A Reinvestigation of Salvarsan and Related Arsenic Chemistry.

Abstract

In 1910 the first deliberately targeted search for a new chemotherapeutic agent came to fruition when Paul Ehrlich introduced Salvarsan for the treatment of syphilis. This thesis presents a detailed review of the history and literature leading up to and following on from Ehrlich’s discovery and thoroughly investigates the chemistry of Salvarsan and related species. A series of arylarsonic acids was prepared and fully characterised by electrospray mass spectrometry, NMR and X-ray crystallography for six examples. A detailed analysis of the hydrogen bonding in crystals of these molecules showed that they adopt several characteristic motifs which govern the packing in the crystals. Two of the examples containing NH2 groups crystallised as zwitterions while one NH2 containing example containing other bulky groups was is its molecular form. Salvarsan (cyclo 3-amino-4-hydroxyphenylarsenic(I)) was prepared by several different methods and analysed in detail using high resolution electrospray mass spectroscopy. This showed that Salvarsan consists of small cyclic species of the type (RAs)n where R is 3-NH2-4-OHC6H3 and n is three or greater. The dominant species in an aqueous solution of Salvarsan were found to be (RAs)3 and (RAs)5 . A detailed analysis is presented of impurities in Salvarsan prepared by different methods and also in a sample of original commercial Salvarsan. Mixtures of (RAs)n and (R’As)n exchange R groups in aqueous solution at room temperature, as shown by ESI-MS. ESI-MS studies are reported for the oxidation product of Salvarsan, RAs(OH)2 (commercially known as Mapharsen) and related As(III) compounds. Oligomers involving As-O-As linkages were found in solution and one tetrameric example (R = 3-NO2-4-OHC6H3) was isolated and structurally characterised. Preliminary ESI-MS studies showed that As(III) species bind to thioredoxin, a possible target for the pharmaceutical activity of Salvarsan and its derivatives.