In 1910, Paul Ehrlich introduced the arsenic-based drug Salvarsan as a remedy for syphilis, a sexually transmitted disease that was exacting a toll on public health similar to that of HIV in recent decades. His methodical search for a specific drug to treat a specific disease marked the beginning of targeted chemotherapy.

As a medical student, Ehrlich was fascinated that aniline and other newly available synthetic dyes could be used to stain specific microbes. This early passion led him to predict that chemists would be able to create "magic bullets," agents that would "be able to exert their full action exclusively on the parasite harbored within the organism."

Ehrlich soon took aim at syphilis, a disease that was then endemic, incurable, and often deadly. Scientists had just fingered a tiny, parasitic bacterium known as Treponema pallidum as the root cause of syphilis. So Ehrlich assembled a multidisciplinary team of scientists--including chemist Alfred Bertheim and bacteriologist Sahachiro Hata--in hopes of finding a magic bullet capable of killing the syphilis-causing bacterium without harming its human host.

Ehrlich chose a known organic arsenic compound as a chemical starting point and, with Bertheim's help, synthesized hundreds of related organoarsenic compounds. Each of these compounds was tested for biological activity, toxicity, and distribution in rabbits infected with the syphilis-causing bacteria. Number 606 (Salvarsan) proved to be the best candidate. A single dose of the compound cured the rabbits.

The drug made its way to the clinic with speed unheard of in this day and age: Discovered in the fall of 1909, Salvarsan was in clinical use by 1910. Salvarsan proved to be amazingly effective, particularly when compared with the conventional therapy of mercury salts. Manufactured by the German chemical company Hoechst, Salvarsan quickly became the most widely prescribed drug in the world. It was the world's first blockbuster drug and remained the most effective drug for syphilis until penicillin became available in the 1940s.

Salvarsan's success represented the promise of modern medicine--that effective synthetic drugs could be devised to treat disease. But it fell short of being a perfect magic bullet. Patients with later stages of syphilis didn't respond as well to the drug. And physicians found the drug difficult to handle and administer properly. Salvarsan was distributed in powdered form; doctors had to dissolve it in several hundred milliliters of pure, sterilized water and then inject it intravenously, taking care to minimize air exposure.

Some of the side effects attributed to Salvarsan turned out to be due to improper handling and administration of the drug, causing Ehrlich to observe that "the step from the laboratory to the patient's bedside ... is extraordinarily arduous and fraught with danger." He poured himself into helping doctors standardize handling and administration of the drug and eventually developed an easier-to-handle derivative of Salvarsan with improved water solubility.

Despite the key role it played in medical and pharmaceutical history, the chemical structure of Salvarsan has remained controversial. Ehrlich's synthesis involved reduction of 3-nitro-4-hydroxyphenylarsonic acid with dithionite, yielding a product with the empirical structure RAs•HCl•H 2 O (where R = 3-amino-4-hydroxyphenyl). By analogy with known azo compounds, Ehrlich postulated that Salvarsan contained an As=As double bond.

Although this assignment persists in textbooks and reference volumes even today, advances in inorganic chemistry called this structure into question in the late 1970s. Such As=As bonds are only stable in molecules with extensive steric protection, notes chemistry professor Brian K. Nicholson of the University of Waikato, Hamilton, New Zealand. It was suggested that the drug might have a polymeric or oligomeric structure instead, but full chemical characterization remained elusive.

That changed earlier this year, when Nicholson and colleagues reported that Salvarsan is in fact a mixture of cyclic As-As bonded species (Angew. Chem. Int. Ed. 2005, 44, 941). This mixture of (RAs) 3 and (RAs) 5 serves to slowly release RAs(OH) 2 , the oxidized species that likely gives rise to Salvarsan's antisyphilis properties, he says. Now that Salvarsan's true chemical identity is known, the Waikato group is working to shed light on another century-old mystery: how the drug exhibits such exquisite specificity for T. pallidum.

Arsphenamine

Name: 4,4'-(1,2-Diarsenediyl)bis[2-aminophenol]dihydrochloride

CAS Registry: 139-93-5

Other names: Salvarsan

Introduced: 1910, Hoechst

Sales: By 1923, 2 million doses of arsphenamine and neoarsphenamine, a more water-soluble derivative, were being produced each year in the U.S. alone.