Activation of Trans Geometry in Bifunctional Mononuclear Platinum Complexes by a Piperidine Ligand

Abstract

A paradigm for the structure-pharmacological activity relationship of bifunctional platinum antitumor drugs is that the trans isomer of antitumor cisplatin (transplatin) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit cytotoxicity in tumor cells that is even better than that of the analogous cis isomers. We reported recently (Kasparkova, J., Marini, V., Najajreh, Y., Gibson, D., and Brabec, V. (2003) Biochemistry 42, 6321-6332) that the replacement of one ammine ligand by the heterocyclic ligand, such as piperidine, piperazine, or 4-picoline in the molecule of transplatin resulted in a radical enhancement of its cytotoxicity. We examined oligodeoxyribonucleotide duplexes bearing a site-specific cross-link of the transplatin analogue containing the piperidine ligand by biochemical methods. The results indicate that in contrast to transplatin, trans-(PtCl 2 (NH 3 )(piperidine)) forms stable 1,3-intrastrand cross-links in double-helical DNA that distort DNA and are not readily removed from DNA by nucleotide excision repair system. Hence, the intrastrand cross-links of trans-(PtCl 2 (NH 3 )(piperidine)) could persist for a sufficiently long time, potentiating its toxicity toward tumor cells. trans-(PtCl 2 (NH 3 )(piperidine)) also forms in DNA minor interstrand cross-links that are similar to those of transplatin so that these adducts appear less likely candidates for genotoxic lesion responsible for antitumor effects of trans-(PtCl 2 (NH 3 )(piperidine)). Hence, the role of structurally unique intrastrand cross-links in the antitumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic ligand may predominate.The more widespread clinical applicability of cis-diamminedichloroplatinum(II) (cisplatin) 1 (Fig. 1A) and its analogue cis-diamminecyclobutanedicarboxylatoplatinum(II) is limited to a relatively narrow range of tumors (1-3); some tumors have natural resistance to these platinum drugs, whereas others develop resistance after the initial treatment.Cisplatin also has limited solubility in aqueous solution and is administered intravenously. There are also significant problems in terms of inducing severe side effects (especially kidney damage and vomiting/nausea). The drawbacks coupled with cisplatin and cis-diamminecyclobutanedicarboxylatoplatinum(II) toxicity have been the impetus for the development of improved platinum drugs. The paradigm for structure-pharmacological activity relationship of platinum complexes is that the trans isomer of cisplatin (transplatin) (Fig. 1A) is clinically ineffective. To this end, however, several new complexes of the trans structure have been identified that exhibit an enhanced cytotoxicity in tumor cell lines, such that cytotoxicity is equivalent or even better than that of the analogous cis isomers and, indeed, cisplatin itself (for reviews, see Refs. 4 -6). Examples of such new antitumor transplatinum compounds are (i) analogues containing planar amine ligand of ...

Molecular Aspects of Antitumor Effects of a New Platinum(IV) Drug

“…Bulky, helix-distorting DNA adducts, such as those generated by various chemotherapeutics, including cisplatin, are removed from DNA by nucleotide excision repair (NER), which is an important component of the mechanism underlying biological effects of these agents. Efficient removal of CLs formed in DNA by platinum antitumor compounds has already been reported for various NER systems, including human and rodent excinucleases (Zehnulova et al, 2001;Kasparkova et al, 2003a). The result presented in Fig.…”

“…7A, lane 4, is consistent with these reports. The major excision fragment contains 28 nucleotides, and other primary excision fragments are 24-29 nucleotides (Reardon et al, 1999;Zehnulova et al, 2001;Kasparkova et al, 2003a). The 1,2-GG intrastrand CL of adamplatin(II) was also excised by both human and rodent excinucleases (shown for rodent excinuclease in Fig.…”

Interactions of DNA with a New Platinum(IV) Azide Dipyridine Complex Activated by UVA and Visible Light: Relationship to Toxicity in Tumor Cells

“…considerably changes the binding mode of the trans-Pt II species with DNA, the major pharmacological target of antitumor platinum complexes (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). These transplatin analogues exhibited promising toxic effects in various human tumor cell lines including those resistant to conventional cisplatin.…”

Palladium(II) and platinum(II) bis(thiosemicarbazone) complexes of the 2,6-diacetylpyridine series with high cytotoxic activity in cisplatin resistant A2780cisR tumor cells and reduced toxicity

“…These disadvantages have driven the development of improved 50 platinum-based anticancer drugs different from the traditional cisplatin 51 structure and which could probably have different DNA-binding modes 52 as well as exhibit different biological profiles [6][7][8][9][10].…”