Combinatorial chemistry Merrifields peptide synthesis

Since the introduction of sohd-phase peptide synthesis (SPPS) on lightly crosslinked polystyrene (PSty) by Merrifield in 1962,this technique has been optimized in all its aspects and has subsequently found widespread application in many other fields of organic chemistry, e.g. for the synthesis of oligonucleotides, for catalysis, for the immobilization of enzymes in biotechnology, and for the preparation of polymeric reagents. A new but very rapidly growing field of application of this revolutionary method is the use of solid-phase techniques in combinatorial chemistry for the synthesis of hbraries of compounds whose constituents differ widely in their chemical nature. ... 

One of the key technologies used in combinatorial chemistry is solid-phase organic synthesis (SPOS) [2], originally developed by Merrifield in 1963 for the synthesis of peptides [3]. In SPOS, a molecule (scaffold) is attached to a solid support, for example a polymer resin (Fig. 7.1). In general, resins are insoluble base polymers with a linker molecule attached. Often, spacers are included to reduce steric hindrance by the bulk of the resin. Linkers, on the other hand, are functional moieties, which allow the attachment and cleavage of scaffolds under controlled conditions. Subsequent chemistry is then carried out on the molecule attached to the support until, at the end of the often multistep synthesis, the desired molecule is released from the support. 

One of the cornerstones of combinatorial synthesis has been the development of solid-phase organic synthesis (SPOS) based on the original Merrifield method for peptide preparation [19]. Because transformations on insoluble polymer supports should enable chemical reactions to be driven to completion and enable simple product purification by filtration, combinatorial chemistry has been primarily performed by SPOS [19-23], Nonetheless, solid-phase synthesis has several shortcomings, because of the nature of heterogeneous reaction conditions. Nonlinear kinetic behavior, slow reaction, solvation problems, and degradation of the polymer support, because of the long reactions, are some of the problems typically experienced in SPOS. It is, therefore, not surprising that the first applications of microwave-assisted solid-phase synthesis were reported as early 1992 [24],... 

Modern combinatorial chemistry involves a number of steps that begin with the creation of a library of molecules that are closely related in structure. The library can be created in two ways (a) parallel synthesis, which is simultaneous synthesis of numerous products in separate discrete reaction vessels (b) combinatorial synthesis, of numerous reactions within one single reaction vessel followed by separations. The initial successes in parallel synthesis have been in solid peptide synthesis of proteins, which was based on Merrifield s solid-phase peptide synthesis. 

Merrifield s concept of a solid-phase method for peptide synthesis and his development of methods for carrying it out set the stage for an entirely new way to do chemical reactions. Solid-phase synthesis has been extended to include numerous other classes of compounds and has helped spawn a whole new field called combinatorial chemistry. Combinatorial synthesis allows a chemist, using solid-phase techniques, to prepare hundreds of related compounds (called libraries) at a time. It is one of the most active areas of organic synthesis, especially in the pharmaceutical industry. 

One of the major tools in combinatorial chemistry has been rooted in the ingenious solid-phase synthesis of peptides by Merrifield.1... 

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

Although the solid-phase technique was first developed for the synthesis of peptide chains and has seen considerable use for this prupose, it has also been used to synthesize chains of polysaccharides and polynucleotides in the latter case, solid-phase synthesis has almost completely replaced synthesis in solution. The technique has been applied less often to reactions in which only two molecules are brought together (nonrepetitive syntheses), but many examples have been reported. Combinatorial chemistry had its beginning with the Merrifield synthesis, particularly when applied to peptide synthesis, and continues as an important part of modem organic chemistry. ... 

Solid-phase synthesis of peptides was pioneered by Bruce Merrifield in the early 1960s. This work, for which he won the Nobel Prize in 1984, set in motion the modern approach to drug discovery called combinatorial chemistry. Through combinatorial chemistry, millions of compounds are generated by the synthesis of libraries on solid supports and screened for therapeutic activity by high-throughput assays. The importance of this work is attested by the numerous combinatorial research units that are now an integral part of most major pharmaceutical companies. 

One of the most developed methods used in combinatorial chemistry libraries preparation is solid-phase organic synthesis (SPOS) based on the Merrifield method for peptide synthesis [128]. A great number of such libraries have been prepared on a solid support, generally a functionalized polystyrene resin cross-linked with a small amount of divinylbenzene. Recently, it was demonstrated that micro-wave irradiation can be applied to solid-phase immobilized reagents to reduce significantly the reaction time. Those readers who are interested in such processes we would like to refer to more extensive reviews published by Chamberlin et al. [129] and Kappe [130], while in this chapter we are giving most common examples. 

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