Stereochemistry and Drug Action Isomers and types of
Stereochemistry and Drug Action Isomers and types of isomers Constitutional Isomers Functional Group Isomers Positional Isomers Geometric Isomers Stereoisomers Enantiomers Diastereomers Meso Compounds 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 Functional Group Isomers Same molecular formula, but different functional groups, e.g., n-propanol and methyl ethyl ether C H3 C H3 N H2 HN O O O C H2C H3 O 3,4-M D A (E cstasy) p h en acetin (analgesic) Positional Isomers Same molecular formula, same functional groups, but different positions of functional groups, e.g., n-propanol and i-propanol Ph
C O OEt Ph C O O Et N N C H3 M e p irid in e (A n a lg e s ic ) CH3 (n o t a n a lg e s ic ) MEDC 527 Fall 2008 2 Stereochemistry and Drug Action 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. OH HO H H H H HO tra n s -D E C (E s tro g e n ic ) HO c is -D E S (n o n e s tro g e n ic ) MEDC 527 Fall 2008 3
Stereochemistry and Drug Action Geometric Isomers (cis/trans) other examples N H3C H N Triprolidine (E) Trans isomer, i.e., E, is 1000-times more histaminic than cis, Z Me Me OH Me Vitamin A has all E double bonds, any Z would make it inactive! MEDC 527 Fall 2008 4 Stereochemistry and Drug Action Stereoisomers Enantiomers . pair of stereoisomers that are related to each other as non-superimposable mirror image isomers Meso compounds stereoisomers that have more than one chiral center and are super-imposable on their mirror images Diastereomers . pair of stereoisomers containing more than one chiral center and are not mirror images of each other CH3 CH3 CH3 CH3 H Cl
Cl H H Cl Cl H Cl H H Cl H Cl Cl H C2H5 I C2H5 II C2H5 III C2H5 IV What will be the effect of changing the Et group to Me? MEDC 527 Fall 2008 5 Stereochemistry and Drug Action
Stereo Isomers Enantiomers . arise .. four different substituents on a tetrahedral carbon .. can also come about because of a tetrahedral nitrogen or phosphorus .. may also arise due to bridge nitrogens/phosphorus R4 O Cl- +N R3 R1 R2 R3 N R2 MEDC 527 Fall 2008 R1 6 Stereochemistry and Drug Action Identify chiral centers (carbon, nitrogen, phosphorus) MeO MeO O O + * N O O
OMe H3C N+ * OMe CH3 OMe MeO OMe OMe Atracurium besylate (neuromuscular blocking agent) MEDC 527 Fall 2008 7 Stereochemistry and Drug Action Identify chiral centers (carbon, nitrogen, phosphorus) S N H3C O SCH3 N N N H3C O Nicotine N-oxide Thioridazine N-oxide MEDC 527 Fall 2008 8
Stereochemistry and Drug Action Identify chiral centers (carbon, nitrogen, phosphorus) * HO O NH2 OH OH warfarin Nor-epinephrine CH3 H3C HO * * * * * * cholesterol * * CH3 * HO H3C O Ph HO * O
* N * * N quinine * CH3 H3C HO 14R O 13S H 5R 6S HO 9R N CH3 morphine MEDC 527 Fall 2008 9 Stereochemistry and Drug Action Enantiomers and projections Standard Projection D H H3C
H CH3 Even D makes it different H Saw Horse Projection H3C D CH3 CH3 Ph H Cl H H Cl C2H5 MEDC 527 Fall 2008 D Ph Cl H H Cl CH3 CH3 CH3 Fischer Projection Ph
D Ph Cl H H Cl C2H5 10 Stereochemistry and Drug Action Identification of Enantiomers or Chiral Centers Step 1 identify chiral center 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 Step 3 visualize molecule so that the group of lowest priority is directed away Step 4 draw (or visualize) Newmann projection of the remaining three groups Step 5 write the priority order 1, 2 and 3; draw (or visualize) an arrow traveling from 123 Step 6 if the arrow travels clockwise, the chiral center is R; otherwise it is S H H3C D D3 H4 Ph H3C2 Ph1 D3 MEDC 527 Fall 2008
2 CH3 R Ph 1 11 Stereochemistry and Drug Action Identification of Enantiomers or Chiral Centers H H3C D3 H4 D Ph H3C2 Ph1 D3 R 2 CH3 Ph 1 View from bottom 2 CH3 H D Ph 4 H
CH3 View from side Ph1 D3 MEDC 527 Fall 2008 2 CH3 S 3D Ph 1 12 Stereochemistry and Drug Action Identification of Enantiomers or Chiral Centers D Ph Ph Ph Cl CH2CH2CH3 HO H H OH CH3NH H H
NHCH3 C2H5 (-)-ephedrine vasoconstrictor MEDC 527 Fall 2008 C2H5 (+)-ephedrine 13 Stereochemistry and Drug Action Properties of Enantiomers Physical properties bp, mp, solubility, pKa, pKb, thermal stability, etc. . all identical Rotate the plane of polarization of plane polarized light the phenomenon of optical activity Polarizer Tube Analyzer MEDC 527 Fall 2008 14 Stereochemistry and Drug Action Properties of Enantiomers Reactivity with chiral molecules . e.g., enzymes, receptors, .. drug action/metabolism Ph Ph HO (R) (S) CH3NH (S) H H OH
H H NHCH3 (R) CH3 I (-)-Ephedrine (vasoconstrictor) 36 Ph Ph CH3 II (+)-ephedrine H (S) (S) CH3NH H CH3 III (+)-pseudoephedrine 11 (S) OH 7 CH2Ph MeNH H CH3 I Methamphetamine 10X more potent
CNS stimulant Less cardiovascular HO H (R) NHCH3 (R) H CH3 IV (-)-pseudoephedrine 1 (R) CH2Ph NHMe H CH3 II desoxyephedrine MEDC 527 Fall 2008 15 Stereochemistry and Drug Action Properties of Enantiomers NH2 NH2 O N O N R S S
S Ph Ph CH3 CH3 H3C N H H H3C Cis-4-methylaminorex Potent amphetamine psychostimulant Effective dose (5.5 mg/Kg) H CH3 COOH H3C N (>150 mg/Kg) H HOOC MeO OMe S(+) Naproxen
R(-) MEDC 527 Fall 2008 16 Stereochemistry and Drug Action Why do chiral molecules react differently with biological molecules? B C A C A B B A A A C A A C B A R S MEDC 527 Fall 2008 17
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