemistry. Vol. 32. pp. 1–20. doi:10.1007/978-3-642-13185-1_1. ISBN978-3-642-13184-4.
^In Germany, it was the practice to designate compounds by their development number. Another compound known commonly in Germany by its number is parathion, which was the 605th compound to be developed in a search for insecticides. It is commonly known as E605 (E stands for Entwicklungsnummer, German for "development number").
^"Archived copy". Archived from the original on 2015-02-21. Retrieved 2015-02-21. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)CS1 maint: archived copy as title (link)
