Synthesis of novel potential antitumor agents: 2,6-dimethoxyhydroquinone-3-mercapto-acetyl peptide conjugates

This paper reports on an ongoing study of the use of short chain peptides as carriers of a potential anti-tumor agent: 2,6-dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA). In an effort to carry out anti-cancer drug design, we synthesized three new peptide-DMQ-MA conjugates: DMQ-MA-Arg-Arg-Ome, DMQ-MA-Lys(Cbz)-Arg-Ome, DMQ-MA-Lys(Cbz)-Arg-Arg-Ome; two new DMQ-MA-peptide-Chlorambucil (CRB) derivatives: DMQ-MA-Lys(CRB)-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Lys(CRB)-Arg-Ome and four tripeptide-cytotoxic agent conjugates: DMQ-MA-Lys(DMQ-MA)-Phe-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Ile-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Val-Arg-Ome, DMQ-MA-Lys(DMQ-MA)-Lys(Cbz)-Arg-Ome. These conjugates were synthesized by coupling protected amino acid residues according to Pfp/DCC methods (Pfp: Pentafluorophenol, DCC:N,N'-Dicyclohexyl-carbodiimide) in solution. After deblocking the Boc- group of the Lysine, the conjugation was achieved by reaction with the pentafluorophenyl ester of DMQ-MA in DMF. The CRB in the side chain was coupled by deblocking the lysylcarbobenzyloxy protecting group Cbz and then reacting with the pentafluorophenyl ester of Chlorambucil(CRB). Further studies on cytotoxicity and sequence specificity of DNA alkylation of these five new conjugates are being investigated.