Disulfide linker

Fig. 9.8 Evolution of a fragment from Tethering with extenders to a potent caspase-3 inhibitor. Simple replacement of the disulfide linker with an alkyl linker resulted in a low micromolar inhibitor (4), and rigidification (5) and functionalization (6) of this linker led to increasingly potent inhibitors. The salicylic acid hit itself (7) had no detectable binding.

All of these features contrast with the structure of the second extender-fragment complex, shown in Fig. 9.9b. Here, the extender forces itself into the S2 pocket, but the disulfide linker then curves back to place the thiophene sul-fone into the S4 pocket. The sulfone makes some of the same hydrogen bonds as the salicylic acid and the aspartyl residue in the tetrapeptide but with completely different chemistry. The flexibility of caspase-3 to accommodate different... 

A similar approach to a DCL of bivalent ligands linked by flexible disulfide spacers was taken by Daiueli and coworkers [24]. Their library consisted of the antitumour agents thiocolchicine and podophyllotoxin, derivatized to form disulfide-linker homo- and heterodimers (Scheme 2.5). The components could be effectively exchanged in the presence of catalytic thiol in orgaiuc solvents. 

Scheme 7.9. Use of a disulfide linker for the non-site specific connection of amphipathic peptides and carbohydrates to amine terminated dendrimers.

Four recent examples of universal linkers/supports, in which the first nucleoside is anchored onto the preformed linker-support construct, are shown in Fig. 2.14. The disulfide linker 2.33 has been used to prepare terminal 3 -phosphate ONs (94, 95) through cleavage with a solution of ammonia in dithiothreitol. The photolabile linker 2.34 (96) is used to prepare 3 -alkyl carboxylic acids. The allyl-based linker 2.35 (97) is used to prepare free 3 -OH ONs by cleavage with Pd(0) and treatment with an aqueous buffer at pH 10. The linker 2.36 (98) differs from those discussed so far in... 

Figure 37 Bifunctional photocross-linking affinity purification reagents with cleavable linkers, (a) Diazirine-modified LacNAc probe with a biotin tag and a cleavable acylsulfonamide linker, (b) Aryl azide Le probe with a biotin tag that contains a cleavable disulfide linker.

Thiols have also been artificially introduced at the end of peptide sequences, with the advantage that the orientation of the peptide on the surface is not restricted by the geometry of cysteine. Furthermore, the use of disulfide linkers provides stronger adhesion forces per molecule, as they result in the formation of two gold-thiol links per molecule (Yasutomi et al., 2004 Yasutomi, Morita, Kimura, 2005). 

Supports for 3 -Thiol End Groups A 3 -thiol function can also be incorporated into oligonucleotides to serve as a convenient attachment site for either enzymes or fluorescent dyes. In a multistep method (45), nucleosides or nucleotides may be derivatized with either 1,6-hexanedithiol and mercaptoethanol or 3,3 -dithiodipropanol, respectively, to yield 3 -disulfide linkers (Fig. 9). 

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