1. Chemistry 301 Q1 September 21, 2017: Agenda Lecture: Continue Med Chem
Lab today (1-4 pm): 1) GC/MS training in small groups (~ 4 people) with Jia today starting at 1 pm; 2) be sure you’re using the online data repository for your elab notebook, spectra, etc.; 3) please gather 1H and 13C NMR data, IR, melting point, and GC/MS data for your purified intermediates/products; 4) schematic chemistry update to Rob/talk with Rob in person ; 5) more “gifts”
Next time in lecture: Continue talking med chem
Due: schematic update -- if you needed more time after Tuesday, please get to Rob as soon as possible
Homework: keep working on chemistry
Note: Rob off-campus this Friday; next Thursday no pre-lab lecture (yes lab 1-4 pm!) as Rob is co-presenting webinar on honey bee health research for Agilent that morning

2. Solubility – Varying aromatic substituents to vary pKa
We can change the pKa of an aromatic amine or carboxylic acid by adding electron-donating or withdrawing substituents to the ring!
Remember the position of such a substituent can affect a more distant group through induction and/or resonance
It was found that the substitution of a –NO2 group for a –Cl group in the development of oxamniquine (right) improved activity, and a pKa change was thought to be involved. How?

3. Solubility – Using “bioisosteres” for polar groups
Bioisosteres are functional groups that have similar chemical or physical properties but which may improve such characteristics as bioavailability, toxicity, etc.
Medicinal chemists use these frequently!
One example is the substitution of the tetrazole group for a carboxylic acid
Both have an acidic proton and exist in ionized form at pH 7.4, but the tetrazole is 10x more lipophilic than a carboxylate anion so drug absorption is increased!
Some cool acid
isosteres!

4. Fighting chemical and enzymatic degradation – Steric shields (from Star Wars?)
We talked earlier about the body’s ability to break down drugs. Is there anything we can do to prevent/decrease/eliminate this degradation?
Do we want to eliminate it?
As you can imagine, esters and amides are readily hydrolyzed in our gut; what if we don’t want that to happen to a drug?
We can put in a bulky group – a steric shield – near the functional group to make hydrolysis more difficult!
Figures are from G. Patrick’s “An Introduction to Medicinal Chemistry” 5th Ed.

5. Fighting chemical and enzymatic degradation – Use of bioisosteres
Remember, the key to bioisosteres is that they are groups substituted for other groups that preserve biological activity but improve some other aspect of the drug
We can replace the –CH3 in the ester below with an –NH2 to give a carbamate; it has the same valency around the central atom and size, BUT the electronics are different! How? Why does that matter?
You might also use an amide. Such bioisosteric replacements may be specific to certain categories of drugs.
You can also manipulate the electronic effects (inductive effects) of, e.g., esters to “tune” the ease of their hydrolysis

6. Fighting chemical and enzymatic degradation – Steric and electronic modifications teamed-up!
What has been changed in the short-acting local anesthetic Procaine to produce the longer acting anesthetic Lidocaine?
Is there a place for both?