Tyrosine derivatives

Phenylalanine- and Tyrosine-Derived Alkaloids. Carbohydrate metaboHsm leads via a seven-carbon sugar, ie, a heptulose, derivative to shikimic acid [138-59-0] (57), C H qO, which leads in turn to prephenic acid [126-49-8] (58), (43). 

Criado, S. Escalada, J. P. Pajares, A. Garcia, N. A. (2008). Singlet molecular oxygen [02(lAg)]-mediated photodegradation of tyrosine derivatives in the presence of cationic and neutral micellar systems. Amino Acids, Vol. 35, No. 1, (June 2008), 201-208, ISSN 0939-4451... 

Several such polymers have by now been prepared and were found to possess a variety of interesting material properties. Tyrosine-derived poly(iminocarbonates) (see Sec. IV) would be a specific example. These polymers were synthesized by means of a polymerization reaction involving the two phenolic hydroxyl groups located on the side chains of a protected tyrosine dipeptide (12). 

FIGURE 6 Molecular structures of poIy(CTTE), poly(CTTH), and poly(CTTP), a homologous series of tyrosine-derived polymers used in a study of the effect of the C-terminus protecting group on the materials properties of the resulting polymers. Cbz" stands for the benzyloxycarbonyl group (47). 

FIGURE 7 Tyrosine-derived poly(iminocarbonates) used to evaluate the effect of various side chain configurations on the physicomechan-ical properties of the resulting polymers. 

In a related series of experiments, the amino group and/or the carboxylic acid group of tyrosine were replaced by hydrogen atoms. The corresponding tyrosine derivatives are 3-(4 -hydroxyphenyl)-propionic acid, commonly known as desaminotyrosine (Dat), and tyramine (Tym) (structures 3-5). 

The thermal properties of tyrosine-derived poly(iminocarbonates) were also investigated. Based on analysis by DSC and thermogravi-metric analysis, all poly(iminocarbonates) decompose between 140 and 220 C. The thermal decomposition is due to the inherent instability of the iminocarbonate bond above 150°C and is not related to the presence of tyrosine derivatives in the polymer backbone. The molecular structure of the monomer has no significant influence on the degradation temperature as indicated by the fact that poly(BPA.-iminocarbonate) also decomposed at about 170 C, while the structurally analogous poly(BPA-carbonate) is thermally stable up to 350 C. 

The mechanical properties of tyrosine-derived poly(iminocarbon-ates) were investigated using the procedures described in ASTM standard D882-83 (Table 2). Solvent-cast, thin polymer films were prepared, cut into the required shape, and tested in an Instron stress strain tester. Since the films were unoriented, noncrystalUne samples, the results are representative of the bulk properties of the polymers. In order to put these results into perspective, several commercial polymers were tested under identical conditions. In addition, some literature values were included in Table 2. 

Initially, the cytotoxicity against chick embryo fibroblasts of BPA, tyrosine, tyrosine dipeptide, and the dipeptide derivatives used in the synthesis of the polymers shown in Fig. 7 were evaluated in a comparative experiment (43). The surface of standard tissue culture wells was coated with 5 mg of each test substance. Then the adhesion and proliferation of the fibroblasts was followed over a 7-day period. Among all test substances, BPA was clearly the most cytotoxic material. Monomeric tyrosine derivatives containing the ben-zyloxycarbonyl group were also cytotoxic, while tyrosine itself, tyrosine dipeptide, and most of the protected dipeptide derivatives did not noticeably interfere with cell growth and adhesion and were therefore classified on a preliminary basis as possibly "nontoxic."... 

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. ... 

In order to test the tissue compatibility of tyrosine-derived poly-(iminocarbonates), solvent cast films of poIy(CTTH) were subcutaneously implanted into the back of outbread mice. In this study, conventional poly(L-tyrosine) served as a control (42). With only small variations, the experimental protocol described for the biocompatibility testing of poly(N-palmitoylhydroxyproline ester) (Sec. III. 

