Chemistry and molecular biology of platinum anticancer drugs

Abstract

Important features of DNA structure and the reactions of platinum complexes with solvent and media components are reviewed. Within the context of this background information are presented details of the binding of the anticancer drugs cis-[Pt(NH3)2Cl2] (cis-DDP), [Pt(en)Cl2], and [Pt(NH3)2(CBDCA)] (carboplatin), as well as the chemotherapeutically inactive isomer trans-DPP, to DNA, After hydrolysis of the chloride ligands from cis-DDP, the {Pt(NH3)2}2+ moiety primarily forms a crosslink between adjacent guanosine nucleosides on the same strand of the DNA double helix. The resulting adduct has been structurally characterized on single-stranded DNA in the solid state by X-ray diffraction and on single-stranded and duplex DNA in solution by NMR spectroscopy. Platinum binds to the N7 atoms of the guanine rings, unstacks the bases, and switches the sugar pucker of the 5'-nucleotide from C2f-endo to C3f-endo. Molecular mechanics calculations of both single- and double-stranded DNA-platinum adducts have been carried out to model additional features of the structures. An intrastrand crosslink also forms between adjacent adenosine and guanosine nucleosides in DNA treated with cis-DDP. Studies with monoclonal antibodies demonstrate that cis-[Pt(NH3)2{d(pGpG)} ] and cis-[Pt(NH3)2{d(pApG)} ] adducts on duplex DNA are structural analogs of one another, and that carboplatin forms the same adducts as cis-DDP. The regioselectivity of cis-DDP and [Pt(en)Cl2l binding to DNA is controlled by local sequences in which the principal d(pGpG) targets are embedded. This selectivity can be modified by addition of external intercalators, such as ethidium bromide, during the plat-ination reaction. Similar behavior occurs for AO-Pt, a novel molecule in which dichloroethylenediamineplatinum(II) is linked by a hexamethylene chain to acridine orange. The preferred binding sites of trans-DPP on single-stranded DNA have also been mapped. This isomer forms intrastrand crosslinks between two guanosines, or an adenosine and guanosine, having one or more intervening nucleotides. Structural studies by NMR spectroscopy have been carried out on trans-{Pt(NH3)2} adducts of d(GpTpG) (N7-G(1),N7-G(3)), d(GpCpG) (N7-G(1),N7-(G(3)), and [d(ApGpGpCpCpT)]2 (N7-A(l),N7-G(3)). Antinucleoside antibodies show clearly that trans-DPP adducts are more disruptive of the PNA double helix than those formed by cis-PPP since the intervening nucleotides in the former cannot form Watson-Crick base pairs with their complements on the unplatinated strand. A strategy for investigating the cytotoxicity, mutagenicity, and repair of intra- and interstrand crosslinks formed by cis-PPP, trans-DDP, and their analogs is presented. Specifically, construction of M13 DNA containing the cis-[Pt(NH3)2{d(pGpG)} ] adduct built into a unique, programmable site in the genome is described. Chemical and biological studies of such substrates should enable unambiguous information to be obtained about the viability and lethality of individual Pt-PNA adducts in vivo and, ultimately, lead to the design of better heavy metal anticancer drugs. © 1987, Walter de Gruyter. All rights reserved.