Towards Antitumor Active trans-Platinum Compounds

Abstract

Substitution of NH(3) by a range of amines in trans-[PtCl(2)(NH(3))(2)] produces compounds with cytotoxicity significantly improved over the parent transplatin and in many cases equivalent to that of cisplatin. This microreview summarizes the chemistry and biology of trans-platinum compounds containing principally planar amines and succinctly reviews the current status of anticancer relevance of the trans-platinum geometry. The nature of bifunctional DNA adducts (intrastrand, interstrand) is remarkably dependent on the nature of the amine. Further, the stability of monofunctional adducts allows for competitive production of DNA-protein crosslinks and overall the results suggest that the trans-platinum chemotype may offer significant potential for design of selective DNA-protein crosslinking agents. A subset of proteins known to bind to DNA modified by trans-platinum is that comprised of zinc fingers - model studies show the potential for formation of heteronuclear thiolate-bridged species as precedent for zinc displacement from the biomolecule.

Figure 1

Cytotoxic transplanar amine platinum compounds (TPAs)

Figure 2

Structures of selected trans-platinum compounds with carrier ligand other than planar amines

Scheme 1

Proposed scheme for hydrolytic activation of transplatin

Figure 3

Interstrand cross-link for cisplatin ⁸⁷³, (left) and transplatin (right) highlighting the markedly different DNA bending induced by platinum compounds.

Figure 4

Schematic representation of the modes of DNA interstrand cross-linking by transplatin (left), cisplatin (center), and trans-[PtCl₂(NH₃)(iquin)]. The latter is a representative example of the effect of a planar amine on DNA adduct structure. ,

Figure 5

Molecular model of the monofunctional DNA adduct of trans-[PtCl₂(NH₃)(tz)].

Figure 6

Postulated competition between DNA-DNA and DNA-protein crosslink formation in trans-Pt adducts