Combinatorial synthesis of peptides

Combinatorial Synthesis Of Peptide Hydroxamic Acids with Hydroxylamine-Linked Resin... 

The ease, simplicity, and repetitive nature of solid-phase synthesis led to the development of automated synthesizers (Section 4.3.6). In addition, the advent of solid-phase peptide synthesis laid the groundwork for the development of combinatorial synthesis of peptide libraries that are now being used for the discovery of lead analogues for drug discovery (Section 4.3.7)... 

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. 

A linker originally designed for solid-phase synthesis of peptides is the backbone amide linker (11) (BAL), this anchoring approach has now been extended to the combinatorial synthesis of diverse amide [31], hydroxamate [32], oligosaccharide [33] and heterocyclic small molecule libraries [34-36]. 

Horton, D.A., Bourne, G.T., and Smythe, M.L. Exploring privileged stmctures the combinatorial synthesis of cyclic peptides./. Comput.-Aided Mol. Des. 2002, 36,415-430. 

Other examples of Ugi reactions combined with RCM have been described in the literature. Hebach and Kazmaier reported the synthesis of conformationally fixed cyclic peptides [70] and Beck and Domling synthesized biaryl-containing natural product-like macrocycles using this method [41]. The same group also reported combination of Passerini and Horner-Wadsworth-Emmons reactions to obtain butenolides [67] and another variation for the combinatorial synthesis of thiazoles [69]. 

Horton DA, Bourne GT, Smythe ML (2002) Exploring privileged structures the combinatorial synthesis of cyclic peptides. Mol Divers 5(4) 289-304... 

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. 

Gilbertson. S.R. and Wang. X. (1999) The parallel synthesis of peptide based phosphine ligands. Tetrahedron, 55. 11609-11618 Gilbertson. S.R. and Wang. X. (1995) The combinatorial synthesis of chiral phosphine ligands. Tetrahedron Lett.. 37. 6475-6478. 

Houghten and co-workers[145] introduced a method for combinatorial synthesis of a per-alkylated peptide library using nonspecific N-alkylation. The peptides were synthesized by SMPS methodology 146 in combination with repetitive amide N-alkylation on the solid support after each coupling step. Peptides were synthesized on MBHA-PSty resin using Fmoc chemistry. After Fmoc deprotection the a-amino group was protected by Trt to prevent N -alkylation and to allow only amide alkylation. The on-resin amide alkylation was achieved by amide proton abstraction using LiOtBu in THF followed by nonfunctionalized alkyl and aryl halides in DMSO. 

The concept of reducing the number of reaction vessels and exponentially increasing the number of synthesized compounds was brought to a next level of simplicity by the split-and-pool method of Furka et al.5 The split-and-pool method was independently applied by Lam et al.6 in a one-bead-one-compound concept for the combinatorial synthesis of large compound arrays (libraries) and by Houghten et al.7 for the iterative libraries. Now several millions peptides could be synthesized in a few days. In Furka s method the resin beads receiving the same amino acid were contained in one reaction vessel—identical to Frank s method—however, the beads were pooled and then split randomly before each combinatorial step. Thus the method is referred to as the random split-and-pool method to differentiate it from Frank s method in which each solid-phase particle was directed into a particular reaction vessel (the directed split-and-pool method). 

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

The first installment in this series (Volume 267, 1996) mostly covered peptide and peptidomimetic based research with just a few examples of small molecule libraries. In this volume we have compiled cutting-edge research in combinatorial chemistry, including divergent areas such as novel analytical techniques, microwave-assisted synthesis, novel linkers, and synthetic approaches in both solid-phase and polymer-assisted synthesis of peptides, small molecules, and heterocyclic systems, as well as the application of these technologies to optimize molecular properties of scientific and commercial interest. 

For many of the prominent inhibitor families (Fig. 3.6.1, Boxes 12 and 13), the available synthetic strategies do not fulfil these requirements. In the synthesis of peptide aldehydes, e.g., the parallel synthesis of variable structures without race-mization is an unsolved problem. The same applies to the synthesis of many peptide isosteres such as the norstatines or the l,3-diamino-2-propanols. Typically, combinatorial variation of the N-terminal and C-terminal positions can be easily attained. The side chain of the isosteric building block itself and its stereochemistry can, however, currently be varied only by a synthetic effort this excludes versatile variation of the central inhibitory element. 

Automated synthesis of peptide and oligonucleotide libraries was initiated about 10 years ago [4], Within the last three years, there has been much attention focused on the generation of combinatorial libraries of small molecules. As with biopolymers, the use of solid resin support was central to the advance of this field. In solid-phase synthesis, one of the reactants is covalently bound to the solid support and an excess of the other reactants may be used in each step to drive reactions to completion. Purification of the intermediates and final product is easily achieved through extensive washing of the resin after each chemical step. For the purpose of high throughput synthesis, cleavage of the final... 

Besides classical resin beads, other polymeric carriers were also used for the synthesis ofpeptide libraries in various formats. Poly aery late-grafted polypropylene pins were used for the synthesis of the first combinatorial chemical library [1,2], This type of support continues to be heavily used in multiple peptide [27] and non-peptide [28] library synthesis. Cellulose paper, originally used by Frank et al. as a solid-phase support for oligodeoxy-ribonucleotide synthesis [29], has also been used as the support for multiple SPOT synthesis of peptide libraries [30,31], Polystyrene-grafted polyethylene film (PS-PE) may also be used in combinatorial peptide library synthesis [32], The specific feature of the membrane type of carrier is its dividability. This feature has been used for the synthesis of libraries with a nonstatistical distribution of library members, where no compound is missing and none is represented more than once [33],... 

All of these demands were fulfilled for the synthesis of peptides long before combinatorial chemistry gained the importance that it has to-... 

Soluble PEG supports have been used for different applications such as the synthesis of peptides (241, 245) and peptidomimetics (246) soluble-supported catalysts (247-249), reagents (250-253), scavengers (254), and traceless linkers (255-257) to improve purification protocols (258, 259) and high-loading PEG-derived soluble supports (260), particularly in the synthesis of arrays of small organic molecules (261-275). Several recent reviews (276-281) illustrate their usefulness but also show how additional efforts could make PEG liquid-phase combinatorial synthesis more reliable. 

The development of the synthesis of peptides on solid supports has also had a strong impact on other areas of organic synthesis. From the very beginning, some research groups tried, with some success, to export the idea from peptide synthesis to, for instance, the monoalkylation and monoacylation of carboxylic acids,the synthesis of aldehydes and ketones, or to the use of resin-bound dienes or dienophiles to trap reactive intermediates.PI This pioneering work has been fundamental to the much more recent explosion of combinatorial chemistry on solid supports. Synthesis on solid supports has also found application in the synthesis of oligonucleotides, PI oligosaccharides,PI peptide-DNA hybrids,P°l and peptide nucleic acids (PNAs).P l... 

The principal difference between the synthesis of individual peptides and peptide libraries is that mixtures of amino acids, rather than individual amino acids, are incorporated into selected or all positions of the sequence of peptide libraries. However, all current peptide chemistry strategies can be used for the synthesis of peptide libraries. In general, library synthesis requires greater emphasis on simplicity and reproducibility of the synthesis process. Although soluble supports have also been used for peptide library synthesis,the majority of methods used to synthesize peptide combinatorial libraries utilize Merrifield s concept of solid-phase synthesis,which is based on the sequential assembly of peptides after covalent attachment of the C-terminal amino acid to a polymeric solid support. This enables the excess of reagents to be removed by simple wash and filtration processes, and avoids the... 

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. ... 

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