Transcript interaction of drugs with biological matrices

Stereokimia
Kenapa perlunya mempelajari stereokimia?
Pharmacological activity of compounds(drugs) depend mainly on
their interaction with biological matrices (drug targets), such as
proteins (receptors, enzymes), nucleic acids (DNA and RNA) and
biomembranes (phospholipids and glycolipids).
All these matrices have complex three-dimensional structures which
are capable to recognize (bind) specifically the ligand (drug)
molecule in only one of the many possible arrangements in the
three-dimensional space. It is the three-dimensional structure of the
drug target that determines which of the potential drug candidate
molecules is bound within its cavity and with what affinity. This
section concerns factors which control three-dimensional shape of
organic molecules (drugs) viewed from the perspective of their
interaction with potential biological targets.
Stereokimia
Why is drug chirality an important knowledge for future pharmacists?
The current trend in drug markets is a rapid increase of the sales of
chiral drugs at the expense of the achiral ones. By the year 2000 chiral
drugs, whether enantiomerically pure or sold as a racemic mixture, will
dominate drug markets. It is therefore important to understand how
drug chirality affects its interaction with drug targets and to be able to
use proper nomenclature in describing the drugs themselves and the
nature of forces responsible for those interactions.
EXAMPLES OF DRUGS SOLD AS SINGLE ENANTIOMERS
• Levomoprolol/Levotensin
• Levodropropizine/Levotuss
• Levofloxacin/Cravit
• Barnidipine/Hypoca
• Dexfenfluramine/Isomeride
• Ibuprofen/Serectil
FACTORS THAT MAKE UP 3D-STRUCTURES OF RECEPTORS AND DRUGS
The importance of most factors affecting the 3D-shape of the drug and
receptor molecules is illustrated on the example of the oligopeptide
chain above. Such an oligopeptide is a linear molecule which is built
by atoms separated from each other by a certain distance (bond
length), endowed with a certain charge (due to bond polarity) or
hydrophobicity (a property of repelling water), related to more distant
sites in the molecules by a rotation angle about the single bond, and
featuring more rigid fragments such as bonds with partial double bond
characters. In addition, the orientation of the R group (amino acid side
chain) is very important (chirality of the amino acid), as it determines
the shape of the cavities lined with the oligopeptide chains. These
factors are itemized below:
GLOSSARY OF TERMS RELATED TO 3D-STRUCTURE OF MOLECULES
STRUCTURE is the complete arrangement of all the atoms of the
molecule in space as determined by such methods as X-ray
diffraction (as defined by Cartesian coordinates of all atoms). This
terms is the broadest one and includes constitution (nature of
atoms, their number, the type of bonds and manner in which they
are linked together(connectivity)), conformation and configuration.
CONFORMATION is the spatial arrangement of atoms in the molecule
of the given constitution and configuration. Conformation can be
changed without changes in constitution and configuration by a
rapid(?) rotation about single bonds and pyramidal inversion(?) at
some centers.
CONFIGURATION is the spatial arrangement of atoms that
distinguishes molecules of the same constitution (isomers), other
than distinction due to differences in the conformation.
SYMMETRY is a regular occurrence of certain patterns within an object
or structure (at macro- or microscopic level). These patterns are
generated by the presence of symmetry elements such as center of
symmetry; symmetry axes; symmetry planes.
GLOSSARY OF TERMS RELATED TO 3D-STRUCTURE OF MOLECULES
CHIRALITY is a property of an object which is non-superimposable with its
mirror image. Most objects in the environment are chiral. In chemistry this
term applies to molecules, specific conformations of molecules, as well as to
macros copic objects such as crystals. Chirality is removed if and object
molecule acquires a plane of symmetry, or a center of symmetry. The molecule
can remain chiral with a limited combination of symmetry axes.
ENANTIOMERS are molecules related to each other as a real object to its mirror
image. Enantiomers are therefore related to each other through the reflection
by the mirror plane, and are not superposable. Not all object/mirror-image
pairs constitute enantiomers, but only those which are not superimposable
after any rotation/translation of the whole object, or its mirror image.
Enantiomeric relation does not bear the aspect of energy; the conformational
isomers existing in the fast interconversion are still considered enantiomers.
