Stereochemical Aspects on Drug Effects

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11/2/2010 1 بسم الله الرحمن الرحيم

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11/2/2010 2 Stereochemical Aspects on Drug Effects By Bilal Ahmad Ghalloo M.Phil.Pharm.Chemistry Islamia university Bahawalpur Punjab (Pakistan)

Isomerism : 

11/2/2010 3 Isomerism Isomerism is the phenomenon whereby certain compounds, with the same molecular formula, exist in different forms owing to their different organisations of atoms. The concept of isomerism illustrates the fundamental importance of molecular structure and shape in organic chemistry.

Types of isomerism : 

11/2/2010 4 Types of isomerism

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11/2/2010 5 Stereochemistry refers to the 3-dimensional (3D) properties and reactions of molecules. What is the stereochemistry? 2D vs 3D

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11/2/2010 6 Significance of Stereochemistry on Drug Effects Drug molecules must generally interact with biomolecules (e.g. Receptors and Enzymes) in a very specific way to elicit a pharmacological response. The lock-and-key concept Receptor = lock Drug = key

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11/2/2010 7 Stereochemistry has its own language and terms that need to be learned in order to fully communicate and understand the concepts. Chirality or Handedness What is Chirality? Chiral comes from the Greek word “cheir” meaning “HAND” Hands are non-superimposable mirror images — they are chiral

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11/2/2010 8 Constitutional Isomers vs Stereoisomers

The Stereogenic Centre: : 

11/2/2010 9 The Stereogenic Centre: A Stereogenic centre is also known as a chiral centre. It is characterized by an atom which has  different groups bound to it in such a manner that its mirror image is non-super imposable.

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11/2/2010 10 The molecule labeled A and its mirror image labeled B are not superimposable. No matter how you rotate A and B, all the atoms never align. Thus, CHBrClF is a chiral molecule, and A and B are different compounds. A and B are stereoisomers—specifically, they are enantiomers. A carbon atom with four different groups is a tetrahedral stereogenic center. Chiral Molecules

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11/2/2010 11 Other molecules are like socks. Two socks from a pair are mirror images that are superimposable. A sock and its mirror image are identical. A molecule or object that is superimposable on its mirror image is said to be achiral. Achiral Objects and Molecules

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11/2/2010 12 Do these molecules conatain a Plane of Symmetry (Mirror Plane)? Achiral Molecules

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11/2/2010 13 In general, a molecule with no stereogenic centers will not be chiral . With one stereogenic center, a molecule will always be chiral. With two or more stereogenic centers, a molecule may or may not be chiral, e.g. Meso compound (contains a plane of symmetry or a mirror plane) Achiral molecules contain a plane of symmetry but chiral molecules do not. A plane of symmetry is a mirror plane that cuts the molecule in half, so that one half of the molecule is a reflection of the other half. Chiral vs Achiral

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11/2/2010 14 To locate a stereogenic center, examine the four groups—not the four atoms—bonded to each tetrahedral carbon atom in a molecule. Stereogenic Centers

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11/2/2010 15 Larger organic molecules can have two, three or even hundreds of stereogenic centers. Number of Stereogenic Centers in a Molecule

Cis/Trans Isomers : 

Cis/Trans Isomers

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11/2/2010 17 Cis/trans Isomers Stereoisomers are isomers that differ only in the way the atoms are oriented in space. The prefixes cis and trans are used to distinguish these isomers. The cis isomer has two groups on the same side of the ring. The trans isomer has two groups on opposite sides of the ring.

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11/2/2010 18 Cis/Trans 1,2-dimethylcyclopentanes There are two different 1,2-dimethylcyclopentanes—one having two CH3 groups on the same side of the ring and one having them on opposite sides of the ring. A and B are stereoisomers.

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11/2/2010 19 Trans E Entgegen (opposite) Cis Z Zusammen (together) Can have different physical properties, e.g. melting/boiling pt.

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11/2/2010 20 One of a pair of molecular species that are mirror images of each other and not superposable. They are mirror-image stereoisomers. Enantiomers

R/S Isomers : 

R/S Isomers

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11/2/2010 22 Since enantiomers are two different compounds, they need to be distinguished by name. This is done by adding the prefix R or S to the IUPAC name of the enantiomer. Labeling Stereogenic Centers with R or S

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11/2/2010 23 R or S Enantiomers

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11/2/2010 24 Positioning the Molecule for R/S Assignment

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11/2/2010 25 R-enantiomer (Clockwise Rotation) S-enantiomer (Counterclockwise Rotation)

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11/2/2010 26 If two isotopes are bonded to the stereogenic center, assign priorities in order of decreasing mass number. Thus, in comparing the three isotopes of hydrogen, the order of priorities is: Priority of Isotopes on a Stereogenic Center

Resolution of Enantiomers : 

11/2/2010 28 Resolution of Enantiomers React a racemic mixture with a chiral compound to form diastereomers, which can be separated. =>

Examples from drugs : 

11/2/2010 29 Examples from drugs

Examples from drugs : 

11/2/2010 30 Examples from drugs Many drugs are optically active, with one enantiomer only having the beneficial effect. In the case of some drugs, the other enantiomer can even be harmful, e.g. thalidomide.

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11/2/2010 31 In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness. This led to many disabilities in babies and early deaths in many cases.

