Synthesis and cytotoxicity studies of novel cyclic peptide-2,6-dimethoxyhydroquinone-3-mercaptoacetic acid conjugates.
In an effort to investigate the use of small-ring-size cyclic peptides as carriers of new antitumor agents, we synthesized three cyclic tripeptide-cytotoxic agent conjugates. The cytotoxic agent conjugated to the epsilon-amino group of the lysyl residue of the cyclic peptides is 2,6-dimethoxyhydroquinone-3-mercaptoacetic acid (DMQ-MA), (Sheh et al., 1992). The cyclic peptides were synthesized by coupling protected amino acid residues in solution and the subsequent cyclization performed by the pentafluorophenyl ester method as described previously (Sheh et al., 1985, 1987, 1990). After deblocking the lysyl-Z group of the peptides, the conjugation was achieved by reaction with the pentafluorophenyl ester of DMQ-MA. The three cyclic peptides exhibited potent cytotoxicity against two solid tumor cell lines (KB and PC-9) under the synergistic activation of L-ascorbic acid. Electron spin resonance (ESR) studies of DMQ-MA and two conjugates showed that massive hydroxyl radicals were generated as a non-linear function of L-ascorbic acid concentration. These studies indicate that the hydroxyl radical is a possible mediator of cytotoxicity for these conjugates and that small-ring-size cyclic peptides are potentially useful carriers of cytotoxic agents.
Sheh
L
L
Department of Chemistry, Tunghai Christian University, Taichung, Taiwan, ROC.
Dai
H Y
HY
Kuan
Y H
YH
Li
C J
CJ
Chiang
C D
CD
Cheng
V
V
D002470:Cell Survival / Q000187:drug effects; D003603:Cytotoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004578:Electron Spin Resonance Spectroscopy; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000633:toxicity; D066298:In Vitro Techniques; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000633:toxicity; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003603:Cytotoxins; D006873:Hydroquinones; D010456:Peptides, Cyclic; C081862:2,6-dimethoxyhydroquinone-3-mercaptoacetic acid