Exploration of the medical periodic table: towards new targets (PARTIAL)

Exploration of the medical periodic table: towards new targets†

Nicolas P. E. Barry and Peter J. Sadler*

University of Warwick, Department of Chemistry, Gibbet Hill Road, Warwick, UK. E-mail: N.Barry@warwick.ac.uk; P.J.Sadler@warwick.ac.uk

Received 11th February 2013, Accepted 3rd April 2013

First published on the web 1st May 2013

Chem. Commun., 2013, 49, 5106--5131

26 pages

ABSTRACT AND FULL LENGTH OF ARTICLE: http://pubs.rsc.org/en/content/articlehtml/2013/cc/c3cc41143e

This article is a review of current research and interests in metallodrugs and their interactions with (proposed) target sites.  While DNA was commonly used as a target site for anticancer drugs, for instance, this has changed due to the challenge of isolating cytotoxicity to cancerous cells and sparing normal cells.

In the introduction section, the author presents a medical periodic table showing the 24 essential metals, radioisotopes, and elements currently used in therapy and diagnosis.  It also provides a table listing metallodrugs or chelating agents in development, clinical trial, or approved for clinical use.

The authors note that all essential metals should be investigated for therapeutic functions but there are some whose biochemistry is still unknown. They also propose a strong focus on characterizing target sites and the molecular mechanism.  Research in metallodrugs is also involved in investigating a range of target sites as described in this paper.

1. METAL-BASED ANTICANCER DRUGS

DNA TARGETING

Direct Coordinative DNA Binding

PLATINUM: See Chart 1 for a list of platinum-based anticancer drugs that are approved or undergoing trials.  The target site for cis-platin is nuclear DNA.  DNA adduct formation is important for the mechanism of these metallodrugs.

There has been interest in developing similar platinum-based compounds that are structurally different from cis-platin in the hope that they would form different DNA adducts with different biological activity.  Polyplatinum complexes have been developed with a highly positive charge leading to a stronger electrostatic recognition of DNA; they are also thought to be more flexible.  These drugs passed Phase I trials but not Phase II trials.

Low spin octahedral PtIV complexes have the advantage over PtII square complexes because they are less prone to substitution reaction and therefore more likely to reach the tumor site unchanged.  They also are more water-soluble.

In general, the new PtIV complexes being developed are unpredictable in terms of their rate and extent of localization in vivo compared to active PtII species.

RUTHENIUM: Because of the toxicity of platinum-based drugs, other active metals are being considered.  One example is ruthenium.  New drugs being developed use RuIII complexes but RuII organic arene complexes also show promise. One of these RuIII anticancer drugs called NAMI-A has antimetastatic activity that is thought to be due to the combined effects of on the control of angiogenesis and anti-invasive properties towards tumor cells and blood vessels and not due to interactions with DNA.  Another RuIII complex drug is known to target DNA and cause apoptosis.  RuIII is thought to be activated by reduction to RuII in vivo. The paper describes current thinking on the biochemical basis for the anticancer activity of RuII arene complexes.

OSMIUM: A heavy congener of ruthenium, osmium is considered relatively inert compared to ruthenium because of its slower kinetics.  The paper describes the potential of altering the biochemical activity of osmium based on its aqueous properties, e.g. the rate of hydrolysis by using the right chelating ligand and can be made active in vivo.  The paper notes that injected OsO4 has been used to treat chronic synovitis.

IRIDIUM: IrIII anticancer complexes bind to DNA but are also known to react with NADH producing hydrogen catalytically.  This finding presents a new potential target site to explore.

Non-covalent DNA Binders

-Instead of forming covalently bonded adducts, metals can intercalate between DNA base pairs to induce mutagenesis due to structural and functional changes in duplex DNA.  These changes can lead to inhibition of transcription, replication, and repair.  These intercalators have potentials as antibiotics, antibacterials, antitumor agents, etc.  Table 3 in the article gives a list of metallo-intercalator complexes (zinc, gold, silver, copper, lead, platinum, nickel, iridium, rhenium, cobalt, and ruthenium).

Coordination plus Intercalation: Dual Mode DNA Binders

This dual capability is present in metal complexes with sigma bonded aromatic side arms or organometallic complexes with pi-bonded arenes. These complexes are capable of binding to DNA through direct metal coordination to a DNA base and an attached aromatic ligand intercalating between bases. The paper gives examples Pt complexes with planar aromatic ligands that can exhibit this dual function (ethidium bromide is one). A biphenyl RuII complex given as an example binds strongly to G bases in DNA but also its phenyl substituent intercalates.  Examples of RhII dual function complexes are also given. In the case of some IrIII complexes, the ability to intercalate into DNA increases their anticancer potency.  Combining two metals in one complex also appears to facilitate both coordinative binding and intercalation ability.

G-Quadruplex Binders

This binding action occurs in the G-rich areas of telomeres in human genes that contain many repeats of the sequence d(GGTTAG). A Ni-Cu complex was prepared in the presence of telomeric human DNA and was observed to effectively bind to telomeric DNA by end-stacking.  Targeting telomerase is an effective anticancer activity.  Table 4 in the article provides a list of complexes with this function that have been investigated.

SELECTIVE DNA BINDING

Metallodrugs with sequence specificity

The selectivity of the binding to DNA can be enhanced by ligands that have sequence specificity. A PtII complex with linear and hairpin polyamide ligands has been shown to recognize 7-base pair sequences.  Specific selectivity can also help reduce side effects and resistance to platinum-based drugs.  A nucleotide can also be incorporated into the complex that can complementary bind to a DNA strand to form a triple helices.

Protein mediated DNA recognition

Another method for enhancing DNA recognition is the formation of a ternary complex that has a presenter protein and a small molecule that can bind to both protein and target.  The antibiotic rapamycin has such a structure.

PROTEIN TARGETING