Download Stereospecific Synthesis and Combinatorial Chemistry File

Stereospecific synthesis and combinatorial
chemistry
L.O. To be able to describe examples of stereospecific
synthesis as used in the production of drugs.
To find out how combinatorial chemistry techniques are
used in the pharmaceutical industry
Stereospecific synthesis
Racemic mixtures – addition of H- or CN- to carbonyl compounds.
This process is used in the laboratory synthesis of lactic acid (2hydroxypropanoic acid) from ethanal.
Stereospecific compounds – Formation of lactic acid in our
muscles. The lactic acid prodced here is only the + isomer. This is
because the reaction is catalysed by enzymes (natural catalysts
made up of proteins) which are stereospecific (the active site
causes this – lock and key hypothesis).
OPTICAL ISOMERS
(enantiomers)
= 4 different groups bonded to
a central C atom
such that one isomer is the non-superimposable
mirror image of the other
W
W
C
C
Y
Chiral (or
asymmetric)
carbon
Y
X
X
Z
Z
mirror
Hands!
Chirality and drug synthesis
Most drugs act on proteins. These are either in enzymes or
sensitive receptors on the surface of cells. These receptors
respond to chemicals released from nerve endings and hormones.
A particular way drugs can work is by targetting the active site of
a specific enzyme. E.g. Sulfonamide drugs and penicillin act by
killing dangerous bacteria by targeting enzymes.
The key issue is to make sure the drug targets the bacterial
enzyme active site specifically and does not affect any enzymes
in the human the bacteria has infected.
In our bodies, most molecules interact very selectively with the
active sites in the protein structures of enzymes. The molecules
are chiral but our bodies only work with 1 of the isomers.
Chiral compounds in the news…...
Most drugs are therefore chiral BUT the 2 optical
isomers will act on the body in different ways. Ideally
one isomer is effective and one has no effect. But……….
Thalidomide:
One optical isomer helps morning sickness.
The other one causes birth defects.
Thalidomide occurs as a racemic mixture! Chrial
separation was ESSENTIAL but did not occur.
Chiral compounds in the news…...
L-Dopa: Parkinson’s disease treatment (Dopamine)
Ritalin
http://www.chm.bris.ac.uk/motm/thalidomide/start.html
http://www.thalidomide.org.uk/home.aspx
Thalidomid
e activity
p241
Combinatorial chemistry
Technique used by large pharmaceutical companies to
synthesise a large number of compounds quickly.
Combinatorial chemistry allows chemists to carry out
many reactions using computer-controlled equipment,
producing milligrams of each product.
In combinatorial chemistry reagents are mixed and
conditions controlled automatically. Once made, each
can be quickly tested for its effectiveness as a drug
before being made conventionally on a larger scale if
successful.
Combinatorial chemistry
96-well plate allows 96 reactions to be carried out at
any one time.
For example, esters can be synthesised using 8
different carboxylic acids and 12 different alcohols.
Combinatorial chemistry
Combinatorial chemistry
Visit the following website to find out more about
combinatorial chemistry and prepare a 1-page or
3-slide summary of this vital pharmaceutical technique.
http://www.rsc.org/education/teachers/learnnet/alchemy/index2