For the purpose of the determination whether two conformations are
enantiomeric, they are considered to be rigid. The existence of enantiomers is
usually (but not always) associated with at least one chiral center.
Enantiomers have exactly the same energies, and therefore are not
differentiated by physical measurements other than optical rotation (rotation
of the plane of polarized light).
GLOSSARY OF TERMS RELATED TO 3D-STRUCTURE OF MOLECULES
DIASTEREOMERS are any molecules which have an identical
constitution, but are not related through the mirror reflection
operation. Diastereomers could be compounds with two or more
chiral centers, in which not all chiral centers have opposite
configuration to a corresponding chiral centers in another molecule
(the whole molecule would be the mirror image of the other and thus
an enantiomer). Diastereomers do not have to possess chiral
center(s), they only need to differ by a spatial difference not related
to mirror reflection. Thus, diastereomers could be nonchiral cis/trans
-isomers of cyclic or olefinic (alkene) compounds. Diastereomers and
enantiomers are frequently jointly referred to as stereoisomers.
STEREOISOMERS: a combined term including enantiomers and
diastereomers
SYMMETRY ELEMENTS
1. Center of Symmetry
The center of symmetry i is a point in space such that if a line is drawn
from any part (atom) of the molecule to that point and extended an equal
distance beyond it, an analogous part (atom) will be encountered.
This symmetry element is sometimes also called "the point of inversion"
SYMMETRY ELEMENTS
2. Plane of Symmetry
Planes, centers and alternating axes correspond to "symmetry operations of
the second kind" or "improper operations" since they bring into
coincidence the material point of an object with its mirror reflection.
A plane of symmetry is a reflection plane which brings into coincidence
one point of the molecule with another one through the mirror
reflection.
SYMMETRY ELEMENTS
2. Plane of Symmetry
Planes, centers and alternating axes correspond to "symmetry operations of
the second kind" or "improper operations" since they bring into
coincidence the material point of an object with its mirror reflection.
A plane of symmetry is a reflection plane which brings into coincidence
one point of the molecule with another one through the mirror
reflection.
SYMMETRY ELEMENTS
3. Axis of Symmetry
Symmetry axis Cn, also called n-fold axis, is an axis which rotates the object
(molecule) around by 360ø/n, such that the new position of an object is
superimposable with the original one.
GRAPHICAL REPRESENTATION OF NONPLANAR MOLECULES
Fisher projection:
The tetrahedral atom
is
viewed
perpendicularly
to an edge formed by
connecting two of its
ligands. The
convention
is that the two
vertical
bonds in the
projection
are pointing behind
the
plane of projection
(plane of paper
sheet),
and the two
horizontal
Wedge projection
It is obtained by viewing the tetrahedral center perpendicularly to the plane
formed
by three atoms. One of the remaining atoms is oriented behind the plane of
projection
(dashed bond), one towards the viewer (boldface bond). Note that, in contrast
to
Fisher projection, the rotation of the wedge projection about axes
perpendicular or
coplanar with the plane of projection does not change anything. This
projection is
therefore by far less ambiguous than Fisher projection. In the case of large
linear
molecule the molecule backbone has to be drawn in the fully extended
conformation.
Newman projection:
The molecule with two tetrahedral centers is viewed along the C-C
axis.
The atom in front is represented as a three-way branch, the atom
in the
back as a circle with three outgoing bonds. This projection is most
useful
inconsideration of steric relation between ligands linked to adjacent
tetrahedral centers and is most popular.
.
Sawhorse projection:
The C-C bond is viewed at an angle. The atom shown on the left
of the
projection is also the one in the front. This projection is difficult
to use
with acyclic molecules but is most popular for representation
of cyclic
molecules e.g. saturated six-membered rings .
.
Haworth projection:
.
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
Chirality (enantiomerism)
It is very important from the point of view of drug development
and
its mechanism of action. Since most of the natural (biological)
environment consists of enantiomeric molecules (aminoacids,
nucleosides, carbohydrates and phospholipids are chiral
molecules) it
makes sense that drugs developed are also chiral.
