A chemist will tell you that molecules changed the world. The book, Molecules That Changed The World, by KC Nikolaou and T Montagnon will have you believing it by page 333. The synthesis of urea is credited as not only the earliest contribution to organic synthesis, “but as the single most important blow to the vestigial theory” held in the 1700’s. “Despite using the terms daily, chemists often forget that the classifications of inorganic and organic compounds originally arose from the theory of vitalism, which divided matter into two classes based upon the response of the material to the application of heat.” Plants burn, rocks don’t.
What was apparent, and explained by Nobel prize winner (1902) Emil Fischer, is that principles such as asymmetry, the intrinsic importance of organic chemistry in understanding biological mechanisms, and the art of extracting, identifying, and synthesizing naturally occurring compounds and their analogues for medicinal purposes are important. These concepts have been the foundation of our understanding how to treat horses with equine protozoal myeloencephalitis and polyneuritis equi. Our story is similar to the story of Aspirin, the most successful medication in history, because treatments we use are steeped in history, synthesis, and hormone chemistry.
Aspirin’s story is using the medicinal properties of a natural product that is optimized through subtle chemical manipulations, and began 3500 years ago. Egyptian physicians advocated salicin, in herbal preparations of myrtle bark, as a remedy for rheumatism and back pain. Humans are not the only ones that seek this chemical from the bark of trees such as willow. Supposedly, forest monkeys and apes nibble on the bark of these trees for pain relief.
The first ever clinical trial used pulverized, dried willow bark that was given in a tea or beer, to 50 patients, and published by Edward Stone in 1763. Advances came in 1828 when Johann Andreas Buchner removed tannins and other impurities obtaining a relatively pure sample which he called salicin. Ten years passed until Raffaele Piria made the next advance by hydrolyzing salicin, splitting it into its sugar and phenolic components. Later, he succeeded in oxidizing the hydroxymethyl group of the phenolic fragment to make salicylic acid. In 1853 another chemist, Charles Frederic Gerhardt prepared acetylsalicylic acid and with that step, Aspirin was born. The best was yet to come.
In 1859 Hermann Kolbe synthesized Aspirin by heating the sodium salt of phenol in the presence of carbon dioxide under pressure and commercialized the process, laying the foundation for todays pharmaceutical industry. What came next is the realization that salicylic acid wasn’t a panacea because there were unpleasant side effects. The effort was on to modify the chemical structure in order to obtain a derivative that might be devoid of the undesirable side effects such as foul taste, mucosal membrane irritation, vomiting, and ulcerations.
The breakthrough came in 1897 when a chemist at Bayer, Felix Hoffmann, synthesized acetylsalicylic acid. Bayer now owned the miracle drug they trademarked as Aspirin. Aspirin was used in experiments to determine the mode of action increasing the knowledge of pain and inflammatory mechanisms. Prostaglandins were identified in 1935 and the cascade of biochemical reactions associated with inflammation were revealed. Finally, in 1971 three scientists linked the ability of Aspirin to inhibit a critical enzyme step in the prostaglandin pathway.
The protagonist Aspirin is heroic. However, the story isn’t complete without considering the antagonist. New research spawned the new generation of ‘super-analgesic’ drugs such as Celebrex and Vioxx that didn’t have the side effects of Aspirin. Yet, unexpected side effects were noticed, like heart attacks and strokes with long term use. The popular drug Vioxx, with $2.5 billion dollar sales, was removed from the market in 2003. Isn't it ironic that Aspirin is frequently used to reduce the incidence of myocardial infarction and stroke? The positive effects of Aspirin on heart disease isn’t through the prostaglandin pathway, but by inhibition of another product from the arachidonic acid cascade, thromboxane A2, a hormone discovered in 1975.
Aspirin is a synthetic chemical derived from natures molecule that has profound effects on prostaglandin mediated inflammatory pathways and in an alternate pathway, inhibits the clotting cascade driven by a hormone. Our path, clinical trials using hormones and synthetic chemical-mimics to modulate pathologic inflammatory pathways (non-prostaglandin mediated) are similar to Aspirins story.
Presently, we are concerned with chemical modifications of molecules. As you can see from the work on Aspirin, there are unexpected effects with the slightest modification of a molecules structure. Structural changes can be non-enzymatic (degradation) and/or enzymatic.
Non-enzymatic modifications are made by facilitating chemical breakdown products by manufacturing processes, storage conditions, or compounding. Non-enzymatic modifications of a molecule can induce anti-inflammatory effects, make some drugs inflammatory, and in some cases elicit no effect at all. Outcomes depend on the modification that is made to the molecule, intentional or not.
We know that a simple amino acid change, such as a valine, in the protein sequence of a hormone can elicit profound effects on receptor binding, increasing potency and duration. Receptor binding affects the outcome of a treatment. We are also looking a the effects of chemical modifications on hormone receptor binding. We will put all this together in a story and should have quite a story to tell.