Stereochemistry

1. Stereochemistry in Drug Action (D.8) and Drug Design (D9) By Lisa Grossman Max Krakauer Sarah Theobald With revisions by Ms. Smith

2. Drug Action (D.8) D.8.1 Describe the importance of geometrical isomerism in drug action D.8.2 Discuss the importance of chirality in drug action D.8.3 Explain the importance of beta-lactam ring action of penicillin D.8.4 explain the increased potency of diamorphine (heroin) compared to morphine:

3. Review - What Are Stereoisomers? Stereoisomers • two isomers • same molecular formula • same structural formulas but • different spatial arrangements of atoms

4. The Two Types of Stereoisomers • Geometric isomers • Optical isomers

5. Geometric Isomers Geometric isomers (or cis-trans isomers) are molecules with a double bond that form cis and trans isomers. • note that square planar molecules can also display geometric isomerism cisand trans refers to the orientation of functional groups within a molecule

6. Cis (on the same side) Cis-2-butene Molecular Formula- C4H8 Structural Formula- CH3CHCHCH3 Trans (across/opposite sides) Trans-2-butene Molecular Formula- C4H8 Structural Formula- CH3CHCHCH3 Geometric Isomers Different sides Same side

7. Differences in Physical and Chemical Properties for Geometric Isomers • undergo different chemical reactions. • Stability (trans are usually more stable) • Polarity • Boiling/Melting point • Solubility

8. Geometric Isomers and Drugs Because geometric isomers have different chemical and physical properties, they act differently as drugs in our bodies as well. • Example : • cis-platin used for chemotherapy - it can • enter cancer cells and interact with DNA • Trans- platin - not active

9. Optical Isomers Optical isomers • have a chiral center • non-super imposable mirror images

10. Optical Isomers Terminology Chiral: if a molecule is chiral ( or displays chirality) this means the molecule has two optical isomers Chiral centre: the central carbon in an optical isomer with four bonds each attached to a different group. Enantiomer: another name for a molecule that is found in optical isomers. For example, ibuprofen has a two enantiomers, a left rotating enantiomer and a right rotating enantiomer. Racemic mixture: A mixture of 50% left rotating and 50% right rotating optical isomers

11. How can you tell if a molecule is chiral? Optical isomers will always have a chiral (central) carbon with four single bonds each attached to a different substituent. • Example: Which molecule is not chiral? • CH3CHClOH • CH3CHCOOHNH2 • BrCH2COOH

12. Using a Polarimeter A polarimeter is a machine that can tell what optical isomer a substance contains by giving a rotational quantity in degrees • If the rotational value is positive the optical isomer is right handed. • If the rotational value is negative the optical isomer is left handed.

13. Using a Polarimeter If a molecule rotates at +24 degrees, is it right handed or left handed? Right If a molecule rotates at -24 degrees, is it right handed or left handed? Left If a molecule rotates at 0 degrees, is it right handed or left handed? Both-it is 50% Right and 50% Left (This is called a racemic mixture.)

14. Optical Isomers and Drugs • Optical Isomers interact differently in our bodies because our bodies themselves are chiral. • Thus important to make sure you have the right optical isomers in your drugs. • Thalidomide tragedy- one enantiomer stops morning sickness in pregnant women. The drug was sold as a racemic mixture to reduce costs. However, it was later discovered that the other enantiomer causes severe birth defects. • Many drugs are still sold as a racemic mixture to reduce costs, including advil, motrin, and vitamin E.

15. D.8.3 Explain the importance of beta-lactam ring action of penicillin • Penicillin • R group • carboxylic acid group • Beta-lactam ring • heteroatomic four-membered ring • strained ring (90°vs 109.5°) is very • reactive • open ring binds with enzyme needed for • synthesis of linkages in bacterial cell walls • so… bacteria burst

16. D.8.4 explain the increased potency of diamorphine (heroin) compared to morphine: • Heroin • two polar hydroxyl groups replaced by two less polar ester groups • more fat soluble • more readily absorbed into the non-polar environment of the central nervous system and the brain

17. Drug Design(D.9) D.9.1 Discuss the use of a compound library in drug design. D.9.2 Explain the use of combinatorial and parallel chemistry to synthesize new drugs D.9.3 Describe how computers are used in drug design D.9.4 Discuss how the polarity of a molecule can be modified to increase its aqueous solubility and how this facilitates its distribution around the body D.9.5 Describe the use of chiral auxiliaries to form the desired enantiomer

18. Synthesis of New Drugs • often starts with ‘lead’ compound - pharmacologically active • uses organic chemistry to make small changes to the drug’s structure to produce a more effective drug • more potent, fewer side effects • result is a compound library – a collection of related compounds that can be tested for their pharmacological activity

19. Combinatorial Chemistry (Combi-Chem) • a way of synthesizing and testing potential new drugsthat reduces time and costs • a set of reactants are reacted in all possible combinations • resulting compounds are cataloged by computers, called a compound (or combinatorial) library • library is tested in the laboratory en masse (all at once) for pharmacological activity • large libraries increase the chances of finding better drugs