Frequently only one stereoisomer is active, and sometimes the
other
one is toxic (the current policies of FDA in drug approval is that
the
inactive enantiomer in the racemic drug has to be shown to be
devoid
of any toxicity or undesired side-effects).
A drug upon administration undergoes a series of steps before
exerting its activity. At each step the structure of the drug and
hence
its chirality influences the further metabolism
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
.
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
The reason for chiral recognition by drug receptors is a three-point
interaction of the agonist or substrate with the receptor or enzyme
active
site, respectively.
.
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
Example: Only the (-) enantiomer of epinephrine has the OH group
in the
binding site, and therefore has a much more potent pressor activity
.
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
The D(-) lactoyl choline is hydrolyzed much more slowly than the
L(+)-isomer due to favorable binding of the OH group in the
latter case.
.
INTERACTION OF DRUGS WITH BIOLOGICAL MATRICES
Likewise, cis/trans isomers of cyclic compounds, or Z/E isomers of
alkenes are also expected to have different binding potency and
therefore also different biological activity.
.
RULES FOR SPECIFICATION OF CHIRALITY
1. Chiroptical properties
Any material which rotates the plane of the polarized light is termed
"optically
active." Compounds featuring chiral centers are optically active unless
they
possess symmetry plane or a symmetry center (see above). An isomer of
optically active compound can rotate the plane of polarized light to the left
(levorotatory), in which case it will be designated (l, or -), or to the right
(dextrorotatory) in which case it will be termed (d, or +).
There are following properties associated with enantiomerism:
1. Enantiomeric molecules interact in a different manner with another
enantiomeric molecules (such as biological receptors, but also with
simple chiral organic molecules); it regards both weak interaction such
as forming weak complexes, as well as chemical reactions (bond
breaking or forming).
2. Enantiomers can not be distinguished by their interactions with achiral
molecules, nor by their physical properties measured by techniques
other than those using in-plane-, or circularly-polarized light.
1. Chiroptical properties
Several rules for specifying chirality have been adopted from the time
of van't Hoff. The L/D systems relies on the chemical correlation
of the configuration of the chiral center to D-glyceraldehyde. The
compounds which can be correlated without inverting the chiral
center are named D (capital D), those correlated to its enantiomer
are designated as L (capital L).
IMPORTANT NOTE: Although D-glyceraldehyde is dextrorotatory
(rotates the plane of polarized light to the right), the compounds
correlated to D-glyceraldehyde do not have to be dextrorotatory,
i.e. could rotate light to the left. Therefore, D-prefix is not
correlated with the (+) or (-) specific rotation, and the D-compound
can be l, (or -), and vice versa L-compound can be d (or +). This
nomenclature system is slowly being abandoned in favor of the
Cahn-Ingold-Prelog (CIP) nomenclature, with the exception where
the DL-nomenclature has been used traditionally, and is more
useful (D-carbohydrates or L-aminoacids).
1. Chiroptical properties
EXAMPLE:
An antiinflammatory agent such as Ibuprofen has two configurations(R and S).
However, only S-configuration has pharmacologic properties. The
demonstration(video) of superposition between the S and R
configurations indicates that they are enantiomers. They are
nonsuperposable mirror reflection of each other
2. Cahn-Ingold-Prelog Rules
For the tetrahedral chiral center C with four inequivalent substituents the rule
is adopted for designation of chirality.
• First ligands are ordered by the ligand precedence rules as 1,2,3 & 4.
• The central atom and three ligands are viewed from the direction of C 4
vector where 4 is a ligand of lowest precedence.
• If the ligands 1-3 are ordered such that the movement from the ligand of the
highest precedence (1) to the third (3) passing the second (2) in between is
in the clockwise direction (sequence 1 2 3) the configuration is designated
as R (rectus, written in italic, capital). On the other hand if the same
requires movement in the anti clockwise direction the configuration is
designated as S (sinister). The configurational designation is preceded by
the number specifying the location of the chiral center, i.e. 2R with one
chiral center at the 2-position and R configuration, or 2R, 3S, 4R with
multiple chiral centers.
3. Ligand precedence rules
Ligands of the higher atomic number precede those with lower ones, e.g. Br precedes Cl
(Br>Cl).
