Strong Closed-Shell Interactions in Inorganic Chemistry.

The platinum drugs, cisplatin, carboplatin, and oxaliplatin, prevail in the treatment of cancer, but new platinum agents have been very slow to enter the clinic. Recently, however, there has been a surge of activity, based on a great deal of mechanistic information, aimed at developing nonclassical platinum complexes that operate via mechanisms of action distinct from those of the approved drugs. The use of nanodelivery devices has also grown, and many different strategies have been explored to incorporate platinum warheads into nanomedicine constructs. In this Review, we discuss these efforts to create the next generation of platinum anticancer drugs. The introduction provides the reader with a brief overview of the use, development, and mechanism of action of the approved platinum drugs to provide the context in which more recent research has flourished. We then describe approaches that explore nonclassical platinum(II) complexes with trans geometry or with a monofunctional coordination mode, polynuclea...

The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs

Biochemical Modulation of Cisplatin Mechanisms of Action: Enhancement of Antitumor Activity and Circumvention of Drug Resistance

From the metal ions and metal compounds that are known to bind to DNA, many anticancer Pt(II) and Ru(II)/Ru(III) compounds are known to have ligand-exchange kinetics in the same order of magnitude as the division of tumor cells. The present article discusses this process in detail with special attention to cisplatin and related compounds and the cellular binding sites and processes of such compounds. Detailed platinated DNA structures are presented and discussed in light of the mechanistic studies of metal antitumor compounds. It is now known that platinum antitumor drugs eventually end up on the DNA. However, it remains a challenge to understand how (fast) they reach the DNA and how they are removed. The kinetics of ligand exchange around platinum appear to play a crucial role, and the possible role of other ligands as intermediates, especially those with S-donor sites, is of great interest. New types of Pt compounds with additional functionalities influencing DNA binding and kinetics are discussed in the context of steric and H-bonding properties. A comparison is made with more sterically crowded Ru complexes. The effects on activity and correlations with structural and kinetic properties are clues in understanding the biological activities of these classes of compounds.

https://www.pnas.org/content/pnas/100/7/3611.full.pdf

New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA

Platinum(IV) antitumour compounds: their bioinorganic chemistry

The hydrolysis products of cis-dichlorodiammineplatinum(II) 2. The kinetics of formation and anation of the cis-diamminedi(aqua)platinum(II) cation

The hydrolysis products of cis-dichlorodiammineplatinum(II) 3. Hydrolysis kinetics at physiological pH

The hydrolysis products of cis-diamminedichloroplatinum(II). I. The kinetics of formation and anation of the cis-diammine(aqua)chloroplatinum(II) cation in acidic aqueous solution

Stereochemistry and reaction rates of anionopentaamine complexes of cobalt(III) and chromium(III)

The hydrolysis products of cis-diamminedichloroplatinum(II) 6. A kinetic comparison of the cis- and trans-isomers and other cis-di(amine)di(chloro)platinum(II) compounds

Donald A. House

Papers

The hydrolysis products of cis-dichlorodiammineplatinum(II) 2. The kinetics of formation and anation of the cis-diamminedi(aqua)platinum(II) cation

The hydrolysis products of cis-dichlorodiammineplatinum(II) 3. Hydrolysis kinetics at physiological pH

The hydrolysis products of cis-diamminedichloroplatinum(II). I. The kinetics of formation and anation of the cis-diammine(aqua)chloroplatinum(II) cation in acidic aqueous solution

Stereochemistry and reaction rates of anionopentaamine complexes of cobalt(III) and chromium(III)

The hydrolysis products of cis-diamminedichloroplatinum(II) 6. A kinetic comparison of the cis- and trans-isomers and other cis-di(amine)di(chloro)platinum(II) compounds