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.

Structures of cisplatin, carboplatin, oxaliplatin, and pyriplatin. The bifunctional platinum complexes (cisplatin, carboplatin, and oxaliplatin) are clinically approved anticancer drugs in the United States. Pyriplatin is an exploratory lead compound for a class of monofuntional, platinum-based anticancer drug candidates.

Fig. 2.

Structures of monofunctional platinum(II) complexes and N-heterocyclic ligands (Am) described in this study. These nine different N-heterocyclic ligands were selected to systematically modify the steric protection around the platinum center.

Fig. 3.

Comparison of the X-ray crystal structures of picoplatin, quinoplatin, and phenanthriplatin. The platinum-carbon distances shown reveal that these three complexes exhibit similar degrees of steric protection from incoming nucleophiles. Data for picoplatin are from reference .

Fig. 4.

Intracellular distribution of Pt in cancer cells treated with cisplatin, pyriplatin, or phenanthriplatin. Cells were treated with 5 μM platinum complex for 3 h. Platinum uptake is presented in units of pmol of Pt per 10⁶ cells.

Fig. 5.

Progress of reactions of (A) pyriplatin and phenanthriplatin with 16 equiv of 5′-dGMP at 37 °C or (B) 1 equiv of N-acetyl methionine (N-AcMet) at 37 °C, both in 10 mM PBS buffer (pH* = 7.4) monitored by ¹H NMR spectroscopy. pH* refers to a pH measurement uncorrected for the effect of deuterium on the electrode.