Rules of the Day
4-23-2023
Click here for a copy of the lectures notes I wrote in class
Click here for a copy of the handouts I used in class today
1. Final Piece of Aromatic Chemisty. Rings with a Bad group are so deactivated that neither the Friedel-Crafts alkylation or acylation will work. However, you can add multiple NO2 groups to the same ring if you run the reaction long and hot enough.
2. Course Content Refresh and Reframe: The decarboxylation and Diels-Alder reactions both occur because their transition states have aromatic character, and therefore these reactions have a much lower activation energy than you might have thought.
3. Many syntheses are carried out with a starting material reversibly attached to beads. This has the advantage of allowing exchange of reagents and isolation of products by simple filtration. This process can be automated! Mind officially blown! An efficient coupling strategy has been worked out for the solid phase synthesis of the phosphodiester bonds of DNA and RNA on glass beads by machine. You can order these on-line, they show up overnight by Fed-ex the next day!
6. Click here for a good description of the HIV lifecycle. The AIDS virus is a single stranded RNA retrovirus meaning a virus particle is a single strand of RNA surrounded by virus proteins. Once inside host cells, the RNA is reverse transcribed to DNA, that then integrates into the genomes of host cells. After an unknown signal the DNA becomes active and is transcribed to long polyprotein mRNAs. A polyprotein transcript is produced from the mRNA called GAG-POL that is cleaved into functional proteins by the AIDS protease.
7. Enzymes catalyze reactions by 1) having acids, bases and nucleophiles in the active site in exactly the right places in 3-dimensions AND 2) by stabilizing transition state structures.
8. The AIDS protease is an aspartyl protease that uses two carboxylic acid groups and a water molecule to hydrolyze an amide bond at neutral pH and at room temperature.
9. Drugs are designed to interfere with the biochemical steps that are unique to the virus, in particular the reverse transcriptase (RNA to DNA) and AIDS protease steps (cleavage of GAG-POL polyprotein into individual virus proteins).
10. The AIDS protease inhibitors are designed to resemble the key tetrahedral intermediateof the amide hydrolysis reaction while maximizing complementary contacts within the active site.
11. Because the reverse transcriptase step makes a significant number of errors, the HIV genome mutates quickly and the target enzymes (reverse transcriptase and AIDS protease) can become resistant to any one drug, so "cocktails" of several drugs are used to counteract resistance.
12. Mindblowing Alert #3 I believe that developing a treatment for AIDS in about a decade stands alongside getting to the moon as one of this countries great technical achievements. The core ideas behind creating the drug are based on 1) understanding the mechanism of the enzyme reaction to be inhibited, 2) design possible drugs that bind only to the disease target, 3) synthesize then test thousands of derivatives to find the precious few that can be taken as pills and cause minimum side effects, make sure they are safe and effective, then synthesize them in large amounts in pure form, batch after batch.
Homework:
No reading or quizzes but you need to watch this video on Nucleophilic Aromatic Substitution. THIS RARE BUT IMPORTANT REACTION WILL BE ON THE FINAL
Click here for the first Carbohydrate Video (Module) you are also required to see. THIS MATERIAL WILL BE ON THE FINAL
Click here for the second Carbohydrate Module Video (Module) you are also required to see. THIS MATERIAL WILL BE ON THE FINAL
Click here for the Rules of the Day associated with these videos
Click here to get a copy of the blank Mechanism Sheets used in these videos
Click here to see the filled-in Lecture Notes from the recordings to help you follow along.
Start working on the Homework Problem Set 11, due at 10 PM on Monday, April 24. Click here to access the Homework Problem Set 11. We will be grade it for completion only. There is no Aktiv learning portion of this homework, just Gradescope.
When you are ready, you should start working on the Final Practice Homework problems. You will not turn this in, the answers are also posted already. These problems cover the last material of the course, including some covered in the modules linked immediately above.