Amino Acid Ester Side Groups

The first bioerodible polyphosphazenes synthesized possessed amino acid ester side groups (25). The structure and preparation of one example is shown in Scheme V. The ethyl glycinato derivative shown... 

Most poly(organophosphazenes) are stable to water. Only a selected few are not. These include polymers with amino acid ester side groups, and species with imidazolyl, glyceryl, or glucosyl side units. These will be discussed later. 

The main class of bioerodible polyphosphazenes that have been developed so far are polymers with amino acid ester side groups. They are prepared by the reaction of poly(dichlorophosphazene) with the ethyl or propyl esters of amino acids such as glycine, alanine, phenylalanine, and so on (reaction (57)).196 The ethyl or propyl ester of the amino acid must be used as the nucleophile in this reaction for two reasons. First, a free carboxylic acid unit would provide a second nucleophilic site that could lead to... 

Laurencin and coworkers213 have used a different approach to control the rate of bioerosion of polymers with amino acid ester side groups. They used hydrophobic 4-methylphenoxy cosubstituents ( 50%) to slow the rate of hydrolysis, and these polymers were employed to study the rate of release of inulin. Similar polymers are also being developed by the same investigators as tissue engineering substrates for bone regeneration.214"218... 

Amino acid ester side groups are not the only units that sensitize the system to hydrolysis. The imidazolyl group has an even greater effect.197-198-219 For example, polymer 3.86, prepared by the reaction of poly(dichlorophosphazene) with imidazole, is so unstable hydrolytically that it decomposes in moist air to imidazole, phosphate, and ammonia. This is too high a sensitivity for most biomedical applications. Hence, an emphasis has been placed on the study of polymers such as 3.87 in which a hydrophobic cosubstituent group, such as aryloxy, is present to reduce the rate of erosion. 

Table 3.2 Amino Acid Ester Side Groups That Have Been Linked to Polyphosphazenes to Generate Hydrolytic Instability and Bioerosion...

Another type of application can arise from the hydrolytic instability of certain poly(aminophosphazene)s such as those that contain amino acid ester side-groups (Fig. 3.55). 

Fig. 3.55. Polyphosphazenes containing amino acid ester side-groups...

For the hydrolytic degradation of polyphosphazenes several mechanisms have been proposed (Allcock et al, 1977-1994 Goedemoed et al., 1988). Ffowever, analysis of the degradation products revealed that the main hydrolysis pathway involves release of the amino acid ester side group, followed by hydrolysis of the ester with formation of the amino acid and the alcohol (Crommen et al, 1992) (Fiigpre 12). 

Polyphosphazenes have also been prepared using modified amino acid ester side-chain substituents (Table 7). Studies show that the polymer containing the smallest hydrophobic side-chain constituent, glycine ethyl ester, exhibited the most rapid degradation. This was attributed to the lower steric hindrance that the small side-chain group could provide in... 

Allcock also used different types of poly[(organo)phosphazenes] based on ethyl and benzyl esters of amino acids as side groups (Allcock et al., 1994). Small molecules like ethacrynic acid, a diuretic, and Biebrich Scarlet, an azo dye, w ere incorporated as model release components. 

Reaction with Phosgene. This reaction of amino acid esters is used for preparing the corresponding isocyanates, especially lysine diisocyanate [4460-02-0] (LDI). LDI is a valuable nonyellowing isocyanate with a functional side group for incorporation in polyurethanes. 

The steric bulk of steroid structures prevents their use as the only organic side group present. However, mixed-substituent polymers that contain both steroidal side groups and amino acid ester or other cosubstituent units can be readily synthesized. If a saturated A ring is present in the steroid, linkage to the polymer chain is complicated by side reactions that result from dehydration of the steroid (chlorophosphazenes are powerful dehydrating agents). 

The polymer-bound p-nitrobenzophenone oxime (71d) has been found to be a suitable support for stepwise peptide synthesis. Protected peptides can be assembled on 70d by coupling and deprotection steps similar to those employed in the usual Merrifield solid-phase procedures (Scheme 39). Cleavage of peptides from 71d can be accomplished with hydrazine and amino acid esters under mild conditions, which do not affect benzyl ester side-chain protecting groups. 

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