Synthesis and characterization of complexes of p-isopropyl benzaldehyde and methyl 2-pyridyl ketone thiosemicarbazones with Zn(II) and Cd(II) metallic centers. Cytotoxic activity and induction of apoptosis in Pam-ras cells

摘要

It is known that metallic complexes of methyl 2-pyridyl ketone thiosemicarbazone (HL~1) and p-isopropyl benzaldehyde thiosemicarbazone (HL~2) may have potential antitumor activity. We have prepared complexes of HL~1 and HL~2 with Zn(II) and Cd(II). The cytotoxic activity shown by these compounds against cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-DDP) indicates that coupling of HL~1 and HL~2 to Zn(II) and Cd(II) centers may result in metallic complexes with important biological properties since they display IC_(50) values in a #mu#M range similar to that of the antitumor drug cis-DDP. Moreover, it is interesting to note that the Zn/HL~2 complex exhibits specific cytotoxic activity against Pam-ras cells (cis-DDP resistant cells which overexpress the H-ras oncogene) with an in vitro therapeutic index of 3.26 versus 0.78 for cis-DDP. Treatment of Pam-ras cells with the IC_(50) value of the Zn/HL~2 compound induces a 'DNA ladder' (fragmentation of genomic DNA in nucleosome units) indicative of apoptosis in this ras-transformed cell line. In contrast, a 'DNA smear' (non-specific fragmentation of genomic DNA) is observed in Pam 212 normal cells treated with the IC_(50) of this compound. The analysis by circular dichroism (CD) spectroscopy of the interaction of the Zn/HL~2 compound with calf thymus DNA (CT DNA) indicates that it produces stronger alterations on the double helix conformation than cis-DDP. So, these results suggest that Zn/HL~2 may be considered a potential antiumor agent.