1. For ligands with the same type of atoms linked to the center C, the precedence is
determined based on the atomic numbers of ligands in the next sphere, e.g. ligand with
C-O sequence precedes C-C. If no difference is detected, the determination is based on
the distinction in the next spheres, and search is continued until the difference is
detected.
2. The coordination number of non-hydrogen atoms is assumed to be 4, i.e. atoms bonded
with multiple bonds are considered to be bonded to multiple atoms, e.g. carbonyl
carbon is treated as if it was bonded to two oxygen atoms, and carboxyl carbon as if it
was bonded to three oxygens (these are then called phantom atoms). Ligand
duplication is also necessary in the cases of cyclic systems
3. Ligands of the same atomic number, but a higher atomic mass precede those with a
lower atomic mass, e.g. D precedes H (D>H). This criterion applies only after the
previous ones were exhausted.
4. For compounds where only configurational (not constitutional) differences between
ligands are detected, the following rules apply:
•
The olefinic ligand that has the chiral center and another ligand on the same side of the
double bond (cis) precedes the one with the trans-configuration.
•
Ligands with R,R or S,S precede R,S or S,R.
•
R precedes S
3. Ligand precedence rules
.
4. Helical Chirality
Certain natural, as well as unnatural linear polymers assume helical
conformation: e.g.
right-handed B-DNA, left-handed Z-DNA, protein alpha-helices. The hydrated
lipids
can form chiral mesophases, whereby chirality is due to small rotation of each
layer
versus the adjacent layers in the multilayer stack. These macromolecules or
aggregates
are said to have helical chirality.
The chirality of such compounds is determined by determining the screw
sense of the
helix. If the screw is right handed the chirality is P(plus), if it is left handed the
chirality
is M(minus). Conformations of simple chain compounds can also be treated as
if they
had helical chirality
5. Z/E Geometry of Double Bonds
The same Prelog's precedence rules, as discussed earlier, apply to
geometrical isomers of olefinic compounds and alicyclic
compounds. Precedence of ligands at both nodes of the double
bonds is determined pairwise. If both higher precedence ligands
are on the same side of the double bond the configuration is Z, if
on the opposite sides the configuration is E.
6. cis/trans Geometry of Alicyclic Compounds
The cyclic systems use the traditional cis/trans nomenclature. When
specifying geometry (cis/trans) the precedence of substituents is
also determined based on the precedence rules set forth earlier.
The situation is simple in the case of disubstituted systems,
however, in the case of multiple substitution the geometry of the
ring system has to be specified with respect to a selected
reference indicated by the the symbol "r" (italic). Example:
7. Relative Configurations in Compounds with Multiple Chiral
Centers.
The most unambiguous notation employs Prelog's descriptors R,S.
For
example for D-glucose (below) the correct specification of chirality is
2R, 3S,
4R, 5S. Note that only R,S descriptors are italicized and the chirality is
specified with the numerical prefix denoting this position.
The configuration of racemic compounds is specified by using RS
notation for
each chiral center. Note that the relative configurations have to be
preserved
in order to correspond to a given diastereomers Thus racemic glucose
would
be described as 2RS, 3SR, 4RS, 5SR. (in contrast, 2SR, 3SR, 4RS, 5SR
would
correspond to racemic mannose).
7. Relative Configurations in Compounds with Multiple Chiral
Centers.
The use of CIP nomenclature requires assignment of R,S descriptors
for every center. The quicker way (older and a more ambiguous
one) is by using threo/erythro nomenclature. This notation is based
on the four-carbon sugars threose and erythrose. It requires
vertical projection of the sugar main chain; threo-compounds are
defined as those that have two ligands of higher precedence on
each carbon atom on the opposite sides of the chain, erythro on
the same side. The ambiguity arises from the question what should
be used as the main chain
8. Mezo Compounds and Pseudoasymmetry
In compounds in which two or more
chiral
ligands of the central atom are constitutionally identical but have the opposite
configuration the central atom is
formally
chiral because it has four different
ligands
(even though the difference is only in
ligand
configuration). However, since such a
compound also has a plane of symmetry
it is,
in fact, achiral as a whole. The central
atom
is termed a pseudoasymmetric center.
The
configuration of such atom is
determined
according to normal precedence rules
assuming that R precedes S. In contrast,
in
molecules in which the two ligands of
the
central atom havethe same configuration
the
central atom is achiral, but the molecule
CONFORMATION
DEFINITION
Conformation is a spatial arrangement of a molecule of a given constitution and
configuration.
In the case of a four atom molecule linked in a chain manner, rotation of atom A or D
about the
inner B-C bond by an angle leads to a different mutual relation of atom A and D and
results in
population of a set of different rotational isomers or "conformations".
The single parameter differentiating such conformers is an angle between two planes
that
contain atoms ABC and BCD in themselves. This dihedral angle is called a "torsion"
angle
and is most frequently used for specification of the type of conformations.
The conformation of a molecule containing two tetrahedral atoms linked together can
be represented as a "sawhorse" or as a Newman projections. In the Newman
projection the molecule is viewed along the axis of a rotatable bond.
Isomers
.
Isomers
1. STRUCTURAL ISOMERISM
a. Chain isomerism
b. Position isomerism
c. Functional group isomerism
2. STEREOISOMERS
a. Enantiomer
- atropisomer
b. Diastereomers
- Two or more sterocentre
- Geometric (cis / trans) isomerism
Geometric (cis / trans) isomerism
How geometric isomers arise
To get geometric isomers you must have:
• restricted rotation
(involving a carbon-carbon double bond)
• two different groups on the left-hand end of the bond
and two different groups on the right-hand end.
It doesn't matter whether the left-hand groups are
the same as the right-hand ones or not.
Geometric (cis / trans) isomerism
The effect of geometric isomerism on physical properties
• The table shows the melting point and boiling point
of the cis and trans isomers of 1,2-dichloroethene.
Isomers
Cis
Trans
•
•
Melting point (0C)
-80
-50
Boiling point(0C)
60
48
The trans isomer has the higher melting point;the cis isomer
has the higher boiling point.
Both of the isomers have exactly the same atoms joined up in
exactly the same order. That means that the van der Waals
dispersion forces between the molecules will be identical in
both cases.The difference between the two is that the cis isomer
is a polar molecule whereas the trans isomer is non-polar.
Geometric (cis / trans) isomerism
•
•
•
Both of the isomers have exactly the same atoms joined up in
exactly the same order. That means that the van der Waals
dispersion forces between the molecules will be identical in
both cases.The difference between the two is that the cis
isomer is a polar molecule whereas the trans isomer is nonpolar.
Both molecules contain polar chlorine-carbon bonds, but in
the cis isomer they are both on the same side of the molecule.
That means that one side of the molecule will have a slight
negative charge while the other is slightly positive. The
molecule is therefore polar.
Because of this, there will be dipole-dipole interactions as well
as dispersion forces - needing extra energy to break. That will
raise the boiling point
Geometric (cis / trans) isomerism
Enantiomers:
A mixture of these cannot be separated by normal GC or HPLC
techniques
Diastereomers:
Different physical/chemical properties in chiral/achiral environments.
A mixture of these can be separated by normal GC or HPLC
techniques
Geometric (cis / trans) isomerism
Stereogenic center (stereocenter) –
a point in a molecule bearing groups such that an interchange of any two groups will
produce a stereoisomer. Number of possible stereoisomers = 2n , n = # of stereocenters.
Relative vs. Absolute Configurations
•
Relative configuration - 3-D structure is not known but it is known that one structure
is the mirror image of the other.
•
(+) or d - dextrorotatory - cpd that rotates light to the right.
•
(-) or l - levorotatory - cpd that rotates light to the left.
•
(±) - racemic mixture - 1:1 mixture of (+) and (-) cpds, zero rotation.
•
Enantiomeric excess:
•
Absolute configuration - 3-D structure is known.
R, S Nomenclature
(-)-alanine
1.
a.
b.
2.
3.
Prioritize - assign a priority to the groups around the stereocenter
increasing atomic mass of the atom attached to stereocenter
in case of a tie move to the next atom
Place - place the lowest priority group in the back.
Connect a  b c
Separation of Enantiomers
A) Resolution
B) Pasteur's Method