Unnatural D-amino acids as building blocks of new peptidomimetics.

offers many advantages as newly designed drugs. The benefits include enhanced stability to proteolytic enzymes, better transport through cellular membranes, increased bio-availability, changing agonist to antagonists potency and higher affinity in ligand-receptors interactions. D-amino acids are used to design and obtain new peptidomimetics by their incorporation in place of the natural L-amino acids, either at a specific position, or throughout the whole peptide. D-phenylalanine is one of the preferred amino acids. Addition of hydrophobic phenyl ring results in better transport properties of peptidomimetics through cellular membranes and better enzymatic stability (1, 2). Up to now D-phenylanine and derivatives have been successfully used in design of new efficient peptidomimetics. 4-fluoro-D-phenylalanine derivative implicate in new agonist of melanocortin receptors (MCRs). A common structural feature present in all endogenous ligands (MSH, ACTH) of the melanocortin receptors (MCRs) is His-Phe-Arg-Trp sequence, which has been identified as the minimal peptide fragment necessary for activating the receptors. Further structural modifications toward α-MSH showed that inverting Phe to the D-configuration resulted in an analog with enhanced potency and enzymatic stability. Replacement of the phenyl ring of D-Phe side chain in one of His-DPhe-Arg-Trp analogue with 4-fluorophenyl group led to potent MCRs agonist with enhanced selectivity (3). Synthetic decapeptides, Cetrorelix and Abarelix belong to third-generation of modified gonadotropin releasing hormone (GnRH) antagonists and contain in their structures D-4-chlorophenylalanine. GnRH, a linear decapeptide synthesized by gonadotropic cells of hypothalamus, is a central mediator of the human reproductive axis. Cetrorelix and Abarelix reveal high antagonistic activity against naturally occurring GnRH and are used for treatment of sex hormone-dependent disorders (4, 5). Another important example of peptidomimetic with D-phenylalanine presence is Octreotide ñ a synthetic somatostatin analogue with similar but more prolonged pharmacological effects. Octreotide is used to treat acromegaly and also to reduce flushing episodes and watery diarrhoea caused by cancerous tumors (carcinoid syndrome) (6). Furthermore, D-amino acidñcontaining peptides are especially important as pharmaceuticals due to their strong antibacterial activity. Many of them (Bacitracin A, Fungisporin, Gramicidin S, Tyrocidine, Polymyxin,) contain D-phenylalanine (2). In the present work we report the application of hydantoinase method to obtain D-phenylalanine derivatives. Hydantoinase method consist of three steps: