1. Chemistry 301 Q1 September 14, 2017: Agenda
Reflections on Synthesis Day 1 (9/12)
Lecture: TLC, flash chromatography, Med Chem Intro
Lab today (1-4 pm) – Rob must leave at 4 pm today for a VC with MSK at 4:15 PM: 1) TLC, 2) chromatography, 3) next reactions?, 4) each group discuss their synthesis plans with Rob briefly during lab at some point, 5) start using the data repository (organized by target ID number)!
Next time in lecture: Continue talking med chem
Due: nothing
Homework: keep working on chemistry

2. Reflections on Day 1 Synthesis
Cooling baths: level of cooling medium, foil to prevent evaporation, CO2 chunks vs. ice
Secondary containers for reactions: a great back-up
Stopping reactions: When? How? Why?
Addition of chemicals: speed, dependence on volume/method used to add – application to solids and liquids
Opening any chemical outside of hood

3. TLC, Flash Chromatography, Hi-Vac
- What do you need to do? Why? How?
Flash Chromatography:
Your experience in 225 vs. this synthesis
Rob’s way vs. what you may have seen before, e.g. dry transfer
Hi-Vac:

4. Let’s talk about some fundamental Med Chem topics!

5. Some Key Med Chem Concepts
Pharmacodynamics: “the study of how a drug binds to its target binding site and produces a pharmacological {biological effect on an organism or a part thereof} effect”
E.g. “the exposure of tumor cells in vitro to varying doses of a new agent to evaluate its dose-response relationship, or a Phase I clinical trial to define the maximally tolerated dose and dose-limiting toxicities in patients.”
(what a drug does to the body!)
Pharmacokinetics: how a drug is absorbed, distributed, metabolized, and excreted (aka ADME). Sometimes you’ll hear the term ADMET or ADME/Tox.
E.g. “a patient has been given an intravenous injection of a post-operative painkiller. The kinetics of pain killers are important as pain relief is closely related to plasma concentration.”
(what the body does to the drug!)

6. A…D…M…E…
Absorption
If orally administered, drug needs to be hydrophobic enough to interact with the fatty cell membranes of the gut wall but hydrophilic enough to resist dissolution in fat globules in gut
Distribution
Once absorbed, drugs enter blood supply – arteries, veins, capillaries. Drugs can pass through pores in capillaries into tissues and aqueous environment around body’s organs. They can act on their target there or may need to enter individual tissue cells to act. Watch out for plasma protein binding and fatty tissue absorption! (Also BBB, placenta, DDIs.)
Metabolism
Enzymes degrade/modify drugs so they’re excreted more readily. Metabolites may be even more active than drug (prodrug approach)! Metabolites must now be identified (including stereochemistry! and biological activity!) before approval.
Excretion:
Blood/kidneys/urine/bladder principally; Blood/liver/bile duct/intestines; Lungs: volatile drugs, metabolites; Skin by sweat!; Less so saliva, breast milk; reabsorption is possible in this process

7. Solubility
Influenced by hydrophilicity/hydrophobicity of the molecule!
Too polar (orally administered) prevents passage across cell membranes in gut wall
Too greasy (orally administered) won’t be absorbed well in gut but rather dissolved in fat globules in gut
We measure the hydrophobic nature of a drug with the partition coefficient (P), which measures relative distribution of a drug in n-octanol/water
Hi P value indicates a relatively more hydrophobic compound; log P values are used typically to measure hydrophobicity

8. Solubility – how can we change it?
To make a molecule less polar, we can “mask” polar groups by, e.g., converting an alcohol or phenol to an ether or ester; a carboxylic acid to an ester or amide; 1˚ or 2 ˚ amines can be converted to amides or 2˚ or 3˚ amines. Be careful, though!
To make a molecule more polar, we can add polar groups!
Next time… A bit more on solubility, on to metabolism

9. Solubility – Changing by varying hydrophobic substituents … we can:
Increase hydrophobicity by a) adding alkyl groups in the carbon skeleton or b) increasing the size of existing alkyl groups
Decrease hydrophobicity by a) decreasing the size of existing alkyl groups or b) removing them
Increase the size of one existing alkyl group and decrease another
Add –F or –Cl (rarely –Br or –I) to increase hydrophobicity