Introduction

Combinatorial chemistry is widely used to describe high throughput synthesis of compounds, both organic and inorganic. In reality, high throughput synthesis activities represent the industrialization of chemistry in much the same way that commodity items, from appliances to motor cars, are made today within a highly industrialized society. Computers and automation have replaced the labor-intensive aspects of chemical synthesis. As is often the case with faster and cheaper technology, this new approach to chemistry has necessitated some concessions in terms of the traditional requirements of characterization and purity. Initially, the emphasis was on the numbers of compounds made and the use of solid-phase synthesis methods. Chemical libraries with essentially no characterization were assayed for biological activity.

In summary, the early experience with chemical libraries was less than stellar. The general belief that smaller rounds of more controlled synthesis would resolve any ambiguity about active "hits" found in the initial screen proved to be overoptimistic, and accounts of failure were common. It quickly became apparent that the use of solid phase, necessary with an encoding strategy, was in itself a challenge for organic chemistry procedures and very different from a chemist's experience of solution phase. The numerically smaller libraries of discreetly synthesized compounds (parallel synthesis) that followed

Integrated Strategies for Drug Discovery Using Mass Spectrometry, Edited by Mike S. Lee © 2005 John Wiley & Sons, Ltd.

by purification became the norm, and very few companies that use a viable "real" combinatorial approach to drug discovery remain. Pharmacopia (still encoding)[1], Affymax (hard-tag encoding)[2], and GlaxoWellcome (mass encoding)[3-5] were among the few with a technology that allowed the use of a "mix and split" procedure that generated bead-based, numerically large compound libraries.

It is worthwhile to note that three consecutive reports in Tetrahedran [6-8] summarized both the progress made in combinatorial chemistry and the challenges that require a technological solution to more fully realize its full potential. In each of these reports, quantitation and characterization of chemistry carried out on the solid phase during the synthesis and at the completion before any biological testing were stated to be urgent priorities. In the absence of the foregoing and due to the widespread belief that solid-phase chemistry was limited with respect to the diversity of chemistries that could be carried out, the industry has invested significantly in equipment-intensive facilities geared to high throughput solution-phase synthesis followed by purification.

The inherent power of a bead-based solid-phase approach to compound libraries for hit identification is in the ability to use a mix- and-split process for numerically large libraries at an economically feasible scale, typically about 1-2 nmole per bead. This chapter outlines the culmination of several years of research by a dedicated team comprising a wide range of expertise for the development of an inherently simple technology based on mass spectrometry. The described technology overcomes many of the perceived disadvantages of a bead-based approach to compound generation, as well as provides the opportunity to rapidly discover and validate new chemistries on solid phase. When coupled with "statistical decoding" [9], this bead-based technology virtually eliminates any possibility of obtaining an ambiguous outcome from either a failed or incomplete synthesis or from a false-positive that occurs during the screening procedure.

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