Brief History of Combinatorial Chemistry

While combinatorial synthesis is a relatively new field of chemistry, Nature has been utilizing the same principles since the beginning. Although biologists had previously recognized the power of combinatorial chemistry, its application to problems relating to chemistry did not emerge until recently. Chemists' confidence in rational design has previously kept them away from systematic explorations in chemical synthesis.

The rather dramatic developments in molecular biology and high-throughput screening increased the demand for large numbers of small organic molecules to be screened against the ever-increasing biological targets. A solution to these challenges came from the peptide and oligonucleotide chemists, who could conveniently implement combinatorial chemistry strategies given the ease with which the amide and phosphate bonds could be constructed from the readily available building block libraries of amino acids and nucleotides respectively.

Solid-phase chemistry was pioneered by Merrifield [1] and applied to the peptide and oligonucleotide fields quite effectively. In the early 1970s developments had already occurred in solid-phase synthesis of nonpeptide and nonoligonucleotide molecules. For example, the groups of Leznoff [2], Frechet [3], Camps [4], Patch-ornik [5] and Rapoport [6] all reported early results on solid-phase synthesis. Camps et al. even applied solid-phase synthesis to the pharmaceutically relevant benzodiazepine system [7].

In Germany in the 1980s Frank and coworkers synthesized collections of oligonucleotides and, later, peptides on circles of cellulose paper [8]. Geysen et al. in

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Australia prepared a library of peptides [9] on functionalized polypropylene pins by immersing them sequentially into various solutions of activated amino acids held in the wells of a microtiter plate. Houghten at The Scripps Research Institute in La Jolla synthesized a library of 260 peptides [10] in polypropylene mesh containers encapsulating polystyrene resin, a process that came to be known as the ''tea-bag'' strategy. Both the pin and the tea-bag techniques went on to gain wide popularity and led to new generations of improved technologies for combinatorial chemistry. Researchers at Affymax reported very large spatially addressable libraries on glass chips using photolithographic techniques in conjunction with photolabile protecting group chemistry [11]. In parallel with the chemical approaches to peptide diversity, phages were being exploited to display very large libraries of peptides [12].

In 1992, Bunin and Ellman reported another synthesis of a benzodiazepine library [13] using the ''multi-pin'' technology pioneered by Geysen. At about the same time, a group of scientists at Parke-Davis reported the construction of hy-dantoins and benzodiazepines using a semiautomated robotic synthesizer [14]. In addition, a Chiron group reported the synthesis of a library of peptoids [oligo(N-substituted glycine)] and a robotic synthesizer of such compounds [15].

In the meantime, an elegant and ingenious strategy for combinatorial synthesis was proposed and demonstrated. This strategy called ''split synthesis'' or ''split and pool'' was introduced by Furka and coworkers at two European symposia in 1988; this work was published in 1991 [16]. The groups of Lam [17] and Houghten [18] independently developed the same technique and also published their results in 1991. These strategies led to the concept of ''one bead-one compound'' and promised the delivery of millions of compounds synthesized simultaneously on beads and with unprecedented rapidity. As elegant as it is, this method left much to be desired in terms of structure deconvolution and quantity of material produced. To solve the first problem, a number of encoding strategies were developed based on technologies ranging from DNA sequences to polychlorinated aromatics as well as nonchemical encoding methods such as radiofrequency tagging and two-dimensional (2D) bar-coding (for further discussion of library encoding, see Chapter 5).

From the early 1990s onwards, the chemical literature exploded with reports addressing all aspects of combinatorial synthesis, including solid-phase chemistry, encoding strategies and molecular diversity.

In the late 1990s alternative strategies were investigated, and an interesting compromise between solid-phase and solution-phase chemistry was found with polymers which are soluble in certain solvents but can be precipitated efficiently in others [19]. Thus the reactions on such polymers are carried out in homogeneous solution while the convenience of purification via a simple filtration is maintained. In a highly efficient extension of this principle, Curran and coworkers [20] have developed a number of fluorous tags which allow extraction of tagged compounds into a three-phase separation system (aqueous, organic, and fluorinated).

Today, many well-known solution-phase reactions have been demonstrated to perform equally well on solid phase [21] and a plethora of reagents have been im mobilized on solid supports [22]. Such techniques lead to high-speed purification procedures and often to higher yields of targeted products, which in turn lead to an increase in efficiency and productivity.

While the peptide and oligonucleotide chemists may have opened the field of combinatorial chemistry, it was left to those chemists concerned with small organic molecules to make the methods widely applicable to more ''lead-like'' and ''drug-like'' structures. Of particular interest were new solid-phase synthetic strategies, new linkers for solid-phase chemistry [23], and new polymer-bound reagents [24].

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