Tyrosine alkylation

Poly(amino acids) are insoluble in common solvents, are difficult to fabricate due to high melting point, and absorb a significant amount of water when their acid content reaches over 50 mol%. To solve these problems, polyesters derived from amino acids and lactic acids [e.g., poly (lactic acid-co-lysine) PLAL] are developed. The PLAL system is further modified by reaction with lysine A-carboxyanhydride derivatives. Another modification of poly(amino acids) includes poly(iminocarbon-ates), which are derived from the polymerization of desaminotyrosyl tyrosine alkyl esters. These polymers are easily processable and can be used as support materials for cell growth due to a high tissue compatibility. Mechanical properties of tyrosine-derived poly(carbonates) are in between those of poly(orthoesters) and poly(lactic acid) or poly(gly-colic acid). The rate of degradation of poly(iminocarbonates) is similar to that of poly (lactic acid). 

Fig. 1.3 Stnicture of tyiosine-daived polycaibonates (DTR desaminotyrosyl tyrosine alkyl ester), where R can be ethyl, isopropyl, butyl, or hexyl groups...

Monomer synthesis from 3-(4 -hydroxyphenyl) propionic acid and tyrosine alkyl esters w as accomplished by carbodiimide mediated coupling reactions, following known procedures of peptide synthesis (Pulapura, 1992 Ertel, 1994) in typical yields of 70%. Monomers carrying an ethyl, butyl, hexyl, or octyl ester pendent chain were investigated extensively (Ertel, 1994 Hooper, 1995). These peptide-like diphenolic monomers were used as starting materials in the synthesis of polycarbonates, polyiminocarbonates, and polyarylates. 

Figure 2 Reaction scheme for the coupling of desaminotyrosine and tyrosine alkyl esters to obtain a diphenolic monomer which carries an alkyl ester pendent chain (Y). Four specific monomers having an ethyl, butyl, hex)4 and octyl ester pendent chain were investigated in detail. EDC = ethyl-3-(3 -dimethylamino)propyl carbodiimide hydrochloride salt (Hooper, 1995).

The diphenol components selected were the desaminotyrosyl-tyrosine alkyl esters described above. The diacids included succinic, adipic, suberic and sebacic acid which contain, respectively, 2, 4, 6, and 8 methylene groups between two carboxylic acid functionalities. With this family of pohoners it is possible to alter independently both the pendent chain lengths as well as the number of flexible methylene spacers in the backbone, creating a family of sixteen structural variants. Hence, these materials serve as a framework upon which to further investigate polymer structure-property relationships. 

Figure 4 Reaction scheme for ihe preparation of tyrosine-derived polyarylates. This reaction scheme is a copolymerization of a diphenol component and a diacid component. The diphenol components are the same desaminotyrosyl-tyrosine alkyl esters used in the synthesis of polycarbonates (Fiipire 3). The pendent chain Y is ethyl, butyl, hexyl, or octyl. The diatid components are succinic acid, adipic acid, suberic acid, and sebacic acid providing a flexible backbone spacer (R) having 2, 4, 6, and 8 methylene groups respectively. DIPC = diisopropylcarbodiimide.

Several desaminotyrosyl-tyrosine alkyl esters and the corresponding tvTosine-derived polycarbonates are available commercially through Sigma Chemical Company. Tyrosine-derived polycarbonates are currently in preclinical evaluations for possible use in orthopaedic implants. Clinical trials in humans have not yet been conducted. Tyrosine-derived poMminocarbonates and polyaiylates are not available commercially. 

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