Further Backbone Modifications

The a-carbon of the oligocarbamate backbone, like that of peptides, is substituted with side chains containing a variety of functional groups. A further backbone modification and conformational restriction can be incorporated via N-acylation followed by reduction of the N-acyl nitrogen, yielding N-alkyl-oligocarbamates (Scheme 7.4) [28]. 

However, all of these studies were performed using model components in vitro—none have examined formaldehyde-induced modifications in vivo. Further, while modification sites have been mapped by MS/MS, intact cross-linked peptide species have not been observed in such experiments.49 This possibly indicates that the covalent bonds of the formaldehyde cross-links are not as strong as those of the peptide backbone. The resulting fragment ion spectra are similar to that of the unmodified peptide with the exception of 12Da or 30Da additions at modifications sites. Thirty Dalton modifications correspond to the addition of formaldehyde while 12 Da modifications indicate water elimination. 

The replacement of amide bonds by retro-in-verso amide replacements (71, 72) and other amide bond isosteres generates pseudopeptides (11). This process was first used to stabilize peptide hormones in vivo and later to prepare transition state analog (TSA) inhibitors. Systematic efforts to convert good in vitro inhibitors into good in vivo inhibitors became the driving force for further development of peptidomimetics. Figure 15.17 illustrates some of the peptide backbone modifications that have been made in an effort to increase bioavailability. Replacement of scissile amide (CONH) bonds with groups insensitive to hydrolysis (e.g., CHaNH) has been extensively practiced. Reviews of this work have appeared (11,73). Removal of the proton donors and... 

For RNA, artificial self-cleaving hammerhead ribozymes with a triazole linkage at the active site are reported [26]. Interestingly, triazole backbone modifications in RNA by CuAAC and SPAAC chemical hgation of 3 -azide and 5 -cyclooctyne oligonucleotides can further be reverse transcribed into DNA while one nucleotide is omitted at the linkage [95]. 

One area where polymer modifications are highly developed is the modification of naturally occurring polymers such as cellulose. For example, the esterification, methylation, or nitration of cellulose gives products that have properties that are quite distinct from the parent material and can be used in a wide range of applications. One of the main challenges in the modification of cellulose is its recalcitrance toward solubilization generally needed for effective backbone modification. Reaction of the solid crystalline material with strong base and carbon disulfide can lead to a soluble material that can be further modified more readily. 

Major chitosan functionalization could be carried out by (1) substitution, introducing small functional groups to the chitosan backbone, and (2) depolymerization by chemical, physical or enzymatic treatments. Moreover, further chemical modifications of the functionalized chitosans can be performed in order to extend the range of their applications [47]. 

Biodegradable polymers and plastics are readily divided into three broad classifications (/) natural, (2) synthetic, and (J) modified natural. These classes may be further subdivided for ease of discussion, as follows (/) natural polymers (2) synthetic polymers may have carbon chain backbones or heteroatom chain backbones and (J) modified natural may be blends and grafts or involve chemical modifications, oxidation, esterification, etc. 

Hydroformylation of nitrile rubber is another chemical modification that can incorporate a reactive aldehyde group into the diene part and further open up new synthetic routes to the formation of novel nitrile elastomers with a saturated backbone containing carboxyl or hydroxyl functionalities. 

A product of this type will have over 50% of its weight derived from maleic anhydride. This very high content of reactive double bonds will lead to a very brittle solid when it is cross-linked with styrene. Without further modification, this solid material will have very high tensile moduli, probably over 600 kpsi, but a very low tensile elongation, way below 1 %. Such a brittle material obviously has only very limited applications. Thus, for most general-purpose applications, it is necessary to incorporate some chemically inert components to soften the polymer backbone. This will reduce the cross-linking density and improve the physical properties of the cured solid. 

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