These results open the exciting possibility of using degradable, tyrosine-derived polymers as "custom-designed" antigen delivery devices. On the other hand, our results indicate that the immunological properties of tyrosine-derived polymers will have to be carefully evaluated before such polymers can be considered for use as drug delivery systems or medical implants. 

Furthermore, our results on the characterization of the physico-mechanical properties of tyrosine-derived poly(iminocarbonates) provide preliminary evidence for the soundness of the underlying experimental rationale The incorporation of tyrosine into the backbone of poly(iminocarbonates) did indeed result in the formation of mechanically strong yet apparently tissue-compatible polymers. 

Figure 42-2. Chemical diversity of hormones. A. Cholesterol derivatives. B. Tyrosine derivatives. C. Peptides of various sizes D. Glycoproteins (TSH, FSH, LH) with common a subunits and unique P subunits.

Eumelanins — These melanins are considered polymers derived from tyrosine derivatives, mainly 5,6-dihydroxyindole-2-carboxylic acid (DHCIA) and dihidrox-yindole (DHl), with high degrees of cross-linking. In vivo eumelanins are associated with proteins and with metals, most frequently copper, zinc, or iron. 

The oxidative polymerization of 5,6-dihydroxyindole (1) and related tyrosine-derived metabolites is a central, most elusive process in the biosynthesis of eumelanins, which are the characteristic pigments responsible for the dark color of human skin, hair, and eyes. Despite the intense experimental research for more than a century,36 the eumelanin structure remains uncharacterized because of the lack of defined physicochemical properties and the low solubility, which often prevents successful investigations by modem spectroscopic techniques. The starting step of the oxidative process is a one-electron oxidation of 5,6-dihydroxyindole generating the semiquinone 1-SQ (Scheme 2.7). 

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

Synthesis of Tyrosine Derivatives. Tyrosine derived monomers were prepared by DCC mediated coupling reactions in THF following standard procedures of peptide chemistry (72). Dat-Tym, Z-Tyr-Tym, Z-Tyr-Tyr-Hex, and Dat-Tyr-Hex (DTH) were purified and characterized according to reference 10. For spectral data of Z-Tyr-Tyr-Hex, see Kohn and Langer (75). 

In order to identify tyrosine derivatives that would lead to polymers that are processible, mechanically strong, and also biocompatible, we initiated a detailed investigation of the structure-property relationships in polyiminocarbonates and polycarbonates. Since the amino and carboxylic acid groups of tyrosine dipeptide (the N and C termini) provide convenient attachment points, selected pendent chains can be used to modify the overall properties of the polymers. This is an important structural feature of tyrosine dipcptide derived polymers. 

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).

Solvent-cast films of tyrosine-derived polyiminocarbonates and polycarbonates were virtually indistinguishable in appearance and exhibited similar morphological features. When examined by X-ray diffraction, using an automated Scintag Pad V diffractometer all tested films were found to be completely amorphous. The lack of ordered domains in solvent-cast films seemed to be a general feature of tyrosine-derived polyiminocarbonates and polycarbonates, irrespective of the pendent chain configuration of the monomeric dipeptide. 

Initial tests in the rat revealed a high degree of tissue compatibility of Dat-Tyr-Hex derived polymers. More detailed tests are now in progress. In addition, tyrosine derived polymers are currently being evaluated in the formulation of an intracranial controlled release device for the release of dopamine, in the design of an intraarterial stent (to prevent the restenosis of coronary arteries after balloon angioplasty), and in the development of orthopedic implants. The use of tyrosine derived polymers in these applications will provide additional data on the biocompatibility of these polymers. 

The author acknowledges the assistance of Mr. Israel Engelberg, who performed some of the mechanical tests. The X-ray diffraction data were collected in the laboratory of Professor M. Greenblatt (Department of Chemistry, Rutgers University) by Ms. Aruna Nathan. The author thanks Mr. Chun Li and Mr. Satish Pulapura for their part in the synthesis and characterization of tyrosine derived polymers. 

Pulapura, S. and Kohn, J. Tyrosine Derived Polycarbonates New Polymers for Medical Applications, manuscript in preparation. 

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