Fundamentals of Medicinal Chemistry

6 Combinatorial Chemistry

6.1 Introduction

The rapid increase in molecular biology technology has resulted in the develop-

ment of rapid efficient drug testing systems. The techniques used by these

systems are collectively known ashigh throughput screening. High throughput

screening methods give accurate results even when extremely small amounts of

the test substance are available. However, if it is to be used in an economic

fashion as well as efficiently this technology requires the rapid production of a

large number of substances for testing, which cannot be met by the stepwise

approach of traditional organic synthesis methods (Figure 6.1).

C 4 H 9 Br+H 2 N COOH C 4 H 9 NH COOH C 4 H 9 NH COOCH 2 CH 2 N(C 2 H 5 ) 2

HOCH 2 CH 2 N(C 2 H 5 ) 2

Tetracaine

N-Alkylation Esterification

Figure 6.1 A traditional stepwise organic synthesis scheme illustrated by the synthesis of the

local anaesthetic tetracaine

Combinatorial chemistry was developed to produce the large numbers of

compounds required for high throughput screening. It allows the simultaneous

synthesis of a large number of the possible compounds that could be formed

from a number of building blocks. The products of such a process are known as

acombinatorial library. Libraries may be a collection of individual compounds

or mixtures of compounds. Screening the components of a library for activity

using high throughput screening techniques enables the development team to

select suitable compounds for a more detailed investigation by either combina-

torial chemistry or other methods.

The basic concept of combinatorial chemistry is best illustrated by an example.

Consider, the reaction of a set of three compounds (A1–3) with a set of three

building blocks (B1–3). In combinatorial synthesis, A 1 would simultaneously

Fundamentals of Medicinal Chemistry, Edited by Gareth Thomas
#2003 John Wiley & Sons, Ltd
ISBN 0 470 84306 3 (Hbk), ISBN 0 470 84307 1 (pbk)