Monofunctional and higher-valent platinum anticancer agents

Abstract

Platinum compounds represent one of the great success stories of metals in medicine. Following the serendipitous discovery of the anticancer activity of cisplatin by Rosenberg, a large number of cisplatin variants have been prepared and tested for their ability to kill cancer cells and inhibit tumor growth. These efforts continue today with increased realization that new strategies are needed to overcome issues of toxicity and resistance inherent to treatment by the approved platinum anticancer agents. One approach has been the use of so-called "non-traditional" platinum(II) and platinum(IV) compounds that violate the structure-activity relationships that governed platinum drug-development research for many years. Another is the use of specialized drug-delivery strategies. Here we describe recent developments from our laboratory involving monofunctional platinum(II) complexes together with a historical account of the manner by which we came to investigate these compounds and their relationship to previously studied molecules. We also discuss work carried out using platinum(IV) prodrugs and the development of nanoconstructs designed to deliver them in vivo.

Figure 1

Different pathways of cisplatin before and after it enters the cell.

Figure 2

Molecular mechanics energy minimized structure of ethidium intercalated into platinated DNA. Copyright American Chemical Society, 1988.

Figure 3

Diagram of a DNA dodecamer platinated with pyriplatin as revealed by X-ray crystallography. PDB code: 3CO3.

Figure 4

Diagrams of duplex DNA from crystal structures of transcribing RNA pol II stalled at the site of pyriplatin binding. A) Addition site opposite platinated G (orange) is empty and the pyridine ring is directed toward the 5′ end of the platinated strand. PDB code: 3M4O B) Addition site occupied by CMP (orange) with pyridine now directed more toward the 3′ end of the platinated strand. PDB code: 3M3Y.

Scheme 1

DNA-Binding Mechanism of Cisplatin where “G” Represents a Guanine Base

Scheme 2

Oxidation Reactions of Cisplatin with Hydrogen Peroxide in Protic Solvents* *The molecular diagram of cis,cis,trans-[Pt(NH₃)₂Cl₂(O₂CH)₂] is depicted with thermal ellipsoids drawn at the 50% probability level. Full crystallographic details are provided in Supporting Information in CIF format.

Scheme 3

Nucleophilic Reactivity of cis,cis,trans-[Pt(NH₃)₂Cl₂(OH)₂]

Scheme 4

Design and Preparation of Single Walled Carbon Nanotubes to Deliver a Platinum(IV) Prodrug* *The molecular diagram of cis,cis,trans-[Pt(NH₃)₂Cl₂(OCH₂CH₃)(OH)] is depicted with thermal ellipsoids drawn at the 50% probability level. Full crystallographic details are provided in Supporting Information in CIF format.

Scheme 5

Design and Preparation of Gold Nanoparticles to Deliver a Platinum(IV) Prodrug* *Molecular diagram of cis,cis,trans-[Pt(NH₃)₂Cl₂(O₂CH₂CH₂COOH)(OH)] is depicted with thermal ellipsoids drawn at the 50% probability level. Full crystallographic details are provided in Supporting Information in CIF format.

Scheme 6

Design and Preparation of Polymer Nanoparticles to Deliver a Hydrophobic Platinum(IV) Prodrug

Scheme 7

Design and Preparation of Polymer Nanoparticles to Deliver Polymer-Conjugated Platinum(IV) Prodrugs

Chart 1

Chemical Structures of Platinum-Based Anticancer Drugs in Clinical Use Worldwide

Chart 2

Monofunctional Platinum Complexes^{a a}Designations refer to the names of the N-donor ligands.

Chart 3

Platinum(IV) Complexes with Biologically Active Carboxylate Ligands

Chart 4

Platinum(IV) Complexes with Biologically Active Ligands Attached by Amide-Bond-Forming Reactions