1. Drug Action (D 8 ) Pages 425-427 1) Definitions 2) Geometrical Isomerism 3) Chirality 4) Beta-lactam ring (Penicillin) 5) Heroin

2. Definitions  Isomerism: The existence of two or more molecules having the same molecular formula, but with different bonding arrangements of atoms, or different orientation of their atoms in space  Stereo-isomerism: Isomerism arising from differences in the shapes of molecules (includes geometric and optical isomerism) Same molecular and structural formulas, but different arrangement of the atoms in space

3. Definitions: Types of Stereo-Isomerism  Geometric Isomerism: Occurs in alkenes (double bond: C N H 2N ) when there is restricted rotation around the C-C double bond. It can also occur in ring system where there is restricted rotation about a C-C single bond  Optical Isomerism: Typically occurs when a molecule has no plane of symmetry and can exist in left and right-handed, non- super imposable, mirror images. The molecule must possess a chiral center (asymmetric)  Chiral: the carbon atom is attached to 4 or more different atoms or functional groups Optical isomers rotate plane-polarized light

4. Objective One: Explain the importance of geometrical isomerism in drug action  Physical Properties of Geometric Isomers Different polarity (dipole movement changes) Different boiling and melting points Change in solubility  Chemical Properties of Geometric Isomers Some properties are similar because the isomers have identical functional groups attached. But, can have different pharmacological effects  Due to cis (same side) vs. trans (opposite) arrangements Cis: 1,2-disubsituted alkenes with functional groups or atoms which are on the same side of the molecule Trans: 1,2-disbustituted alkenes with functional groups or atoms on opposite sides of a double bond

5. Example: Cis vs. Trans  Pt(NH 3 ) 2 Cl 2 cis-isomer: cisplatin  Anticaner, used in chemotherapy trans-isomer:  Chemotherapeutically inactive Pt NH 3 H 3 N Cl Cl cis: same side Pt NH 3 Cl NH 3 Cl trans: opposite side

6. Example: Cis vs. Trans (continued)  Cisplatin Square planar molecule, heavy metal complex Can enter the nucleus of a cancerous cell  Cl atoms are replaced by bonds with guanine of the same DNA strand  Prevents replication, disrupts strand  Trans-isomer Cl atoms are in the wrong position so cannot form bond with guanine G G Pt NH 3 H 3 N DNA strand

7. Objective Two: Discuss the importance of chirality in drug action  Enantiomers Non-super imposable mirror images (optical isomers) Differ in their optical activity (aka their ability to rotate the plane of polarized light)  One isomer rotates the light clockwise  Other isomer rotates the light counterclockwise the same amount (equal and opposite)  Example C H3CH3C H OH C2H5C2H5 mirror C H5C2H5C2 H OH CH 3

8. Affect on Medicine  Racemic Mixtures Equimolar mixtures of two enantiomers of the same compound Because the rotation of plane-polarized light is equal but opposite,the mixture is not optically active  Source of Drugs Racemic mixtures not found in nature, so drugs from natural sources (natural or semi-synthetic) are single enantiomers Synthesized drugs are usually racemic mixtures to reduce costs  No refining costs

9. Racemic Mixtures in Medicine  Penicillin V (natural) Synthetic enantiomer (not found in natural source) is not pharmacologically active  Ibuprofen (synthetic drug) First enantiomer=analgesic and anti-inflammatory Other enantiomer=no effects  Thalidomide (synthetic drug) Both enantiomers=active First=relieve morning sickness Second=deformities in limbs, birth defects

10. Objective Three: Explain the importance of beta-lactam ring action penicillin  Structure of Penicillin 3 structural groups:  R group, beta-lactam ring, carboxylic acid group C O R NH O S N CH 3 C OH O R Group beta-lactam ring carboxylic acid group

11. Beta-lactam ring  Heteroatomic, 4-membered: 1 Nitrogen, 3 Carbon  Square planar shape Would prefer to be tetrahedral (has a non- bonding pair of electrons, nitrogen) 90 degree angle puts the ring under chemical stress, increasing reactivity Increased reactivity opens the ring

12. Open Ring  Can covalently bond to transpeptidase Enzyme responsible for the synthesis of bacterial cell walls  Blocks the action of transpeptidase No bacterial growth is possible Bacteria bursts with out the linkage between the cell walls  Penicillin can fight infections!

13. Objective Four: Explain the increased potency of diamorphine (heroin) compared to morphine  Structural Differences Heroin has same Carbon skeleton Two OH groups replaced by CH 3 COO (ester) Ester is less polar, more fat soluble, than OH.  More rapidly absorbed into the nonpolar central nervous system and brain  Heroin Semisyntehtic narcotic More potent, stronger painkiller Highly addictive