SYNTHESIS DNA CLEAVAGE AND CYTOTOXICITY OF SOME NOVEL CYCLIC PEPTIDE-2,6-DIMETHOXYHYDROQUINONE-3-MERCAPTOACETIC ACID CONJUGATES CONTAINING D-AMINO ACIDS

This paper reports an ongoing study of the use of small-ring-size cycl ic peptides as carriers of a potential antitumor agent: 2,6-dimethoxyh ydroquinone-3-mercaptoacetic acid (DMQ-MA). Three new cyclic tripeptid e-DMQ-MA conjugates-cyclo[D-Val-Lys(DMQ-MA)- gamma-aminobutyric acid ( GABA)-], cyclo[Val-Lys(DMQ-MA)-GABA-] and cycle [D-Val-D-Lys(DMQ-MA)-G ABA-] and cyclo[D-Val-D-Lys(DMQ-MA)-GABA-]-were synthesized. The isome ric cyclic tripeptide-DMQ-MA conjugates were designed and synthesized to study the effect of stereoisomerism of the conjugates on cytotoxici ty. The cyclic peptides were synthesized by coupling protected amino a cids in solution and the final cyclization performed by the pentafluor ophenyl ester method as described previously. After removing the lysyl -Z protecting group of the cyclic peptides the conjugation was achieve d by reacting with the pentafluorophenyl ester of DMQ-MA. Electron spi n resonance (ESR) studies of these three cyclic tripeptide-DMQ-MA conj ugates showed that hydroxyl radicals were generated as a non-linear fu nction of L-ascorbic acid (AH(2)) concentration. The IC50 of the cycli c tripeptide-DMQ-MA conjugates against a human pulmonary carcinoma cel l line (PC-9 cells) under the synergistic activation of AH(2) ranges f rom 0.4 to 1.6 mu M, which is significantly lower than the parent comp ound DMQ-MA (6.1 mu M). Agarose gel electrophoresis showed that DMQ-MA and these cyclic peptide-DMQ-MA conjugates are capable of cleaving su percoiled plasmid DNA to open circular and linear forms, even in the a bsence of AH(2). The effects of enantiomeric and diastereomeric variat ions of these cyclic tripeptide-DMQ-MA conjugates on the cytotoxicity against PC-9 cells were discussed.