Diphenols, tyrosine-derived

After 7 days, the acute inflammatory response at the implantation site was evaluated. Bisphenol A resulted in a moderate level of irritation at the implantation site and was clearly the least biocompatible test substance. Tyrosine derivatives containing the benzyloxycar-bonyl group caused a slight inflammatory response, while all other tyrosine derivatives produced no abnormal tissue response at all. These observations indicate that tyrosine dipeptide derivatives, even if fully protected, are more biocompatible than BPA, a synthetic diphenol. ... 

New Diphenolic Monomers for the Design of Tyrosine-Derived Pseudopoly (amino acids)... 

In an attempt to identify more biocompatible diphenols for the design of degradable biomaterials, we studied derivatives of tyrosine dipeptide as potential monomers. After protection of the amino terminus and the carboxylic acid terminus, the reactivity of tyrosine dipeptide (Figure 1) could be expected to be similar to the reactivity of industrial diphenols. Thus, derivatives of tyrosine dipeptide could be suitable replacements for BPA in the synthesis of a variety of new polymers that had heretofore not been accessible as biomaterials due to the lack of diphenolic monomers with good biocompatibility. 

Figure 4. Three naturally occurring tyrosine derivatives (desaminotyrosine, tyrosine, and tyramine) were used to prepare four different monomeric diphenols that carry no pendent chains (Dat-Tym), only a benzyloxycarbonyl (Z) group, only a hexyl ester group, or both types of pendent chains (Z-Tyr-Tyr-Hex).

Resin bound carbodiimides are used in the formation of diphenol monomers used in the synthesis of tyrosine derived pseudo polypeptides. ... 

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.

Hooper, K.A. and Kohn,J. (1995) Diphenolic monomers derived from the natural amino acid a-L-tyrosine Large scale synthesis of desaminotyTOS l-t) rosine alkyl esters./. Bioact. Compat. Polym., 10(4), 327-340. 

Kohn, J. (1991a) Desaminotyrosyl-tyrosinc alkyl esters New diphenolic monomers for the design of tyrosine-derived pseudopoly (amino acids). Polymeric Drugs and Drug Delivery Systems. Washington DC,... 

In an attempt to identify new, biocompatible diphenols for the synthesis of polyiminocarbonates and polycarbonates, we considered derivatives of tyrosine dipeptide as potential monomers. Our experimental rationale was based on the assumption that a diphenol derived from natural amino acids may be less toxic than many of the industrial diphenols. After protection of the amino and carboxylic acid groups, we expected the dipeptide to be chemically equivalent to conventional diphenols. In preliminary studies (14) this hypothesis was confirmed by the successful preparation of poly(Z-Tyr-Tyr-Et iminocarbonate) from the protected tyrosine dipeptide Z-Tyr-Tyr-Et (Figure 3). Unfortunately, poly (Z-Tyr-Tyr-Et iminocarbonate) was an insoluble, nonprocessible material for which no practical applications could be identified. This result illustrated the difficulty of balancing the requirement for biocompatibility with the need to obtain a material with suitable "engineering" properties. 

Monophenols are more slowly acting substrates as they have to be hydroxylated prior to then-oxidation to the corresponding o-quinones [7]. The commonest natural substrates for monophenol oxidase are probably tyrosine and p-coumaric acid or their derivatives. AU o-diphenol oxidases require the basic o-dihydroxyphenol structure for oxidase activity so that catechol is the simplest possible, but not necessarily the best, substrate 4-methyl catechol is usually the fastest [45]. The rate of oxidation of o-diphenols by PPO increases with increasing electron withdrawing power of substituents in the para position. o-Diphenol substitution (-CH3) at one of the positions adjacent to the -OH groups prevents oxidation. These positions should remain free for oxidation to take place [14]. 

The unique property of this enzyme is that the product of the first monoxygenation step, o-diphenol, serves as the electron donor for the reduction of the cupric ions with formation of the corresponding o-quinone 161, 274). The products formed by catecholase activity from tyrosine are extremely reactive and undergo intermolecular reactions to form indole derivatives which subsequently polymerize to melanin. 

Tyrosine is the only major, natural nutrient containing an aromatic hydroxyl group. Derivatives of tyrosine dipeptide can be regarded as diphenols and may be employed as replacements for the industrially used diphenols such as Bisphenol A in the design of medical implant materials (Kigime 1). The observation that aromatic backbone structures can significantly increase the stiffness and mechanical strength of polymers prowded the rationale for the use of tyrosine dipeptides as monomers. 

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