Damanhour University

Faculty of Pharmacy
Department Of Pharmaceutical Chemistry

Essentials of Pharmaceutical Chemistry

Combinatorial Chemistry

Written by,
Student of third year pharmacy,

‫عماد الدين عبدالمنعم محمد ف ليف ل‬

Content:-
 Introduction.

 What is combinatorial Chemistry?

 History of Combinatorial Chemistry.

 Why Combinatorial Chemistry?

 Combinatorial synthesis techniques.

1. Solid Phase.
 Split and Mix Synthesis.
 Parallel Synthesis.
 Multi-pin Synthesis.
 Tea bag Synthesis.
2. Solution phase.

 Applications of Combinatorial Chemistry.

 Deconvolution and screening.

 Conclusion.

 Reference.
 Essentials Of Pharmaceutical Chemistry

Drug Development

Combinatorial Chemistry
Introduction:-
Drug development depends on four steps but two basic
steps that of concern to Medicinal Chemistry, the first is
finding a lead compound and the second is the optimization of
the effect of that lead compounds, Combinatorial Chemistry
has an important role in both finding and optimization the
effect of lead compounds.
What is Combinatorial Chemistry / Synthesis [1]?
In a traditional method if we react two compounds can be
expressed as linear equation[1][2] A+B AB, but with the use of
combinatorial Chemistry, the A compound can be a mixture of
six or more compounds which reacts with the B compound
that can be a mixture of ten compounds, so instead of the
production of an individual product AB, we will get sixty
compound simultaneously in shorter time and depending on
the number of combined reactants we can get tens of
thousands of new lead compounds [2].
But not only combinatorial synthesis helps in the
production of many compounds in short time but also creates
a library of compounds (known as chemical or combinatorial
library) that can be screened to get the most biologically
active lead compounds and used lately in the production and
identifying of proteins and thus synthesizing of new drugs [2].
History of Combinatorial Chemistry:-
Combinatorial Chemistry was introduced under
this name when it was taken up by industry in the
early 1990s.
But the idea of combinatorial chemistry go back
to 1960 when Bruce Merrifield [3][9] started the
study of solid phase synthesis of peptides and in
1984 he won Nobel prize in chemistry for his work
in the field of Combinatorial Chemistry [4].
In 1980, researcher H.Mario Geysen [2] carried
the idea of solid phase synthesis to further steps
by creating chains of different peptides on
separated solid supporters.
In 1982, Dr. Árpád Fukra [4] which is known
as one of the fathers of combinatorial synthesis
published the first split and mix synthesis of
peptides.
In 1985, Tea bag synthesis technique was
done by Richard Houghten [5] and in this same
period of time the synthesis of multi-peptide by
combinatorial chemistry started its advancing.
In 1992, Bunin [6] and Ellman demonstrated the synthesis of
1,4-Benzodiazepine in their publications, this was followed by
multiple publications of other laboratories on similar drug
related molecules which started a race of developing new
methods of Combinatorial Chemistry.
Why Combinatorial Chemistry?
As previously mentioned combinatorial chemistry is able to
produce a large amount of effective optimal compounds in
shorter time and also screening them into libraries, but it’s
also characterized by avoiding the use of extreme conditions
of pressure, heat as well as avoiding the use of inert
atmosphere gases and highly caustic materials in its
reactions unlike traditional methods.
Combinatorial synthesis techniques:-
Combinatorial chemistry is classified into two phases, Solid
phase synthesis and solution phase synthesis.
Solid phase synthesis is divided into number of techniques
such as; Parallel synthesis, Tea bag synthesis, Mix and split
synthesis and Multi-pin synthesis.
In solid phase synthesis [7][9][10], the
reaction is made on a solid support beads
such as Polystyrene resins, Glass/Ceramic
beads or Tentagel resins. The support is
then connected to the functional group or
the lead compounds by a linker chosen
depending on the functional groups that
are directly linked to the linker or on the
compound connected to the linker
(example; Merrifield resin is suitable for
peptide products but not used for
carboxylic acids which uses Wang resin).
Protecting groups are used to block the
reaction of certain functional groups.
 Each solid phase synthesis technique use (beads, linkers
and protecting groups) in their reactions, but each follows a
different method in procedure.
a) Mix and split synthesis technique [7][10] introduced by the
previous picture at which amount of resin beads is divided
into three equal portions then treated with different three
compounds and mixed into a vessel after being treated, the
beads are then washed out and mixed again with the resulted
compounds, then split into three equal groups and the
process is repeated till we obtain the desired library.
b) Parallel synthesis technique [7][10][12]

is done by doing many reactions in

separated vessels (96 well plate usually)
at the same time instead of a series of
reactions, in automated machines
vessels are moved from their slot and
replaced by another and so on, the same
as “Mix and split synthesis”, it results in
many compounds but they are produced
individually in their own vessels.
Still Mix and Split synthesis technique
is still better in finding lead compounds
as it’s capable of producing large
numbers of lead compounds in shorter
time but on the other hand Parallel
synthesis is better in optimization of
effect process.
 c) Multi-pin synthesis technique [7]

