1. Drug Design Geometrical isomerism Chirality
Chiral auxiliaries synthesis
Polarity & Modifications
Ring strain
Combinatorial chemistry
Parallel synthesis

2. Geometrical Isomerism
Against cancer
Inactive

3. DNA without
CIS-platin
DNA with
CIS-platin

4. Chirality
Thalidomide

6. Why chirality matters

7. [ ] Synthesis of One Enantiomer using a Chiral Auxiliary
Asymmetric Synthesis
Synthesis of One Enantiomer using a Chiral Auxiliary
[ ]
Chiral Auxiliary :

9. Polarity

10. MORPHINE
-OH polar groups
Not lipid soluble
Hard to get in brain
HEROINE
Ester less-polar groups
Lipid soluble
Easy to get in brain

11. Modifying polarity
Amine + HCl => hydrochloride salt (ionic, more soluble)‏
Prozac

12. Modifying polarity
Carb. Acid + NaOH => Sodium salt (ionic, more soluble)‏
Aspirin

13. Esters as prodrugs Ester masking polar groups allowing passage through
fatty cell membranes

14. with strain because of different hybridizations
Ring strain
Active ring
with strain because of different hybridizations
Bind to cell wall synthesis enzyme

15. What is Combinatorial Chemistry?
Is an approach that provides efficient synthesis of a large collection of molecules
Screening of libraries of related compounds to isolate the molecule of desirable property
Used in both academia and industries to generate huge libraries of compounds that have important biological properties

16. Combinatorial Chemistry
Combinatorial Library •
4 monomers
Nn Combinations
44 = 256
tetramers

17. Solid Phase Synthesis
resin +
monomer
shake
wash
resin
cleavage
wash

18. Split-Mix Process 33= 27 tag each bead! Mix-Split Couple Mix-Split

19. Solid Phase Library
In 1991s, Houghten & Lam: synthesis of a huge peptide library
20 amino acids
Solid-phase synthesis
202 = 400 dipeptides
DNA: fully automatic (solution)‏
peptide
203 = 8000 tripeptides
carbohydrate
small molecule (drug-like)‏
204 = 160,000 tetrapeptides
ln 1992, Jon Ellman: synthesis of non-peptide drug-like molecules by solid phase synthesis

20. Parallel synthesis On a teflon reaction block Large number of wells
Add different parts at each step
Common conditions

21. 12-well reaction block

22. Add Scaffold to each well

23. Wells after Addition of first reagentSB SC SD SA SB SC SD SA SD SB SC

24. There are now twelve different products
SA1
SB1
SC1
SD1
SA2
SB2
SC2
SD2
SA3
SD3
SB3
SC3

25. Computer aided drug design