Ref – This post is largely based on an amazing review article by one of the most brilliant physicians ever: Chiral Toxicology: It’s the Same Thing…Only Different

Some believe there is a departure from basic chemistry after entering professional pharmacy education. However, encountering numerous drugs in clinical practice, we knowingly focus on clinical properties, clinical evidence, and collaborative efforts with the treatment team.

Chemical principles like isomers are one of these elements we tend to leave behind. We may have tossed the term around clinically lately, but recalling the basic chemistry and subsequent pharmacology is interesting. Although they share the same molecular formula, isomers are chemical structures with different structural formulas. This can translate into entirely different chemical properties. One example is the constitutional or structural isomers with the molecular formula C7H8O that, for example, can be benzyl alcohol (phenyl methanol) or methoxybenzene. They have completely different physical properties but the same molecular weight and formula.

Stereoisomers can be further split into configurational isomers or conformational isomers. Configurational isomers are differed based on their structural rotation when looking down based on a Newman projection. When the optical arrangement is made where the main groups are 180 degrees from each other, it is called the anti-staggered rotation. When the main groups are 60 degrees rotated, they’re now in the gauche arrangement; with 120 degrees, they’re eclipsed, and at zero degrees, they’re totally eclipsed. 

The other main conformational isomer idea is the cyclical conformation of the ring structure. The chair cyclohexane is familiar and is the most stable formation for many.

Configurational isomers, on the other hand (funny since we can use our hands as examples of chiral structures), are broken into two large groups, enantiomers and diastereomers. We’re familiar with these concepts if we know drug names, such as albuterol and levalbuterol.

Albuterol and levalbuterol are identical molecular formula compounds but differ in a three-dimensional arrangement. The chiral carbon on the albuterol structure has an S configuration, whereas, in levalbuterol, it is in the R- configuration. This may not seem obvious since doesn’t “lev” stand for L? In many cases, yes, but in this case, it’s inaccurate based on our modern understanding of these structural relationships. The D (dextrorotatory, or -) and L (levorotatory, or +) are somewhat different in how they’re identified compared to R (rectus) and S (sinister). That is related to the D and L enantiomers are determined based on the structure’s rotation of polarized light. Rotation to the right (clockwise) indicates a D or – characteristic, whereas the L is to the left (or counterclockwise). An example of when this doesn’t correlate accordingly is with albuterol and levalbuterol. Albuterol has an S configuration at its chiral center, whereas levoalbuterol has an R configuration. So one could wrongly assume levalbuterol has an “S” or to the Left confirmation when it’s to the right. However, numerous drugs align with this, including levofloxacin (L or S – ofloxacin) or escitalopram (L or S – citalopram). 

Another structural description includes the cis- and trans-conformation compared to the Z- (zusammen) and E- (entgegen) diastereomers. The cis-trans isomers have their highest priority substituents on the particular side of the bond. Cis- has its substituents on the same side of immovable bonds, whereas the trans has these groups on either side of the immovable bonds. However, when the compound has polysubstituted double bonds, this doesn’t work. We can use the E/Z designation from the Cahn-Ingold-Prelog priority (also established R/S). For Z- the two highest priority groups are on the same side of the double bond, whereas E is on opposite sides. An example of where these can differ includes looking at cisatracurium-atracurium and tretinoin-isotretinoin. The cis is based on two chiral Nitrogens (not carbon) and two chiral carbons with cisatracurium. Conversely, tretinoin has four E- conformations, whereas isotretinoin has three E- and one Z conformations.

A new blog post I wrote on the HYMR Blog!