Azide group toxicity

The [3+2] cycloaddition reaction of azides with terminal olefins is of considerable interest in the modification of biomolecules, because the azide group is abiotic in animals. Especially, the Cu(i) catalyzed cycloaddition reaction of azides with terminal alkynes achieves regioselective formation of 1,4-disubstituted 1,2,3-triazoles and this reaction is currently referred to as click chemistry . In the thermal reaction of azides with terminal alkynes, about 1 1 mixtures of 1,4- and 1,5-disubstituted 1,2,3-triazoles are obtained. Likewise, disubstituted alkynes afford mixtures of the stereoisomers. In order to avoid the cellular toxicity caused by the copper catalyst, Cu-free click chemistry is of considerable interest. The use of strained cyclooctyne derivatives as dipolarophiles was proposed recently. In this manner a novel 6,7-dimethoxyazacyclooct-4-yne was constructed from a glucose analogue s. The disadvantage of this reaction is its significantly slower reaction rate but introduction of fluoro groups adjacent to the triple bond achieves some rate enhancement. ... 

The Schering group also screened twenty-one organic azides for oral hypotensive activity in unanaesthetized rabbits and selected six for further evaluation based on favourable activity compared with sodium azide [330]. All of the organic azides were less toxic than sodium azide, which exhibited toxicity at all hypotensive doses, and the most effective and prolonged reduction in blood pressure was observed with the nicotinoyl and isonicotinoyl azide derivatives (256)-(258). The parent nicotinic and... 

Interestingly, dimer 13 has increased cytotoxicity compared to 4 and 6-11, with an ED5o in the 0.2-0.4 pg/ml range against the same tumour cell lines. Presumably, this increase is a nonspecific effect caused by the presence of the toxic azide functional group. 

Copper-catalyzed azide-alkyne cycloaddition (CuAAC) is one of the most powerful click reactions. The only disadvantage is that the copper is toxic to certain cells [90]. Despite efforts to make the copper complexes more biocompatible [91, 92], the breakthrough was achieved by the Bertozzi group [93] through harnessing the ring strain present in cyclooctyne to accelerate the reaction. A variety of cyclooctynes and one cycloheptyne have subsequently been reported [94, 95]. 

Click chemistry is commonly used in organic synthesis due to its high yield and its rapid kinetic. Although Cu-catalyzed allqme-azide cycload-dition, also called CuAAC, is the most utilized one, " " the intrinsic toxicity of the copper catalyst and its associated removal difficulties limit its application in biology. For instance, to improve dendrimer s water solubility, PEG groups are often incorporated via this method but a recent study conducted by Week and coworkers has observed substantial copper contamination in them. Copper-free strain promoted allq ne-azide cycloaddition (SPAAC) has been more and more employed to avoid this drawback.Nevertheless this last method introduces rigid cyclooctatriazole units that can modify the dendrimer scaffold and thus its properties. 

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