Synthesis and DNA Cleavage Studies of 2,6-Dimethoxyhydroquinone-3-Mercaptoacetic Acid Conjugates

In an effort to investigate the use of short peptide chains as carriers of new anti-tumor agents, we synthesized 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. The cytotoxic agent conjugated to the N-terminal and the ξ-amino group of Lysine of the tripeptide is 2,6-dimethoxyhydroquinone-3- mercaptoacetic acid (DMQ-MA). The tripeptides were synthesized by coupling protected amino acid residues according to Pfp/DCC methods (Pfp: pentafluorophenol, DCC:N,N'-dicyclohexyl- carbodiimide) in solution. Agarose gel electrophoresis showed that these compounds can cleave supercoiled DNA into open-circular form in drug concentration as low as 4-50 μM without H2O2 and UV irradiation. Further studies on their cytotoxicity for these conjugates are ongoing.