Release 2.5.0
This update was driven by the goal of being able to test that the pathway generator could "discover" a well-known, existing pathway for production of a commonly used pharmaceutical drug. Note this goal is distinct from
the goal of discovering a NEW pathway for a common drug. I figured it was important to first show that the pathway search engine could propose a well-established, EXISTING production pathway to verify the accuracy of the engine. Proposing new
cheaper, quicker, or more environmentally favorable synthesis pathways IS an ultimate goal, however.
Tylenol (generically acetaminophen or paracetamol) was chosen as the drug for a number of reasons. For starters, support for the molecule itself (IUPAC name N-(4-hydroxyphenyl)ethanamide) required a minimal number of updates to the interface: addition of support for side skeletons of longer than one carbon length (the methyl radical), support for amines with attachments to the nitrogen atom, and support of the nitrite functional group. As a side note, this was also a good occasion to add support for common IUPAC naming substitutions, in this case benzene and phenol, as many of the intermediates of the production pathway consist of derivatives of the two. Tylenol is also ubiquitous in use as a pain and fever reducing medication and is in fact on the World Health Organization's list of essential medicines, making it a particularly relevant medicine. Finally, the existing pathway of Tylenol production chosen to test for was the Boots method (the original production method), requiring the addition of support for only two more reactions to the pathway search engine.
With the discovery of the Boots method for Tylenol production selected as the goal for the pathway search engine, it was time to add support for the intermediates to the interface and the reactions used in the pathway to the pathway search engine. The molecule the synthesis begins with, phenol, was already supported by the interface. The first intermediate of the synthesis is 4-nitrophenol. This reaction is accomplished by nitration via sodium nitrate, so support for the nitration reaction was added to the search engine. 4-nitrophenol required the interface to add support for the nitrite functional group. Similar to the phosphate and CoA groups, the nitrite is modeled for now as a single atom. The second intermediate, 4-aminophenol again was already supported by the interface. The reaction from 4-nitrophenol to 4-aminophenol used was a reduction with NaBH4, a reaction ALSO already supported by the pathway search engine. Support for the final reaction, acetylation of an amine, was added to the engine, as was support in the interface for Tylenol.
With support in place, we can now perform a full synthesis pathway search from phenol to Tylenol and indeed "rediscover" the Boots method of Tylenol production!
Standards - Per normal, IUPAC nomenclature standards were followed for all intermediates. Of note in this update, N-substituted amine nomenclature is introduced. Furthermore, the common IUPAC naming substitutions of benzene and phenol are introduced. Specifically, the name "cyclohexa-1,3,5-triene" is substituted with "benzene" and both "benzen-1-ol" and "benzenol" are subsituted with "phenol". Also, for now, the nitration reaction used adds a nitrite group in the para orientation of the first functional group in the benzene ring (if any exist). It should be noted that we are using a simplified model of the electrophilic aromatic substitution class of reactions. In reality an ortho-para directing group like the hydroxyl in phenol will yield BOTH para-nitrophenol (4-nitrophenol) and ortho-nitrophenol (2-nitrophenol). Finally, our acetylation reaction will be modeled to work for any amine and not consider steric hindrance for now.
Controls - The control update is pretty straightforward. Adding an ethyl radical can now be accomplished by first adding a carbon atom as an attachment, then adding another carbon atom to extend the first to an ethyl radical. Common IUPAC naming substitutions are automatic and do not require any further controls.
Future considerations - Certainly the two reactions added to the pathway search engine, aromatic nitration and amine acetylation, can be extended to model more robust and complex representations of the reactions. Specifically the aromatic nitration can consider if any existing functional groups serve as para-ortho directing, meta-directing, activating, or deactivating substituents. Furthermore both reactions can consider steric hindrance. In terms of the controls, it is becoming clear that adding an ethyl group (or other functional groups) would be a lot simpler if the user could add the group in one step rather than one atom at a time. We will be moving towards an interface that allows far richer controls for adding substituents. Finally, for now we are using the IUPAC name of N-(1-formylethyl)-4-aminophenol which although works for our purposes is NOT the recognized IUPAC name for acetaminophen as it ignores the amide group. The nomenclature engine will be updated to properly name amides.
OH! And check out the new contact page to provide feedback! We would love to hear suggestions for chemicals and pathways to model!
