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Drug Action and Design IB Chemistry Option D: Drugs and Medicines

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Factors that affect how a drug reacts include: Chirality. Geometrical isomerism. Ring strain ... Chirality Affects Drug Behavior ... – PowerPoint PPT presentation

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Title: Drug Action and Design IB Chemistry Option D: Drugs and Medicines


1
Drug Action and DesignIB Chemistry Option D
Drugs and Medicines
  • Larry J. Scheffler
  • Lincoln High School

2
Drug 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

2
3
Chirality 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.

3
4
Thalidomide
  • 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.
4
5
Thalidomide and Leprosy
  • Treatment of Erythema nodosum leprosum (ENL), a
    painful inflammatory dermatologic reaction of
    leprosy with thalidomide.

5
6
Geometric 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.

6
7
Cis 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.
7
8
Cisplatin 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.
8
9
Ring 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.
9
10
Ring 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.
10
11
Polarity 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.

11
12
Polarity 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.

12
13
Drug Design
  • Part 2

13
14
Combinatorial 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.

14
15
Combinatorial 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.

15
16
Combinatorial 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.

16
17
Combinatorial Chemistry
  • A combinatorial scheme for amino acids

17
18
Parallel 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.

18
19
Drug 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.
19
20
Chiral 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.

20
21
Synthesis 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.

21
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Taxol
  • 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.

22
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