Excursions in polynuclear platinum DNA binding

Abstract

Polynuclear platinum agents are a structurally unique class of anti-cancer drugs, distinct from the cisplatin family. To describe the chemistry and biology of this class, it was necessary to challenge the accepted paradigms for the structure–activity relationships; design new chemotypes and delineate the structures and consequences of their DNA binding modes. This article summarizes the structural changes induced in DNA by both covalent (bond-forming) and non-covalent (ligand recognition) adducts. Solution (Nuclear Magnetic Resonance), solid state (crystallography) and gas-phase (Electrospray Ionization Mass Spectrometry) techniques have all been used to describe the new DNA structures along with molecular biological techniques. The combined approaches allow molecular description of hitherto unobserved adducts such as long-range major-groove interstrand crosslinks; directional isomers on DNA and a third class of ligand–DNA binding, the phosphate clamp. The phosphate recognition is distinct from “classic” minor-groove recognition or intercalation.

Biological evaluation of dimethylpyridine–platinum complexes with potent antiproliferative activity

“…The dinuclear berenilplatinum complexes with amine ligands are cationic in nature and show excellent solubility in water. The adducts formed by these dinuclear platinum complexes are vastly different from the adducts formed by cisplatin 29 . It has been suggested that the distortions induced by these complexes are only weakly recognized by DNA repair proteins.…”

Platinum(II) Complexes in Cancer Therapy

“…36 41 Este complexo liga-se no sulco maior, podendo formar ligações cruzadas flexíveis, intra e interfitas de longo alcance, sendo esta última, a principal delas. 37 Por causa disso, a interação deste complexo causa leves distorções na molécula do DNA, que fazem com que estes adutos não sejam reconhecidos pelas proteínas HMG do sistema biológico.…”

Combining aspects of the platinum anticancer drugs picoplatin and BBR3464 to synthesize a new family of sterically hindered dinuclear complexes; their synthesis, binding kinetics and cytotoxicity

“…[Bis-{trans-diammineplatinum(II)}{μ-N,N′-(ethane-1,2-diyl)bis-(2-methylisonicotinamide)}] chloride dihydrate, complex (10) …”

“…1), which displayed excellent activity in cisplatin sensitive and resistant cancers in both in vitro and in vivo models. 10,17,18 Whilst cisplatin forms short range, rigid, intrastrand cross-links, BBR3464 forms flexible, long and short range, inter-and intrastrand cross-links upon binding, 19 as well as inducing B-to Z-and B-to A-type DNA conformational changes. 18,20 Preclinical trials revealed cytotoxicity at concentrations one thousand times lower than the concentration required by cisplatin; 18 however, in human Phase I trials, systemic toxicity was found to be so severe that the maximum tolerated dose was just 0.9-1.1 mg m −2 , compared to cisplatin with an administrable dose of 20-120 mg m −2 .…”

“…1,8,9 Since the approval of cisplatin in 1979, thousands of analogues have been examined in an effort to produce less toxic derivatives, drugs that can be administered orally, or drugs that are able to circumvent tumour resistance. 2,10,11 Whilst 23 platinum-based drugs have undergone clinical trials, only two (carboplatin and oxaliplatin) have gained worldwide marketing approval. 1,2 One drug currently in Phase II and III clinical trials is cis-amminedichlorido(2-methylpyridine)platinum(II), also known as ZD0473 or picoplatin (see Fig.…”