PHARMACEUTICAL ORGANIC CHEMISTRY RESEARCH

Combinatorial Chemistry

INTRODUCTION :

*Combinatorial chemistry is one of the important new

methods developed by academics and researchers in

the pharmaceutical, chemical, and biotechnology

industries to reduce the time and costs associated with

producing effective, marketable, and competitive new

drugs.

*Simply, scientists use combinatorial chemistry to

create large populations of molecules, or libraries ,

that can be screened efficiently .

* By producing larger, more diverse compound

libraries, companies increase the probability that they

will find novel compounds of significant therapeutic

and commercial value.

*The field represents: a convergence of chemistry and

biology, made possible by fundamental advances in

miniaturization, robotics, and receptor development.

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* And not surprisingly, it has also captured the

attention of every major player in the pharmaceutical,

biotechnology, and agrochemical arena.

*Technique invented in the late 1980s and early 1990s

to enable tasks to be applied to many molecules

simultaneously

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DEFINITION :

*Combinatorial chemistry is a technique by which large

numbers of structurally distinct molecules may be

synthesized in a time and submitted for pharmacological

assay.

*The key of combinatorial chemistry is that a large range

of analogues is synthesized using the same reaction

conditions, the same reaction vessels.

*In this way, the chemist can synthesize many hundreds

or thousands of compounds in one time instead of

preparing only a few by simple methods .

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In the past

*chemists have traditionally made one compound at a

time.

* For example compound A would have been reacted with

compound B to give product AB, which would have been

isolated after reaction work up and purification through

crystallization, distillation, or chromatography.

In contrast to this approach

*combinatorial chemistry offers the potential to make

every combination of compound A1 to An with compound

B1 to Bn.

The range of combinatorial techniques is highly diverse,

and these products could be made individually in a

parallel or in mixtures, using either solution or solid phase

techniques. Whatever the technique used the common

denominator is that productivity has been amplified

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beyond the levels that have been routine for the last

hundred years.

TOOLS:

- Solid-phase synthesis

– Resins

– Reagents (Monomers)

– Linkers

– Screening methods

METHODS :

1-Use of solid supports for peptide synthesis led to wider

applications

2-Products from one reaction are divided and reacted

with other reagents in succession

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Benefits to material science :

1-Combinatorial approaches now being applied to solid-

state and materials applications

2-Also to search for new catalysts

Application of Combinatorial Chemistry :

*Applications of combinatorial chemistry are very wide.

* For example in pharmaceutical companies for drug

designs. For illustrate this, one a practical example:

Transition-state analog HIV protease inhibitors.

-Extensive efforts toward the rational design of aspartyl

protease inhibitors such as renin and HIV have led to

the discovery of several transition-states analog

mimics.

-These templates can serve as the central unit around

which molecular diversity can be generated by

application of appropriate chemistries.

- Recently, solid phase synthesis of hydroxyethylamine

and 1,2-diol transition-state pharmacophore units and

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their utility for synthesis of HIV protease inhibitors have

been reported by two different groups.

-The first instance, bi functional linker are used by

Wang to serve the dual purpose of protecting the

hydroxyl group of these BBs and providing point for

attachment on solid support.

-Thus, one linker possesses a vinyl ether group at one

end and a free carboxylate group at the other.

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-The vinyl ether moiety is reacted with diamino alcohol

BB 1 under acid-catalysed conditions to form an acetal

protecting group and the carboxylic acid group is used

for ester-type linkage to the solid support.

-The other linker possesses a methyl ketone and

carboxylic groups at the two ends, with the ketone

group forming a ketal with diol 3.

-Resulting intermediates 2 and 4 are now well suited

for a bi-directional solid phase synthesis strategy for

preparing C2 symmetric HIV protease inhibitors.

- The two terminal amino groups of 2 and 4 are

deprotected and reacted with a variety of carboxylic

acid, sulfonyl chlorides, isocyanates, and

chloroformates to extend the core unit in both

directions and generate a wide variety of aspartyl

protease inhibitors.

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ADVANTAGES AND DISADVANTAGES :

1-ADVANTAGES:

1-save time

2-fast

3-produce unexpected new compounds

4-used in many biological & chemical applications

5-save money

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2-DISADVANTAGES:

1-Can't used with Many compounds had undesirable

properties like

– Size

– Solubility

– Inappropriate functional groups

2-Early libraries often based on a single skeleton (basic

structure)

3-Limited number of skeletons accessible

4-Individual library members were structurally similar

5-Compounds tended to be achiral or racemic

6-Initial emphasis on creating mixtures of very large

numbers of compounds now out of favor

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REFRENCES :

1-http://www.combichemistry.com/

combichem_applications.html

2-http://en.wikipedia.org/wiki/

Combinatorial_chemistry

3-http://www.wiziq.com/tutorial/2967-Combinatorial-

Chemistry-and-Library-Design

4-http://www.netsci.org/Science/Combichem/

feature02.html

5-http://www.chem.msu.su/rus/books/patrick/part1.pdf

MADE BY SECTION(2) :

1- Jehan Essam Mahmoud (112) .

2-Aya Ahmed Saber Yosif (86).

3-Eman Mohammed Mostafa Sherra (83).

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4-Eman Ahmed Alaa Elshamy .

5-Aya Samir .

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