Base cleavable linker

CLASSICAL LINKER STRATEGIES 1.2.1 Acid and Base Cleavable Linker Units... 

Over the years, a number of cleavable linkers that are acid labile, base labile, or photol-abile have been developed for solid-phase peptide synthesis. (This topic has been covered in detail by several review papers [34-36].) For libraries that require the linker to be cleaved before screening, most of these conventional linkers can be used. Several unconventional linkers have been found to be particularly useful and user-friendly for combinatorial applications (see Fig. 1). Among them are methionine-containing linker [37] and safety-catch benzylhydrylamine linker 1 [38], Bray et al. [39] have utilized an orthogonal peptide-resin linker 2 which allows the final deprotection and removal of contaminating chemicals and the peptide is later released into an aqueous buffer. Hoffmann and Frank [40] recently described a novel safety-catch linker 3 based on the intramolecular catalytical... 

Fig- 2. The two-stage release ofpeptides from iminodiacetic acid-based dual cleavable linker. 

The selected example by Seneci et al. [51] reported the use of an IDA-DC [52] (iminoDiacetic acid based double cleavable) linker for structure determination and controlled release of pool libraries based on teicoplanin aglycone (TD) [53] and tested for their antimicrobial activities. The synthesis and the structure of the linker and the structure of teicoplanin aglycone are shown in Figure 9.15. Starting from iminodiacetic acid the linker was prepared in four trivial chemical steps (the cyclic anhydride used in step 4 was prepared in two steps from iminodiacetic acid) its structure was symmetrical with the amide arm bearing the carboxylic handle for the solid support attachment and the identical other arms bearing protected propylamine groups for the library synthesis. 

Scheme 5 T vo-Step Release of Library Compounds from a Double-Cleavable Linker Based on Iminodiacetic...

Lebl [121,130-134] and Baldwin [126,127] first reported an efficient strategy, in which the advantages of performing assays in solution and structural determination of resin-bound compounds are combined. This method is based on multiple cleavable linkers which can release aliquots of the resin-bound compound, rather than cleaving all the compound bound to one resin bead at once. 

Structurally complex molecules are prepared by multistep reactions. The Q architecture and distance-independent reactions have enabled a single DNA template to direct multiple reactions at different regions. However, after eaeh reaction, strategies need to be developed to remove the reagent DNA strand and to purify the template-linked product from unreacted template in preparation for the next step. A variety of cleavable linker strategies and solid-phase-based affinity purification have been developed to address these two key aspects of multistep DNA-template synthesis. 

Fig. 10.2 Delivery systems for therapeutic proteins. Noncovalent delivery systems include adsorption and encapsulation. By using pairs of interacting molecules, it is possible to implement affinity-based immobilization. Heparin-growth factor and avidin-biotin are shown here as examples. When covalent immobilization is used, the release of the therapeutic protein is dependent on the degradation of the matrix/scaffold. Alternatively, it is possible to use protease cleavable linker for the protein deposition in order to release the growth factor in response to specific proteases.

The successful assembly of organic compounds on a solid support represents only part of the challenge in SPOS. After completion of synthetic sequence, the compounds must be cleaved from linkers attached to polymer by a chemical or photochemical reaction, for example, treatment of a polymer-bound compound with acids, bases, nucleophiles, redox reagents, and even photons. Acid-labile linker and amine-cleavable Marshall linker are two major classes of hnkers used in combinatorial synthesis. 

Acid-labile linkers are the oldest and still the most commonly used linkers for carboxylic acids. Most are based on the acidolysis of benzylic C-O bonds. Benzyl esters cleavable under acidic conditions were the first type of linker to be investigated in detail. The reason for this was probably the initial choice of polystyrene as an insoluble support for solid-phase synthesis [13]. Polystyrene-derived benzyl esters were initially prepared by the treatment of partially chloromethylated polystyrene with salts of carboxylic acids (Figure 3.3). 

Table 3.4. Linkers for carboxylic acids cleavable by base-induced (3-elimination.

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