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11/2/2010 32 S thalidomide (effective drug) The body racemises each enantiomer, so even pure S is dangerous as it converts to R in the body. R thalidomide (dangerous drug)

Examples from drugs : 

11/2/2010 33 Examples from drugs

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11/2/2010 34 S limonene (lemons) R limonene (oranges)

Biological Discrimination : 

11/2/2010 35 Biological Discrimination =>

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11/2/2010 36 OPTICAL ISOMERISM

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11/2/2010 37 With chiral compounds, the plane of the polarized light is rotated through an angle . The angle  is measured in degrees (0), and is called the observed rotation. A compound that rotates polarized light is said to be optically active. Optically Active Compounds

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11/2/2010 38 The rotation of polarized light can be clockwise or anticlockwise. If the rotation is clockwise (to the right of the noon position), the compound is called dextrorotatory. The rotation is labeled d or (+). If the rotation is counterclockwise, (to the left of noon), the compound is called levorotatory. The rotation is labeled l or (-). Two enantiomers rotate plane-polarized light to an equal extent but in opposite directions. Thus, if enantiomer A rotates polarized light +50, the same concentration of enantiomer B rotates it –50. No relationship exists between R and S prefixes and the (+) and (-) designations that indicate optical rotation. Rotation of Polarized Light

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11/2/2010 39 An equal amount of two enantiomers is called a racemate or a racemic mixture. A racemic mixture is optically inactive. Because two enantiomers rotate plane-polarized light to an equal extent but in opposite directions, the rotations cancel, and no rotation is observed. Racemates

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11/2/2010 40 Specific rotation is a standardized physical constant for the amount that a chiral compound rotates plane-polarized light. Specific rotation is denoted by the symbol [] and defined using a specific sample tube length (l, in dm), concentration (c in g/mL), temperature (25 0C) and wavelength (589 nm). Specific Rotation

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11/2/2010 42 Compound Relative Activity Biological Response terbutaline - > + (3000:1) trachea relaxation propranolol S > R (100:1) block tachycardia pindolol - > + (200:1) inhibit tachycardia methadone - > + (3:1) respiratory depression ketamine S > R (4:1) anesthesia tocainide R > S (3:1) antiarrhythmic flecainide + = - antiarrhythmic propafenone + = - antiarrhythmic disopyramide S > R antiarrhythmic disopyramide S > R anticholinergic warfarin S > R (8:1) anticoagulant verapamil - > + (5-18:1) block AV conduction Relative Pharmacodynamic Potency of Selected Enantiomers

STEROSELECTIVITY OF PHARMACOKINETIC PROCESSES : 

11/2/2010 43 STEROSELECTIVITY OF PHARMACOKINETIC PROCESSES DISTRIBUTION Drug Free Fraction Ratio (+/-) + - ibuprofen 0.006 0.0039 1.5 mexilitine 0.283 0.198 1.4 methadone 0.092 0.124 0.7 propoxyphene 0.018 0.018 1.0 propranolol 0.203 0.176 1.2 tocainide 0.17 0.14 1.2 verapamil 0.064 0.11 0.6 warfarin 0.012 0.009 1.3

ChromatographicResolution of Enantiomers : 

11/2/2010 44 ChromatographicResolution of Enantiomers =>

Diastereomers : 

Diastereomers Pair of stereo isomers that have more than one chiral centre and are not mirror images of each other

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11/2/2010 46 A Meso compound is an achiral compound that contains tetrahedral stereogenic centers. All meso compounds contain a plane of symmetry. Compound C has two stereogenic centers but it contains a plane of symmetry, and is achiral; C is a meso compound. Meso Compounds

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11/2/2010 47 Meso Compounds The best way to identify a meso compound is to prove that it is superimposable with its mirror image. However, a quick test is to see if it contains a plane of symmetry: Compounds containing a plane of symmetry are achiral! No plane of symmetry

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11/2/2010 48 An imaginary plane passing through an object and dividing it such that one half is the mirror image of the other half

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11/2/2010 49 The Three Stereoisomers of 2,3-dibromobutane Because one stereoisomer of 2,3-dibromobutane is superimposable on its mirror image, there are only three stereoisomers, not four.

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11/2/2010 50 Structural Isomers

Constitutional Isomers : 

11/2/2010 51 Constitutional Isomers Compounds that have the same molecular formula but different structural formulas In the case of many alkanes there is more than one way to arrange the atoms For example butane and isobutane Both of these alkanes have the molecular formula of C4H10 But their structural formula and arrangement is quite different Section 14.3

Constitutional Isomers : 

11/2/2010 52 Constitutional Isomers Constitutional isomers are isomers that differ in the order in which the atoms are connected. An older term for constitutional isomers is “structural isomers.” Functional Group Isomers Positional Isomers

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11/2/2010 53 Functional Group Isomers Same molecular formula, but different functional groups, e.g., n-propanol and methyl ethyl ether Positional Isomers Same molecular formula, same functional groups, but different positions of functional groups, e.g., n-propanol and i-propanol

ButaneContinuous-Chain or Straight-Chain Structure : 

11/2/2010 54 ButaneContinuous-Chain or Straight-Chain Structure Section 14.3

Isobutane (2-methylpropane)Branched-chain Structure : 

11/2/2010 55 Isobutane (2-methylpropane)Branched-chain Structure Section 14.3

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11/2/2010 56 a) Butane (C4H10) 2-methylpropane (C4H10) 1-butene 2-butene 2-methylpropene cyclobutane methylcyclopropane

References : 

11/2/2010 57 References Organic chemistry by Martland Jones Organic Chemistry by Brown Thomas Organic chemistry by Mary Anne Fox Medicinal chemistry by Burger Internet source