This paper reports an ongoing study of the use of small-ring-size
cyclic peptides as carriers of a potential
antitumor agent:
2,6-dimethoxyhydroquinone-3-mercaptoacetic acid (
DMQ-MA). Three new cyclic tripeptide-
DMQ-MA conjugates--cyclo[D-
Val-Lys(
DMQ-MA)-
gamma-aminobutyric acid (
GABA)-], cyclo[
Val-Lys(
DMQ-MA)-
GABA-] and cyclo[D-Val-D-Lys(
DMQ-MA)-
GABA-]--were synthesized. The isomeric cyclic tripeptide-
DMQ-MA conjugates were designed and synthesized to study the effect of stereoisomerism of the conjugates on cytotoxicity. The
cyclic peptides were synthesized by coupling protected
amino acids in
solution and the final cyclization performed by the pentafluorophenyl
ester method as described previously. After removing the lysyl-Z protecting group of the
cyclic peptides the conjugation was achieved by reacting with the pentafluorophenyl
ester of
DMQ-MA. Electron spin resonance (ESR) studies of these three cyclic tripeptide-
DMQ-MA conjugates showed that
hydroxyl radicals were generated as a non-linear function of
L-ascorbic acid (AH2) concentration. The IC50 of the cyclic tripeptide-
DMQ-MA conjugates against a human pulmonary
carcinoma cell line (PC-9 cells) under the synergistic activation of AH2 ranges from 0.4 to 1.6 microM, which is significantly lower than the parent compound
DMQ-MA (6.1 microM).
Agarose gel electrophoresis showed that
DMQ-MA and these
cyclic peptide-
DMQ-MA conjugates are capable of cleaving supercoiled plasmid
DNA to open circular and linear forms, even in the absence of AH2. The effects of enantiomeric and diastereomeric variations of these cyclic tripeptide-
DMQ-MA conjugates on the cytotoxicity against PC-9 cells were discussed.