Ci A

n ci /ram-[PtCl2(NH3)(piperidine)] /ram--[PtCl2(NH3)(piperazine)]

h3c ch3o ch3 Irans-EE

/ra«.s-fPtCl2(dimethylamine)(isopropyIamine)]

Figure 25.3 Transplatin and its anti-tumor analogues large portion of adducts remains monofunctional. Intrastrand cross-links between non-adjacent guanine residues or between guanine and either adenine or cytosine residues have also been reported. However, while these adducts are stable in single-stranded DNA, they isomerize in double-helical DNA in a number of sequences into interstrand cross-links.33 It has been also suggested33 that in cells transplatin forms only a small amount of cross-links because of the slow closure of the monofunctional adducts coupled to their trapping by intra-cellular sulfur nucleophiles. Importantly, the adducts of transplatin also affect DNA conformation although less severely than the cross-links of cisplatin.

The clinical inactivity of transplatin is considered a paradigm for the classical structure-activity relationships of platinum drugs,31 but, to this end, several new analogues of transplatin which exhibit a different spectrum of cytostatic activity including activity in tumor cells resistant to cisplatin have been identified. Examples are analogues containing iminoether groups of general formula trans-[PtCl2(E-iminoether)2] (imino ether = HN = C(OCH3)CH3) or analogues containing heterocyclic amine ligand of general structure trans-[PtCl2(NH3)(L)], where L = planar amine such as quinoline or thiazole or non-planar amine such as piperidine or piperazine (Figure 25.3).

The replacement of both NH3 groups in transplatin by an iminoether ligand results in a marked enhancement of its cytotoxicity so that it is more cytotoxic than its cis congener and exhibits significant anti-tumor activity including activity in cisplatin-resistant tumor cells.34 The new trans- compound (trans-[PtCl2(E-iminoether)2]) forms mainly stable monofunctional adducts at guanine residues when reacted with DNA.35 These adducts locally distort DNA, are not recognized by HMG-domain proteins and are readily removed from DNA by the NER system. Importantly, the monofunctional adducts of trans-[PtCl2(E-iminoether)2] readily cross-link proteins, which markedly enhances the efficiency of this adduct to terminate DNA polymerization by DNA poly-merases in vitro and to inhibit removal of this adduct from DNA by the NER system.36 Hence, DNA-protein ternary cross-links produced by trans-[PtCl2(E-iminoether)2] can persist considerably longer than the non-cross-linked monofunctional adducts, which potentiates toxicity of this anti-tumor platinum compound toward tumor cells sensitive to this drug. Thus, trans-[PtCl2(E-iminoether)2] represents a quite new class of platinum anti-tumor drugs in which activation of the trans geometry is associated with an increased efficiency to form DNA-protein ternary cross-links thereby acting by a different mechanism than 'classical' cisplatin and its analogues.

The molecular mechanism of the anti-tumor activity of trans-platinum compounds containing heterocyclic ligands has also been extensively investigated.37 Here, we will discuss two distinct series of this class of agents having the general structure trans-[PtCl2NH3(L)]: (i) L = planar ligand, such as quinoline or thiazole; (ii) L = non-planar ligand, such as piperidine or piperazine. There are two major chemical differences between NH3 and a heterocyclic ligand. Steric hindrance by the appropriately positioned H atoms of the ring system reduces chemical reactivity, and surface and stacking interactions become more pronounced over the hydrogen bonding associated with NH3 groups. Importantly, this class of new trans- compounds forms considerably more interstrand cross-links and, even more importantly, they also form 1,3-GXG intrastrand cross-links which are stable in double-helical DNA.

An interesting feature of DNA modification by trans-[PtCl2(NH3)(thiazole)] is that its monofunctional adduct creates a local conformational distortion, which is very similar to that produced in DNA by major 1,2-GG intrastrand cross-link of anti-tumor cisplatin.38 In addition, these monofunctional adducts are recognized by HMG-domain proteins with an affinity similar to the 1,2-GG intrastrand cross-link of cisplatin. The effective removal of the monofunctional adducts of trans-[PtCl2(NH3)(thiazole)] from DNA by NER has also been observed, but it is inhibited if the NER system is supplemented by HMG-domain proteins. Additional work39 has shown that trans-[PtCl2(NH3)(quino-line)] and trans-[PtCl2(NH3)(thiazole)] preferentially form DNA interstrand cross-links between guanine residues at the 50-GC/50-GC sites. It implies that these cross-links are formally equivalent to those formed by anti-tumor cisplatin, but different from those formed by clinically ineffective transplatin (which preferentially forms these adducts between complementary guanine and cytosine residues32). These results have shown for the first time that a simple chemical modification of the structure of an inactive platinum compound alters its DNA-binding mode into that of an active drug and that the processing of the monofunctional DNA adducts of these trans-platinum analogues in tumor cells may be similar to that of the major bifunctional adducts of conventional cisplatin.

The anti-tumor analogues of transplatin-containing non-planar heterocyclic ligands, such as piperidine or piperazine, form 1,3-GXG intrastrand cross-links which are considerably more stable in double-helical DNA than the same adducts of the parent transplatin, distort the DNA conformation and are not readily removed from DNA by the NER system.40,41 Hence, the intrastrand cross-links of these analogues can also persist for sufficient time to potentiate toxicity toward tumor cells. These analogues also form DNA interstrand crosslinks which are similar to those of ineffective transplatin. So, these adducts appear less likely candidates for genotoxic lesions responsible for anti-tumor effects of the analogues containing non-planar heterocyclic ligands. Hence, the role of structurally unique intrastrand cross-links in the anti-tumor effects of transplatin analogues in which one ammine group is replaced by a heterocyclic non-planar ligand may predominate.

Recently, the DNA-binding modes of new cytotoxic trans-platinum compounds containing different aliphatic amines (e.g. trans-[PtCl2(dimethylamine) (isopropylamine)]) have been evaluated in cell-free media.42 The complex trans-[PtCl2(dimethylamine)(isopropylamine)] readily forms DNA interstrand crosslinks. The amount of these cross-links is considerably higher than the amount of the lesions formed under the same conditions by transplatin or cisplatin. In addition, the complex exhibits a preferential binding affinity to alternating purine-pyrimidine sequences in DNA, forms the adduct that inhibits the B-Z transition in DNA and blocks DNA synthesis in vitro more efficiently than the adducts of cisplatin. These particular DNA-binding properties have been proposed to be related to the efficiency of trans-[PtCl2(dimethylamine)(isopropy-lamine)] in inducing apoptosis and some selective killing in a H-ras over-expressing cell line.43

Polynuclear platinum compounds comprise a unique class of anti-cancer platinum agents with distinct chemical and biological properties different from mononuclear platinum drugs.44 The lead compound [{trans-PtCl(NH3)2}2m-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (BBR3464, Figure 25.4) is a trinuclear,

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