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Chirality (stereoisomerism)

• Chiral refers to molecule with a center of three-dimensional asymmetry.

• Many drugs, over 50% of all drugs actually, are chiral (existing as enantiomeric pairs)

  •  Enantiomers (molecules having opposite shapes) are pairs of molecules existing in forms that are mirror images of each other (right-& left-hand) but that cannot be superimposed

  •  Other than lack of superimposition, enantiomers are chemically identical (not necessarily pharmacologically identical), but may be distinguished by the direction in which they rotate polarized light, either dextro (d or +) or levo (l or -) {light rotational effect determined in solution).

    •  Chemical identity is associated with true enantiomers, i.e. associated with a single asymmetric molecular center; If the molecule has 2 asymmetric centers, the molecule is referred to as a diasteriomer.  Diasteriomers have differing physiochemical properties

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  • Consider the above, hypothetical 2 enantiomeric models (1 & 2), each containing a single chiral carbon as well as molecular form 3 which is non-optically active as one can identify a plane of symmetry.

    • Only one of the enantiomers can make a correct 3-point contact with the corresponding receptor position represented by figure  1 above left: (A in the molecule matches up with the alpha  location on the receptor; B in the molecule matches up with the  beta location on the receptor and G in molecule matches up with the gamma location on the receptor. [Above figure from Principles of Drug Action: The Basis of Pharmacology, Third Edition, edited by William . B. Pratt and Palmer Taylor, Churchill Livingston, New York, 1990. p 14: Fig 1-8]

  •  Enantiomers present in equal proportion (50:50) are referred to as racemates.

• Ways looking at chirality:

  • Chirality has to do with "right or left handedness"

    • If an item appears identical to its image in a mirror it is said to be "achiral" -- an example would be a water glass.

    • The basic issues a comparison between an object and its reflection -- if an object is different from its reflection it is said to be chiral; for instance, ones left-hand and right hand are chiral

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    • Note also that when you put your left-hand up to mirror, the image that appears is a right hand-- began illustrating that left and right hands are in fact mirror images of each other yet not superimposable--not surprisingly gloves are not superimposable either!

    • Let's consider the molecule, thalidomide, below:

    • Note the structure of thalidomide:

      • Thalidomide is chiral, i.e. left and right-handed molecular forms are present

        1. One form produced sedation

        2. The other form was responsible for fetal abnormalities.

      • Although the primary therapeutic use for thalidomide today is in treatment of leprosy, in particular a disease complication called erythema nodosum leprosum, thalidomide appears effective in treating certain cancers.

        • Anti-cancer mechanisms include: (1) a reduction in inflammatory proteins including tumor necrosis factor alpha, (2) immune system modulation and (3) an anti-angiogenesis property which blocks formation of new blood vessels. Tumor growth is dependent on angiogenesis.  

        • At present, thalidomide is FDA-approved only for treatment of leprosy; however, yet has obtained "orphan-drug" status in treating brain malignancies.  All other uses are presently "off-label" [June, 2001)

•  From the molecular pointed view, an achiral (NOT chiral) molecule will exhibit an internal symmetry plane, the basis for the mirror image (above); by contrast, a chiral molecule (below) will exhibit an asymmetric center (carbon) and therefore will not exhibit internal symmetry planes

  • The molecule pictured above is called 2-propanol can we can find one internal plane of symmetry-- note the line passing through H-C-OH and the methyl groups (CH₃) symmetrically present both above and below the symmetry line. Each half of the molecule will be an exact mirror image of the other half and will be superimposible.plane of symmetry

  • By contrast, the molecule pictured below, named 2-butanol exhibits no internal plane of symmetry. In the absence of a plane of symmetry, mirror images will NOT be superimposible and therefore constitute enantiomers of each other.

  • Furthermore, chiral molecules will have a carbon atom with four non-equivalent groups attached to it.  This carbon is therefore asymmetric and is designated a stereocenter. 

    • Examining 2-propanol above we note that the center carbon has two equivalent groups attached to it, the two methyl groups 2 x CH₃. 

    • By contrast, in the 2-butanol structure below, we can identify a carbon which has in fact four different groups attached to it:  CH₃, H, OH, CH₂-CH₃. 

• We can identify common objects whose mirror images are superimposible.  For example, a baseball bat has a symmetry plane running through from top to bottom-- but not so the baseball glove. A glass of water has a symmetry plane, again from top to bottom of the glass -- but not so with a pair of shoes.

•  Figures above and below from: "Enantiomers and Chirality" by R. H. Logan, Instructor of Chemistry, Dallas County Community College District, North Lake College. (C) 1997

• Formal Definitions:

  • Chirality refers to a molecular property indicating "handedness". A chiral molecule is not superimposable on its mirror image, has no plane of symmetry, and rotates plane-polarized light. All molecules are chiral when they have one stereogenic (asymmetric) carbon.

  • Stereoisomer refers to  isomers that have the substituent bonding pattern but have different 3D arrangement of the atoms.

    •  Stereoisomers may appear as  enantiomers or diastereomers.

  • Enantiomer refers to a type of stereoisomer. Recall that enantioners are nonsuperimposible mirror-images of each other.

    •  Enantiomers have identical physical properties other than the direction that a solution of each enantiomer rotates plane-polarized light. 

    • The asymmetric center of one enantiomer exhibits an opposite configuration, meaning R or S designation, compared to  the other enantiomer. The  relationship between the absolute configuration (R or S) and the direction of rotation of plane-polarized light (dextrorotatory or levorotatory, i.e. d- or l- form) is not simple. 

• Diastereomers are stereoisomers that are NOT mirror images of each other, by contrast to entantiomers which have stereoisomers that ARE mirror images of one another. 

  • Diastereomers have differing arrangement of atoms in space. One example would be Cis-Trans isomers. The comparison between cis- and trans-2-butene is an example of a pair of diastereomers that do not have asymmetric carbon atoms. 

• Drugs with two asymmetric centers have four diasteriomers (e.g., labetalol (Trandate, Normodyne): an alpha and beta-receptor antagonist)