is the same in idea of Parallel

synthesis, it takes place in 96 well
plates but with 96 long polyethylene
pins used as solid support for
compounds to do the coupling and it
is used mostly for protein synthesis
but the peptides stay on each pin’s
head during synthesis.
d) In Tea bag synthesis [7]
technique, Tea bags are used as
vessels that contain porous mesh
and inside of it the resin beads are
enclosed, the mesh allows
reagents and solvent to pass
through it, by emerging the tea bag
into each reagent the resin beads
couple with reagents that pass
through the mesh and by placing
the tea bag in different reagents it
results into a combinatorial library
of various compounds.
Unlike Solid phase synthesis, Solution phase synthesis [12]
takes place in one vessel/pool of solution where compounds
are mixed together which makes it of more interest for its
similarity to most chemical reactions that take place in a
solution medium, but still Solution phase synthesis is less
used than solid phase synthesis due to the difficulty of
impurities removal from solution during synthesis.
 Now most combinatorial synthesis procedures are made
by automated machines for much more easy and fast
processing with the least error to occur, which offers much
accurate results.
Applications of Combinatorial Chemistry:-
Combinatorial Chemistry helped in the fast production of
variety of libraries of multi compounds of useful biological
activity and drug industry is trying to use the best of
combinatorial synthesis for effective production of drugs and
drug designing.
Examples of Libraries and products produced by
combinatorial synthesis are;
 Encoded benzimidazole library made by split-mix
synthesis and Amino Acids tester Libraries [7].
 Transition-state analog HIV protease inhibitors [13].
Even though combinatorial chemistry plays a great role in
providing large number of libraries that serve as starting
materials for production of more active compounds, but only
one drug (Sorafenib, a multi-kinase inhibitor used for renal cancer) [2] which
was approved by FDA for clinical use while other drugs
produced by this method did not pass clinical trials or get
approval by FDA due to their side-effects or low
bioavailability.
Deconvolution and screening
Deconvolution and screening are the isolation and
identification of the most effective and active compounds in
the resulted libraries and helps in making the process of
combinatorial synthesis less complex [2].
 For smaller libraries, Analytical analysis techniques
combined with chemical cleaving methods can be used for the
identification, isolation and structure determination of the
resulted compounds. Such methods include the use of, IR and
UV Spectra, Mass spectra, NMR spectra and Chromatography
(HPLC, TLC, etc..).
But screening a combinatorial library of over a million
synthesized compounds would be a difficult process, so
“High throughput” [13] one of the screening techniques was
made for such a purpose, an automated method that can
carry on all the synthesis process beside the screening stage,
a fluorescence tagging material is added during synthesis to
allow an easy tracking and visualization of the resulted
compounds also for easier screening, beside the use of
robotic systems that helps the accurate screening of
compounds.
Such technique is used for DNA microarrays (tools used to
analyze and measure the activity of genes) [14] where millions of genes of
DNA on the solid support that can’t be screened on normal
basis.
Conclusion:-
Combinatorial Chemistry has a great effect on lead
compound’s isolation, identification, optimization and
production in large numbers, in shorter time than traditional
methods and in cheaper ways, also provides various methods
/ techniques of finding new lead compounds and optimization
of their effect.
References:-
1. http://www.udel.edu/chem/C465/senior/fall00/DrugDiscovery/Wh
atisCombinatorialChemistry.htm
 http://www.screening-compounds.com/
 http://www.combichemistry.com/
2. http://en.wikipedia.org/wiki/Combinatorial_chemistry#cite_note-5
3. http://en.wikipedia.org/wiki/Robert_Bruce_Merrifield
4. http://szerves.chem.elte.hu/furka/
5. http://en.wikipedia.org/wiki/Richard_A._Houghten
6. http://en.wikipedia.org/wiki/User:Wikibaruch/Barry_Bunin
7. http://members.iif.hu/furka.arpad/BookPDF.pdf
8. http://www.udel.edu/chem/C465/senior/fall00/DrugDiscovery/Soli
dPhaseSynthesis.htm
9. http://en.wikipedia.org/wiki/Solid-phase_synthesis
 http://www.combichemistry.com/cross-linked-
polystyrene.html
10. http://chem3513-
2007.pbworks.com/w/page/15648417/Combinatorial%20Chemist
ry
11. http://www.combichemistry.com/solution_phase_synthesis.htm
l
12. http://www.rsc.org/learn-
chemistry/resource/res00000054/chemistry-now-combinatorial-
chemistry?cmpid=CMP00000042
13. http://www.combichemistry.com/combichem_applications.html
14. http://www.encyclopedia.com/topic/Combinatorial_chemistry.a
spx