Stereochemistry and Drug Action Isomers and types of

Stereochemistry and Drug Action ü Isomers and types of isomers Ø Constitutional Isomers • Functional Group Isomers • Positional Isomers • Geometric Isomers Ø Stereoisomers • Enantiomers • Diastereomers • Meso Compounds Ø Conformational Isomers • Eclipsed, gauche, staggered, syn-clinal, anti-clinal forms • Chair, boat, pseudo-chair, skew-boat MEDC 527 Fall 2008 1

Stereochemistry and Drug Action ü Functional Group Isomers Same molecular formula, but different functional groups, e. g. , n-propanol and methyl ether ü Positional Isomers Same molecular formula, same functional groups, but different positions of functional groups, e. g. , n-propanol and i-propanol MEDC 527 Fall 2008 2

Stereochemistry and Drug Action ü Geometric Isomers (cis/trans) Same molecular formula, same functional groups, same positions, but different orientation around a double bond or on a ring. An important criteria to exhibit geometric isomerism is that the isomers cannot be interconverted through mere rotation around a single bond. MEDC 527 Fall 2008 3

Stereochemistry and Drug Action ü Geometric Isomers (cis/trans) … other examples Trans isomer, i. e. , E, is 1000 -times more histaminic than cis, Z Vitamin A has all E double bonds, any Z would make it inactive! MEDC 527 Fall 2008 4

Stereochemistry and Drug Action ü Stereoisomers Ø Enantiomers …. pair of stereoisomers that are related to each other as non-superimposable mirror image isomers Ø Meso compounds … stereoisomers that have more than one chiral center and are super -imposable on their mirror images Ø Diastereomers …. pair of stereoisomers containing more than one chiral center and are not mirror images of each other Ø What will be the effect of changing the –Et group to –Me? MEDC 527 Fall 2008 5

Stereochemistry and Drug Action ü Stereo Isomers Ø Enantiomers …. arise …. . four different substituents on a tetrahedral carbon Ø …. . can also come about because of a tetrahedral nitrogen or phosphorus Ø …. . may also arise due to bridge nitrogens/phosphorus MEDC 527 Fall 2008 6

Stereochemistry and Drug Action ü Identify chiral centers (carbon, nitrogen, phosphorus) MEDC 527 Fall 2008 7

Stereochemistry and Drug Action ü Identify chiral centers (carbon, nitrogen, phosphorus) MEDC 527 Fall 2008 8

Stereochemistry and Drug Action ü Identify chiral centers (carbon, nitrogen, phosphorus) MEDC 527 Fall 2008 9

Stereochemistry and Drug Action ü Enantiomers and projections Standard Projection Saw Horse Projection Fischer Projection MEDC 527 Fall 2008 10

Stereochemistry and Drug Action ü Identification of Enantiomers or Chiral Centers Ø Step 1 identify chiral center Ø Step 2 assign priority … higher the atomic number, higher the priority … atoms with same atomic number heavier isotope, higher priority … if same priority for immediate atoms, continue down the second atom … double bonds are duplicated; triple bonds are triplicated Ø Step 3 visualize molecule so that the group of lowest priority is directed away Ø Step 4 draw (or visualize) Newmann projection of the remaining three groups Ø Step 5 write the priority order 1, 2 and 3; draw (or visualize) an arrow traveling from 1 2 3 Ø Step 6 if the arrow travels clockwise, the chiral center is ‘R’; otherwise it is ‘S’ D 3 4 2 3 1 MEDC 527 Fall 2008 2 CH 3 ‘R’ Ph 1 11

Stereochemistry and Drug Action ü Identification of Enantiomers or Chiral Centers D 3 4 2 1 3 ‘R’ 2 CH 3 Ph 1 View from bottom 2 View from side 2 CH 3 ‘S’ 4 3 1 MEDC 527 Fall 2008 3 D Ph 1 12

Stereochemistry and Drug Action ü Identification of Enantiomers or Chiral Centers (-)-ephedrine vasoconstrictor MEDC 527 Fall 2008 (+)-ephedrine 13

Stereochemistry and Drug Action ü Properties of Enantiomers Ø Physical properties … bp, mp, solubility, p. Ka, p. Kb, thermal stability, etc. …. all identical Ø Rotate the plane of polarization of plane polarized light … the phenomenon of optical activity MEDC 527 Fall 2008 14

Stereochemistry and Drug Action ü Properties of Enantiomers Ø Reactivity with chiral molecules …. e. g. , enzymes, receptors, …. . drug action/metabolism MEDC 527 Fall 2008 15

Stereochemistry and Drug Action ü Properties of Enantiomers MEDC 527 Fall 2008 16

Stereochemistry and Drug Action ü Why do chiral molecules react differently with biological molecules? R S MEDC 527 Fall 2008 17