20. Combinatorial Chemistry (Combi-Chem) • much of the process is streamlined with technology / computerization / • Robotics can be used to carry out identical chemical processes simultaneously • Known as “parallel synthesis”

21. Example of Synthesis in Combi-Chem: Synthesizing Polypeptides • amino acids (peptides) are the building blocks of protein molecules • amino acids are combined to make dipeptides in condensation reactions. Peptide linkage water

22. Example: Synthesizing Polypeptides Because amino acids (peptides) contain both a carboxylic acid group and an amino group, two amino acids can be combined in four different ways to make dipeptides. Peptide A-Peptide A Peptide A-Peptide B Peptide B-Peptide A Peptide B-Peptide B

23. Plastic bead H C H Cl Example: Synthesizing Polypeptides A simple two stage combi-chem reaction is used to make dipeptides. Starts with a linking group attached to a plastic bead.

24. Plastic bead Plastic bead + amino acid A = + HCl H C H H C H Cl amino acid A Example: Synthesizing Polypeptides Stage one: the carboxylic acid group from an amino acid reacts with the Cl of the linking group… the amino acid now has its amine group ready to react

25. Plastic bead Plastic bead + amino acid B + H2O H H C C H H amino acid A amino acid A dipeptide amino acid B Example: Synthesizing Polypeptides Stage two: Product of previous reaction is washed and then reacted with aa B, forming a peptide bond… making a dipeptide. Later, the plastic bead-CH2 is removed to leave the dipeptide.

26. Plastic bead H C H amino acid A dipeptide amino acid B Example: Synthesizing Polypeptides • Next step? • Continue reactions to make polypeptides or • Remove the plastic bead-CH2to leave the dipeptide.

27. Example: Synthesizing Polypeptides A typical two stage reaction in four containers

28. Example: Synthesizing Polypeptides • a combination of two amino acids makes 4 (22) dipeptides (two stages) • Using three amino acids, makes 9 (32)dipeptides (two stages) • Using three amino acids (three stages) makes 27 (33)tripeptides • Using three amino acids (four stages) makes 81 (34)tetrapeptides

29. Example: Synthesizing Polypeptides So the general formula for the total number of possible polypeptides formed is… Number of amino acids = p Number of stages in the reaction = s Number of polypeptides formed = pS

30. Synthesizing other molecules ???? Scientists quickly realized that this methodology could be applied to other synthesis reactions. Organic heterocyclics are often used as starting materials for potential drugs… with the addition of different branches often leading to new and better drugs.

31. How can Computers Help? mode of drug action in the body usu involves interaction with biological molecules • enzymes • pharmacophore (receptor site) molecular modeling software • more powerful, cheaper, more available • able to convert 2D structure into 3D structure • allows ‘virtual testing’ of drug with receptor site / enzyme A drug may be an Inhibitor molecule (ligand) • interfer with active site of an enzyme…

32. Polarity of Molecules • In general, a drug that is altered to contain an ionic group is more soluble in aqueous solutions (like body fluids)… and therefore more effective. • However - some drugs that are fat soluble are more effective… if their target is the central nervous system… the brain… fatty cell membranes of nerve cells… • mescaline more potent than psylocybin • heroin more potent than morphine

33. Polarity of Molecules – Case in PointAspirin • salicylic acid (2-hydroxybenzoic acid) • fever reducer, pain killer • strong acid • unpleasant to take orally • damaging to membranes lining mouth, esophagus, stomach

34. Aspirin • sodium salicylate • fever reducer, pain killer • soluble ionic salt of salicylic acid • still bitter taste • still damaging to stomach when it reverts to salicylic acid

35. Aspirin • acetyl salicylic acid (ASA) • fever reducer, pain killer • acetate (ethanoate) ester of salicylic acid • relatively tasteless • only weakly acidic • relatively insoluble

36. Aspirin • acetyl salicylic acid (ASA) • called a prodrug • Reacts with water in basic environment of small intestines to form the active salicylic acid molecule. • also available as the sodium salt of ASA • more soluble… more effective

37. Synthesis of Drugs and Chirality How drugs can be synthesized • Derivation from natural sources • Modification of natural substances • Laboratory synthesis Usually only one enantiomer is found in nature, so naturally derived drugs usually contain an excess of one enantiomerswhile laboratory drugs are occasionally racemic mixtures

38. Chiral Auxiliaries • New: stereospecificsynthesis or asymmetric synthesis Stereospecificsynthesis involves the use of chiral auxiliaries to make only one enantiomer of a molecule

39. What is a Chiral Auxiliary? • molecule that attaches itself chemically to the chiral molecule being synthesized • creates conditions which cause the drug synthesis to follow a certain stereospecific path – producing only one type of enantiomer • auxilaryis removed or replaced to leave the desired enantiomer.

40. If you’re still confused, here’s a diagram The top reaction is unmodified… the bottom reaction uses a chiral modifier… Notice the different yields…. Much higher in bottom reaction.