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The composition of Ehrlich's salvarsan: resolution of a century-old debate.

In 1910, Ehrlich introduced the compound 3-amino-4hydroxyphenylarsenic(i) (salvarsan, arsphenamine, or Ehrlich 606) as a remedy for syphilis, a disease caused by the spirochaete bacterium Treponema pallidum. His methodical search for a specific curative for an identified disease can be regarded as the introduction of targeted chemotherapy. Despite its long history and importance, the actual structure of salvarsan is still debated. 2] Ehrlich synthesized the compound by the reaction of 3-nitro-4-hydroxyphenylarsonic acid with dithionite. This simultaneously reduced the NO2 group to NH2 and As V to As to give a material of formula 3-H2N-4-HOC6H3As (Scheme 1). The product was isolated as the hydrated hydrochloride salt of formula 3-H2N4-HOC6H3As·HCl·H2O. This synthesis was not always reproducible, and inevitably gave rise to sulfur-containing impurities, which may have accounted for the variable toxicity of different batches of salvarsan. A two-step process that involved initial reduction of the NO2 group by sodium dithionite followed by reduction of As with hypophosphorous acid was subsequently shown by Christiansen to lead to sulfur-free material (Scheme 1). By analogy with azo compounds, Ehrlich assigned structure 1 to the free base of salvarsan. Although As=As bonds are now known to be found only in sterically crowded molecules, the As=As form is repeatedly cited, with textbooks and reviews still giving structure 1. 2] Various suggestions for the true structure of salvarsan have been proposed, including large polycyclic molecules and polymers, but lack strong supporting data. We now report the first definitive evidence for the composition of salvarsan based on electrospray ionization mass spectrometric data. Salvarsan was synthesized by using a modification of the two-step synthesis first described by Christiansen. The compound was isolated as the hydrochloride, giving consistent yields of a pale-yellow material that was analyzed as the monohydrate, corresponding exactly to Ehrlich s original reports. We also isolated the mixed H2PO2 /H2PO3 salt form (P NMR spectroscopic data) by direct precipitation from the reaction mixture. H and C NMR spectroscopic data were recorded for salvarsan, but were not particularly useful for structural assignment; ESI MS proved much more practical for this purpose. A typical spectrum is shown in Figure 1. Although there are many peaks, they can be readily assigned. Three clear series can be identified (Table 1). The first of these is the major one and consists of [(RAs)n+H] + peaks (R= 3-H2N-4HOC6H3) for n= 3–8. Peaks corresponding to n= 3 and n= 5 are clearly dominant in this series. A lesser series comprises ions generated by loss of R from (RAs)n, that is, [Rn 1Asn] +