Linkers and anchoring

Since the carrier material (e.g., polystyrene, controlled pore glass, polyacryl, cellulose, etc.) also affects the success of the synthesis, they will be considered in the following sections, together with the linkers and anchors under Carrier [19],... 

Linkers and Anchor Croups for Solid Phase Oligonucleotide Synthesis 545... 

Linkers and Anchor Groups for Solid Phase Oligonucleotide Synthesis 561... 

The folding of a protein explained in the Introduction to this chapter creates an intertwined chemical structure. Ponnuswamy et al. (2012) fabricated knotted molecules, similar to protein structure, which took advantage of hydrophobic interactions. The molecular structure was comprised of three hydrophobic naphthalene diimides held together with alanine linkers and anchored at both ends with cysteine amino acid. 

A second strategy is to attach a linker (also referred to as a handle or anchor) to the resin followed by assembly of the molecule. A linker is bifunctional spacer that serves to link the initial synthetic unit to the support in two discrete steps (Fig. 3). To attach a linker to a chloromethyl-PS resin, a phenol functionality such as handle 4 is used to form an ether bond (Fig. 4). To attach the same handle to an amino-functionalized support, acetoxy function 5 or a longer methylene spacer of the corresponding phenol is applied to form an amide bond. Both of these resins perform similarly and only differ in their initial starting resin [4], An alternative approach is to prepare a preformed handle in which the first building block is prederivatized to the linker and this moiety is attached to the resin. For peptide synthesis, this practice is common for the preparation of C-terminal peptide acids in order to reduce the amount of racemization of the a-carbon at the anchoring position [5],... 

There are three different approaches for anchoring the first residue to a support (Figure 5.11) first, the /V-protcctcd residue is anchored directly to a linker that has been elaborated on the support. Second, a stand-alone linker is coupled to the support, after which the protected residue is combined with the linker-resin. Third, the protected residue is combined with a stand-alone linker, and the resulting compound is then coupled to a handle on the support. The first option carries the disadvantage that if it is an ester that is formed, it is often difficult to force the... 

FIGURE 5.11 Three options for anchoring the first residue. Cleavage at the bond between Xaa and the support generates the product (see Figure 5.12). The word resin usually implies a polymer with a handle. For option 1, the handle serves as a linker. Options 2 and 3 allow insertion of a spacer or reference amino acid between the linker and the support. Option 3 allows purification of the iV-acylaminoacyl linker and quantitative anchoring via an amide bond. 

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

The T2 linker has recently been shown to be a versatile backbone amide anchor. Immobilized disubstituted triazenes were acylated with carboxylic acid anhydrides or chlorides to give amide derivatives. These amides were cleaved under very mild conditions using trimethyl chlorosilane. This sequence thus employs the T2 system as backbone amine linker and was demonstrated in the automated library synthesis of substituted amide derivatives.54... 

Because of an increased demand for flexible anchoring of molecules, other new families of linkers such as the sulfur linkers and triazene linkers have emerged. The most abundant type of linkers developed so far are based on benzylic-type groups. 

A large choice of linkers already anchored to the solid support is commercially available. The selection of an appropriate linker for a particular synthesis always takes into consideration the various reaction conditions that must be applied in the course of the library assembly, and what type of functional group is an acceptable attachment point. Generally, the desired target... 

The purpose of this chapter is to delineate strategic considerations and provide practical procedures to enable non-experts to synthesize peptides with a reasonable chance of success. This chapter focuses on Fmoc chemistry, which is now the most commonly employed strategy for solid phase peptide synthesis (SPPS). Protocols for the synthesis of fully deprotected peptides are presented, together with a review of linkers and supports currently employed for SPPS. The principles and the different steps of SPPS (anchoring, deprotection, coupling reaction, and cleavage) are all discussed, along with their possible side reactions. 

The induced PS-PLAi might attack PS-sensitized cells in either an autocrine or paracrine manner. Heparin completely blocked degranulation of a crude mast cell preparation induced by Fc receptor-cross linkers and PS-PI.A, [29]. This indicates that, under normal (heparin-free) conditions, PS-PLAi first anchors to surface he-... 

Kris, R.M. Eelder, S. High Throughput Assay System Using Multi Array Plate Screen, Nuclease Protection, Oligonucleotide Anchors, Bifunctional Linkers, and Mass Spectrometry, PCT Int. Appl. (2000), 111 pp., WO 0037684 Al 20000629. 

Figure 5.1. Explanation of the terms anchor, linker and spacer.

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