Phenanthriplatin, a monofunctional DNA-binding platinum anticancer drug candidate with unusual potency and cellular activity profile

Abstract

Monofunctional platinum(II) complexes of general formula cis-[Pt(NH 3 ) 2 (N-heterocycle)Cl]Cl bind DNA at a single site, inducing little distortion in the double helix. Despite this behavior, these compounds display significant antitumor properties, with a different spectrum of activity than that of classic bifunctional cross-linking agents like cisplatin. To discover the most potent monofunctional platinum(II) compounds, the N-heterocycle was systematically varied to generate a small library of new compounds, with guidance from the X-ray structure of RNA polymerase II (Pol II) stalled at a monofunctional pyriplatin-DNA adduct. In pyriplatin, the N-heterocycle is pyridine. The most effective complex evaluated was phenanthriplatin, cis-[Pt(NH 3 ) 2 (phenanthridine)Cl]NO 3 , which exhibits significantly greater activity than the Food and Drug Administration-approved drugs cisplatin and oxaliplatin. Studies of phenanthriplatin in the National Cancer Institute 60-cell tumor panel screen revealed a spectrum of activity distinct from that of these clinically validated anticancer agents. The cellular uptake of phenanthriplatin is substantially greater than that of cisplatin and pyriplatin because of the hydrophobicity of the phenanthridine ligand. Phenanthriplatin binds more effectively to 5′-deoxyguanosine monophosphate than to N-acetyl methionine, whereas pyriplatin reacts equally well with both reagents. This chemistry supports DNA as a viable cellular target for phenanthriplatin and suggests that it may avoid cytoplasmic platinum scavengers with sulfur-donor ligands that convey drug resistance. With the use of globally platinated Gaussia luciferase vectors, we determined that phenanthriplatin inhibits transcription in live mammalian cells as effectively as cisplatin, despite its inability to form DNA cross-links. (Fig. 1), are currently among the most effective chemotherapies in clinical use for the treatment of cancers (1). These Pt-based anticancer agents typically form bifunctional intra-and interstrand DNA cross-links through covalent bonds with purine nucleobases. These cross-links inhibit transcription and result in cell death (2, 3). Platinum-based drugs are limited by side effects and poor activity in certain types of cancer resulting from acquired or intrinsic resistance (1-3). These limitations evoke a need for new platinum-based chemotherapeutics with novel mechanisms of action.One approach that we have used to circumvent the shortcomings of classic bifunctional platinum-based drugs has been to revisit cationic, monofunctional platinum complexes previously demonstrated to display significant anticancer activity in animal tumor models (4). In contrast to monofunctional platinum(II) compounds, such as [Pt(dien)Cl] + (dien = diethylenetriamine) (5) and [Pt(NH 3 ) 3 Cl] + (6), which early work proved to be inactive, the compound pyriplatin [cis-diamminepyridinechloroplatinum(II)] (Fig. 1) and several of its analogs have significant antineoplastic activity. Moreover, the profile of cellular response to thes...

Third row transition metals for the treatment of cancer

“…The large, planar aromatic phenanthridine ligand might implicate intercalation as a DNAbinding mode for phenanthriplatin, but analysis of competition Scatchard plots obtained by probing the affinity of ethidium bromide for DNA in the presence of this novel monofunctional platinum compound confirmed that it interacts with DNA in a purely covalent manner [33]. The interaction of phenanthriplatin with DNA in Escherichia coli provided further evidence to support the hypothesis that DNA is the ultimate biological target of this anti-cancer agent (figure 4).…”

“…A structural analysis of RNA pol II stalled at a site-specific pyriplatin lesion suggested that, by increasing the steric bulk of the N-heterocyclic ligand, it might be possible to increase transcription inhibition and consequential cytotoxicity [32]. From a panel of different N-heterocyclic ligands, Am, a series of complexes having the formula cis-[Pt(NH 3 ) 2 Cl(Am)] + was prepared [33]. The compound for which Am is phenanthridine showed the most significant results and was termed phenanthriplatin (figure 1).…”

“…Unlike pyriplatin, the overall potency of phenanthriplatin is significantly greater than that of cisplatin. Phenanthriplatin DNA adducts are also able to inhibit RNA pol II [33]. A detailed study of the kinetics of RNA pol II transcription of site-specifically phenanthriplatin-platinated DNA probes revealed that CTP typically inserts in an error-free manner opposite to the platinated dG, and that further elongation is arrested [36].…”

Amide Coupling Reaction for the Synthesis of Bispyridine-based Ligands and Their Complexation to Platinum as Dinuclear Anticancer Agents

“…The limited doses that can be administered to patients also means that tumors can develop resistance 5 . As such, new drugs continue to be developed to improve the side effect profile and overcome acquired resistance, like phenanthriplatin 6 and phosphaplatin 7 .…”

The new ruthenium(II)-bipyridyl complex with O,O'-diethyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoate: Synthesis and characterization

“…As a consequence, complexes with other metal ions have become an area of intensive research. The cytotoxic potential of ruthenium complexes was found three decades ago and the utilisation of ruthenium offers several advantages over platinum-based chemotherapy [4,5]. Ruthenium has the ability to mimic iron in binding to biomolecules, which leads to lower toxic side effects and a different mode of action.…”