Thioether linkers

Examination of genotoxicity of pharmaceuticals is required to assess the interaction of the drug with DNA. These studies are generally not applicable to immunotoxins. Unlike chemotherapeutics that cause cell death through DNA interaction, immunotoxins mediate cell death by preventing protein synthesis. However, immunotoxins use a linker to connect the toxin to the antibody that may need to be examined if it is an organic linker and has the ability to bind DNA (per ICH S6). The majority of immunotoxins use either a nonreducible thioether linker for intact toxins or a disulfide bond for A chains and ribosome-inactivating proteins and do not interact with DNA. 

Balsevich et al. reported the activity and utility of ABA with a 3 -thioether linker arm [29], Sepharose-linked ABA (8) showed specifically bound anti-ABA immunoglobulins, although the form with only a linker (9) was 10 times weaker than ABA in the inhibition of cress seed germination. A fluorescent ABA derivative (10) also showed 1/10 the inhibitory activity of ABA. 

Building on the many examples of thioether linker units, larger numbers of linker units have been reported that utilize the related reactivity profiles of selenium and tellurium compo-nents to achieve multifunctional cleavage. Such linkers tend to be straight-... 

Preparation of Sulfone Linkers. The common means for preparing sulfone linkers are (i) oxidation of the corresponding thioether linker, (ii) using resin-bound benzenesulfinate linker, and (iii) using resin-bound vinyl sulfone. 

Figure 4 Lissamine - gold nanoparticle composite system. Lissamine molecules with dipole moment are attached onto gold nanoparticles of radius r via a thioether linker. The distance between the chromophoric part and the nanoparticle surface is d = Inm.

Scheme 62 Replacement of thioether linkers by carbon-nucleophiles...

A variety of cleavage conditions have been reported for the release of amines from a solid support. Triazene linker 52 prepared from Merrifield resin in three steps was used for the solid-phase synthesis of aliphatic amines (Scheme 22) [61]. The triazenes were stable to basic conditions and the amino products were released in high yields upon treatment with mild acids. Alternatively, base labile linker 53 synthesized from a-bromo-p-toluic acid in two steps was used to anchor amino functions (Scheme 23) [62]. Cleavage was accomplished by oxidation of the thioether to the sulfone with m-chloroperbenzoic acid followed by 13-elimination with a 10% solution of NH4OH in 2,2,2-trifluoroethanol. A linker based on l-(4,4 -dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) primary amine protecting group was developed for attaching amino functions (Scheme 24) [65]. Linker 54 was stable to both acidic and basic conditions and the final products were cleaved from the resin by treatment with hydrazine or transamination with ra-propylamine. 

There is huge potential in the combination of biocatalysis and electrochemistry through reaction engineering as the linker. An example is a continuous electrochemical enzyme membrane reactor that showed a total turnover number of 260 000 for the enantioselective peroxidase catalyzed oxidation of a thioether into its sulfone by in situ cathodic generated hydrogen peroxide - much higher than achieved by conventional methods [52],... 

The development of sulfone linkers, the exploration of sulfone based chemical transformations and cleavage strategies are an important objective in soHd-phase organic synthesis. This kind of Hnker (Tab. 3.7) has been used with thioethers [108], sulfoxides [109], sulfones [110], sulfonic acids and their corresponding derivatives [111]. Because carbon-sulfur bonds can be cleaved under very mild conditions, some Hnkers have been based on this effect. They can be cleaved under reductive conditions ]112, 113], photolytic conditions [114, 115] or with strong bases [116]. Various safety catch Hnkers have been developed based on the fact that thiols can be oxidized to sulfoxides and sulfones [112, 113]. 

Figure 2.10. Schematic diagram of coupling of a thiolated antibody to a linker lipid (maleimide-PEG-phospholipid) which is part of a preformed liposome. The resulting thioether bond is meta-bolically stable. The strategy shown here was used to synthesize OX26-immunoliposomes [111].

The stereochemical outcome of such cycloadditions may be altered by substituents attached to the nitrile oxide-olefin linker. Hassner and co-workers (75,240,253-255) and Kurth and co-workers (256) examined the influence of a stereogenic center a to the dipole in the cycloaddition of alkene-tethered nitrile oxides that feature a sulfur or oxygen atom within the connecting chain (Table 6.13). As expected, the diastereofacial selectivity is increased in the presence of fragments with increasing steric demand. Cycloadditions of thioethers show lower... 

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