The danger of additivity

When one embarks on the treacherous journey in organic chemistry research, proper planning of experiments is of utmost important. Nothing is more dreadful than going from one experiment to the next while changing two different parameters at a time. If you are a chemistry professor mentoring graduate students, I am sure that you wholeheartedly agree with me and may recall cases when this happened to beginning students in your lab (for example, an attempt to concurrently change a concentration and temperature in a reaction). The core of our work is to ensure that we take a rational approach to incremental learning, which is based on looking for cause/effect correlations while focusing on one variable at a time.

The idea of incremental changes goes beyond running experiments and affects our reasoning by implying that additivity should be the guiding light in reaching sound conclusions. I will provide evidence where being too dogmatic about additivity is counterproductive. As you can see, Klebe and co-workers make an excellent point: if you modify the inhibitor on the top left with a methyl group, you will get a molecule, whose binding affinity to thermolysin is improved only marginally (2.2 kcal / mol gain). If you then modify the same starting point with a carboxylic acid, again there is nothing remarkable (1 kcal / mol gain). But if you now do both of these changes (methyl and acid) at the same time, the result is profoundly better than the starting point (6.7 kcal / mol gain). While the underlying reasons for this sort of behavior are complex, this set of examples speaks to the non-additivity of functional groups and suggests that it is wrong to think about molecules as Lego-like agglomerates of functional groups. Every molecule is in its own class and simple functional group additivity is not always a sound guiding principle. You might then ask: does this imply that the vast majority of medicinal chemistry research is misguided? I don’t know. Maybe it is.


Remote control

Remote control of chemical reactivity ranks among the most fascinating aspects of chemistry, particularly if a network of non-covalent interactions is involved. During a recent discussion, one of my graduate students, Joanne Tan, presented an interesting paper detailing one such effect. I asked Joanne to write a summary for my blog, so here it is:

“Ever since my undergraduate years, I have always been turned off by carbohydrate chemistry. It is difficult to functionalize a carbohydrate at a specific hydroxyl group without the need for extensive protecting group manipulations. That is why I like reading about methods that allow one to perform regioselective modification of carbohydrates.

A recent JACS paper by Richard R. Schmidt and coworkers describes “the cyanide effect” – a method for the regioselective O-acylation of carbohydrates. In a typical acylation of a carbohydrate-derived diol, equatorial hydroxyl reacts preferentially. However, in the presence of cyanide anion, the axial OH is acylated instead, furnishing the kinetic product. On the basis of an NMR study, cyanide anion appears to hydrogen bond to the more acidic axial –OH, which increases its nucleophilicity. Particularly interesting is the double hydrogen bonding from the equatorial hydroxyl group to the axial oxygen atom, which serves to stabilize the resulting anion upon deprotonation by cyanide.”


Planarity is overrated

Every now and then I pause and wonder about the role of unnatural amino acids in chemical biology and drug discovery. Apart from obvious gains in accessible molecular diversity of peptide collections, the structural value of some of the commonly used unnatural amino acids it is not immediately clear, at least to me. While diversity is an extremely important consideration, one has to wonder about the molecular-level significance of, say, cyclohexyl alanine. Apart from general hydrophobicity, what would the cyclohexane chair “glued” to a peptide chain impart when thrown into the medley of more mundane amino acids? How will it fare?

I was surprised to find out that the chair I just mentioned does just fine when it comes to stacking. In a thought-provoking study, Gunaydin
 and Bartberger point out excellent stacking abilities of cyclohexane. It appears that unsaturated rings found in drugs may be replaced with their saturated counterparts without losing potency even when it comes to stacking interactions with the side chains of aromatic residues. This should give us a lot of food for thought. What about asymmetric catalysis? Recall the importance of stacking interactions there. When we consider some widely used partially hydrogenated BINOL ligands, invoking stacking interactions in transition state assemblies might not be that outlandish if we think about Gunaydin
 and Bartberger’s eloquent study in structural biology.