EXAM 4 - Organic Synthesis in Drug Development

Question 1

Answer 1

D) combinatorial synthesis

Question 2

What is the goal of linear, convergent, and parallel synthesis?

Answer 2

Goal: Make one compound/set of 10 compounds to study SAR and make sure the quality of the compounds are very good.
(quality over quantity)
* used to make small set of targeted analogues

Question 3

What is the goal of combinatorial chemistry?

Answer 3

Goal: make as many compounds as possible as fast as possible
* tested as mixture of compounds or as single compound (HTS)
* make 5000 compounds with the same scaffold (very similar structure)

Question 4

What is the goal of diversity-oriented synthesis?

Answer 4

Goal: produce as many diverse compounds as possible from a single scaffold
* make 30 compounds that are diverse –> will tell you what structure you might need for your active compound

Question 5

What is the difference between linear+convergent synthesis and parallel synthesis?

Answer 5

Linear + convergent synthesis - describe approaches to a sequence of organic reactions
* almost always multiple reactions

Parallel synthesis - describes approach for 1 reaction

Question 6

Explain what overall yield is.

Answer 6

How much of desired end product obtained based on original starting material.

Question 7

Describe the process of linear synthesis.

Answer 7

Linear - sequential reactions in which product of first reaction is used in the next reaction in a linear fashion.

Question 8

Describe the process of convergent synthesis.

Answer 8

Fragments are synthesized before coupling them together in final reaction
* designed to improve overall yield of final compound
* decrease time bc you can create seperate parts of the compound at the same time then couple them together

Question 9

Describe the process of parallel synthesis.

Answer 9

Performing organic reactions “side-by-side” to generate diverse compounds for SAR.
* using the same intermediate that reactions with a different molecule = diverse products/compounds
* modifications made to lead to create diversity should be done at last possible step.

Question 10

What is the importance of building in diversity at the end of synthetic sequence?

Answer 10

Less reactions required = save time, money, and reagents

Question 11

Of the three techniques, which is used most often?

Answer 11

Most times, all three of the techniques will have to be used to generate SAR to optimize different regions of the lead.
* techniques are not mutually exclusive

Question 12

What is the ideal number of reactions to generate compounds for SAR?

Answer 12

Less than 5 is ideal
Greater than 10 is okay, not ideal

Question 13

What is the best time to add diversity to the compounds?

Answer 13

At the latest possible step
* will save time and money
* early reactions will occur at “large-scale”

Question 14

Answer 14

A) Utilizing a convergent approach increases the overall yield
* also saves time/money

Question 15

Describe how combinatorial chemistry works.

Answer 15

• a particular set of building blocks/precursors are used to prepare all possible derivatives of a given compound class.
• mixture of all possible derivatives (16) can be tested at once
  (instead of 16 seperate assays for each derivative created)
• saves time

Question 16

After testing a mixture of AB compounds, what do you do if its active versus inactive?

Answer 16

Active mixture –> identify the active component
inactive mixture –> store for next HTS

Question 17

Describe what solid-phase organic synthesis (SPOS) is.

Answer 17

Starting compound is covalently bound to an insoluble resin bead –> then sequential reactions are performed to produce a library of diverse compounds
* After wash, the compound you want is still bound to the insoluble resin and won’t wash away but everything else will.

Question 18

Explain the Mix and Split synthesis method of library mixtures.

Answer 18

Classic method to generate large libraries of compounds.
* Take resin and in 4 seperate vials attach 4 different starting compounds
* Bring the 4 vials together and mix into 1 vial
* Seperate into 4 seperate vials (each now containing A, B, C, and D starting compounds)
* Each vial gets a different reagent added in
* 4 vials get mixed together as 1 again (16 different compounds)
* process can be repeated