Chemoselective conjugation

Figure 17.8 Heterobifunctional crosslinking agents containing the PBA or salicylhydroxamate group for chemoselective conjugation purposes.

Positional control of conjugation is essential at two levels in the assembly of nanobiological devices [6-8], Recently developed chemoselective conjugation... 

Small molecules or peptides are then chemoselectively conjugated to the ketone-modified macromolecular scaffold via the amino-oxy functional group to form an oxime bond (see Fig. 5). 

The most common chemoselective conjugation is achieved through thiol coupling to free cysteine (C) groups via maelimide chemistry. In proteins, cysteine residues make up only 1.7% of amino acids, and because they tend to... 

Smith, A.B. Jill, Savinov, S.N., Manjappara, U.V. and Chaiken, I.M. (2002) Peptide-small molecule hybrids via orthogonal deprotection-chemoselective conjugation to cysteine-anchored scaffolds. A model study. Organic Letters, 4, 4041—4044. 

The next series of syntheses is based on conjugate additions. A 2-arylcyclo-hexanone was regio- and stereoselectively added to nitroethylene to access the octahydroindole core present in the alkaloids. This has enabled the total synthesis of (+j-y-lycorane and (+)-crinane (280). Tomioka described a chemoselective conjugate addition - nitro Michael reaction sequence to prepare a- and -lycoranes in their racemic form (281). The addition of an arylcuprate to a D-mannitol-derived... 

Chemoselective conjugation of unprotected peptides in aqueous systems by oxime formation was suggested (Poethko et al. 2004 Schottelius et al. 2004 Thumshirn et al. 2003) as a very effective, time-saving, high yield F-labeling method, which is also adaptable to radiohalo-... 

Carbohydration and polyethylene glycol linkers were combined with chemoselective conjugation to optimize the pharmacokinetics of the peptides investigated. Oxime formation was successfully adopted for chemoselective F-labeling of an aminooxy-modified affibody (Namavari et al. 2008) and a suitable derivative of the hormone leptin (Flavell et al. 2008). Recently, the [ F]FBA synthesis was automated and yielded [ F]FBA after 45 min in radiochemical yields of 54% and radiochemical purity of >99% after automated cartridge purification (Speranza et al. 2009). 

Small F-thiols such as the aliphatic [ F]fiuropropane-l-thiol, a PEG3-derivative ([ F]fluoro-PEG3-thiol) and an aromatic system, 4-[ F]Fluoromethyl-N-(2-mercaptoethyl) benzamide, are also useful prosthetic groups, which allow an efficient chemoselective conjugation to N-chloroacetylated peptides (Glaser et al. 2004). 

Fig. 1. Schematic of the method for monitoring myristoylated and palmitoylated cellular proteins, (a) co-Alkynyl fatty acid probes for detecting protein myristoyiation and paimitoyiation. (b) (o-Alkynyl fatty acids added to growth media are metabolically incorporated into cellular fatty-acylated proteins. The cells are then lysed, Click chemistry is used to chemoselectively conjugate a biotin-azide or rhodamine-azide to fatty-acylated proteins, and the proteome is detected by western blotting or in-gel fluorescence. Alk-CI 3 and Alk-Cf4 are probes for detecting protein myristoyiation, while Alk-CI6 and Alk-CfS detect protein paimitoyiation.

The methodology described by Zhang et al. [148] offers an efficient and chemoselective conjugation method for liposome surface functionalization. The reaction benefits from being performed under mild conditions without the need of a catalyst. Furthermore, methods to engineer bacteria and yeast enabling them to incorporate azido functionalities into proteins have been developed [53]. This enables direct attachment to the triphosphine-functionalized liposome without prior derivatization of the protein. 

Heredia, K.L., Tolstyka, Z.P., andMaynard, H.D. (2007) Aminooxy end-functionalized polymers synthesized by ATRP for chemoselective conjugation to proteins. Macromolecules, 40,4772. 

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