Synthesis of polycyclic hydantoin derivitaves and peptides.

Abstract

Cyclic cage compounds have attracted much attention in pharmaceutical studies. The lipophilic nature of these compounds plays an important role in facilitating the crossing of the cellular membranes, including the blood brain barrier (BBB) and the central nervous system (CNS). Several adamantane and pentacyclo[5.4.0.02,6.03,10.05,9]undecane (PCU) derivatives have shown great potential as antiviral, antibacterial and neuroprotective compounds. The aim of this study includes the synthesis of hydantoin derivatives of adamantane and PCU as anticonvulsant compounds. Fosphentoin sodium (Cerebyx) 48 is a commercial anticonvulsant drug. Structurally, compound 51 and 52 are similar to Cerebyx 48, where the two phenyl groups have been replaced with PCU or adamantane skeleton respectively. The cage skeleton should increase the lipophilic character of the drug whilst the phosphate group should retain the water solubility of the substrate. The attempted synthesis of these compounds is described in Chapter 2. The PCU hydantoin is readily converted to the PCU amino acid. The synthesis of the PCU amino acid 41 and its Fmoc derivative 106 is described in Chapter 3. This compound was incorporated into small peptides, namely Ala-Ala-Ala-PCU-Ala-Ala-Ala-Fmoc and Ala-Val- PCU-Ile for future testing as a potential anti-cancer agent. NMR studies of these peptides are also reported.