Title: Drug Action and Design IB Chemistry Option D: Drugs and Medicines
1Drug Action and DesignIB Chemistry Option D
Drugs and Medicines
- Larry J. Scheffler
- Lincoln High School
2Drug Action
- The effectiveness of a drug is often related to
the chemical structure and polarity of the
substance. - Factors that affect how a drug reacts include
- Chirality
- Geometrical isomerism
- Ring strain
- Polarity
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3Chirality Affects Drug Behavior
- The presence of an asymmetric or chiral carbon
atom in a molecule results in two different
optical isomers or enantiomers. - Two different enantiomers can behave in very
different ways in the body. - The most famous example of this difference was
found in with thalidomide.
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4Thalidomide
- Thalidomide has two optical isomers, one of which
is a tranquilizer while the other is a powerful
teratogen. - Originally used to treat morning sickness during
pregnancy. - Now Used to treat some symptoms of Hansens
disease (Leprosy).
Chiral Carbon
The high incidence of fetal deformities has led
to increased diligence in approving drugs for
use. When new drugs are developed now The
pharmacological activity of each optical isomer
must be studied separately.
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5Thalidomide and Leprosy
- Treatment of Erythema nodosum leprosum (ENL), a
painful inflammatory dermatologic reaction of
leprosy with thalidomide.
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6Geometric Isomers Differ in Behavior
- Geometric isomerism occurs in both organic and
inorganic compounds. - Diaminechloroplatnium (II) is an inorganic
complex that as been used to treat certain types
of ovarian and testicular cancers. - Diaminechloroplatnium (II) exists in both cis and
trans isomers.
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7Cis and Transplatin
- The structures of the cis and trans forms are
shown below
Cis-platin is an effective anticancer drug, while
Trans-platin is not effective at all.
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8Cisplatin as an Anti-cancer Drug
- Cisplatin can diffuse through a cancer cell
membrane. - In the cell it exchanges a chloride ion for a
water molecule forming a complex ion. - This complex ion binds to the cancer cell DNA
preventing it from replicating correctly.
The cis-platin form is just the right size to
bind to the guanine bases on the DNA.
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9Ring Strain
- The action of beta lactams in antibacterial drugs
such as the penicillins is an example of the
effect of ring strain as a drug mechanism. - The general structure of penicillin
The four member ring of the betal lactam contains
a carbon that is sp2 hybridized and a nitrogen
atom and 2 carbon atoms that are sp3 hybridized.
The restrictions of the ring prevent the atoms
from assuming the normal bond angles of 120o
and 109.5o respectively.
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10Ring Strain and Drug Activity
- The amide group in the ring is more reactive due
to the strained ring. - The structure of the beta lactam is similar to
the structures of cysteine and valine. - The beta lactam binds to the enzyme that
synthesizes the cell wall in bacteria blocking
its action. - As a result the bacteria rupture and break and
cannot reproduce.
Note the similarities in structure to the beta
lactam.
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11Polarity and Drug Behavior
- The difference in polarity between molecules
affects their behavior in the body. - The polarity of a molecule affects
- its ability to dissolve in lipids,
- its ability to pass through the lipid membranes
- the degree to which it may bind to an active site
on an enzyme or protein.
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12Polarity Morphine and Heroin
- Heroin is much more potent than morphine (and
more addictive). - The OH groups on morphine are more polar than
the ethanoate ester groups on heroin. - Heroin is more lipid soluble in lipids.
- It can more readily penetrate the blood-brain
barrier and it is absorbed in higher
concentrations in the brain.
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13Drug Design
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14Combinatorial Chemistry
- Drug companies have developed libraries of
compounds which have been screened for drug
activity. - With a given core molecule or pharmacore, and a
large number of substituents, researchers use
computers to enumerate a large number of
structural possibilities. - This virtual library may consist of thousands, or
even millions of 'virtual' compounds. - Researchers select a subset of the 'virtual
library' for actual synthesis, based upon various
calculations and criteria.
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15Combinatorial Chemistry
- An example of a pharmacore and a reactant system.
- By examining multiple possibilities
pharmaceutical chemists can evaluate the medical
efficacy of various molecules for medicinal
value.
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16Combinatorial Chemistry
- The process was originally developed for
polypeptide synthesis with amino acids. - The starting material or pharmacore is covalently
bonded to small polystyrene resin beads. - The beads are reacted with various groups in
successive steps. - The beads are separated from the reaction mixture
and then undergo preliminary screening for drug
activity. - This is usually done by measuring how the
substance affects enzymes or how it may bind to
receptor cells.
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17Combinatorial Chemistry
- A combinatorial scheme for amino acids
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18Parallel Synthesis
- Alternative to combinatorial approach,
- Solid state organic.
- Preparation of a highly reactive intermediate.
- Preparation of individual compounds
simultaneously with various reagents in separate
microcells without mixing intermediates during
synthesis.
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19Drug Polarity Modifications
- Many compounds that are of pharmacological
importance are large complex organic molecules
that are not very polar - They are largely insoluble in water. Their ionic
salts, either as sodium salts or hydrochloride
salts are used to make them more soluble.
Sertraline is an amine compound that is
converted to a hydrochloride salt to make it more
soluble.
Aspirin or acetyl salicyclic acid is converted to
the sodium salt.
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20Chiral Auxillaries
- Traditional synthesis of optically active
compounds results in a racemic mixture with equal
amounts of each enantiomer. - Only one of the enantiomers has pharmacological
value. (i.e. thalidomide). - Separating enantiomers from racemic mixtures is
often difficult and complicated. - The use of chiral auxilliaries makes it possible
to synthesize only one of the two enantiomers. - A chiral auxilliary is a chiral molecule that is
attached to the starting material during a
synthesis that creates the appropriate
stereo-chemical environment so that only one
enantiomer is produced.
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21Synthesis with Chiral Auxilliaries
- A chiral auxiliary is a molecule that is
temporarily incorporated into an organic
synthesis. Its asymmetry allows the formation of
a chiral intermediate followed by selective
formation of one of two stereoisomers depending
on the reagent and/or reaction conditions.
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22Taxol
- The anti-cancer drug TAXOL is found in the
Pacific Yew tree, but there is not a sufficient
supply to meet demand. - Since Taxol is a very chiral molecule, one
possibility is to make it synthetically. - The potential synthesis is very complicated and
would require using several chiral auxilliaries.
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