Platinum intercalators of DNA as anticancer agents

The drawbacks of platinum chemotherapy agents cisplatin, carboplatin and oxaliplatin have inspired the development of compounds with different mechanisms of action. Polyaromatic platinum complexes (PPCs) are a promising anticancer alternative; these bind reversibly with DNA through the insertion of a planar aromatic moiety between nucleobases in a process known as intercalation. PPCs have demonstrated remarkably different in vitro behaviour to cisplatin and exhibited cytotoxicity up to one hundred times greater than cisplatin in many cell lines. This microreview primarily discusses 1,10-phenanthroline-based complexes of the type [Pt(PL)(AL)]2+ (where PL is a polyaromatic ligand and AL is an ancillary ligand), including their cytotoxicity, DNA binding behaviour and biological activity in vitro and in vivo. Other PPCs within the field, including dual-mode DNA binders incorporating tethered acridines and other potently cytotoxic complexes are also covered

Synthesis, characterisation and cytotoxicity of [(1,10-phenanthroline)(1R,2R,4R/1S,2S,4S)-4-methyl-1,2-cyclohexanediamine)platinum(II)]2+ (PHEN-4-MeDACH)

We have synthesised, characterised and examined the cytotoxicity of [(1,10- phenanthroline)(1R,2R,4R/1S,2S,4S-4-methyl-cyclohexanediamine) platinum(II)]2+ (PHEN-4-MeDACH) in the L1210 cell line. The cytotoxicity of PHEN-4-MeDACH in the murine leukaemia (L12010) cell line was 1.8 ± 0.00 μM, comparable with that of [(1,10-phenanthroline)(1R,2R-diaminocyclohexane) platinum(II)]2+ (1.5 ± 0.14 μM) but less cytotoxic than [(1,10-phenanthroline)(1S,2S-diaminocyclohexane)platinum(II)]2+(0.15 ± 0.06 μM) and cisplatin (0.43 ± 0.06 μM)

Combination studies of platinum(II)-based metallointercalators with buthionine-S,R-sulfoximine, 3-bromopyruvate, cisplatin or carboplatin

With current chemotherapeutic treatment regimes often limited by adverse side effects, the synergistic combination of complexes with anticancer activity appears to offer a promising strategy for effective cancer treatment. This work investigates the anti-proliferative activity using a combination therapy approach where metallointercalators of the type [Pt(IL)(AL)]2+ (where IL is the intercalating ligand and AL is the ancillary ligand) are used in combination with currently approved anticancer drugs cisplatin and carboplatin and organic molecules buthionine-S,R-sulfoximine and 3-bromopyruvate. Synergistic relationships were observed, indicating a potential to decrease dose-dependent toxicity and improve therapeutic efficacy

Cytotoxic platinum(II) intercalators that incorporate 1R,2R-diaminocyclopentane

Twelve metallointercalators of the type [Pt(IL)(AL)](2+), where A(L) is either the R,R or S,S enantiomer of 1,2-diaminocyclopentane (DACP) and IL is either 1,10-phenathroline, 4-methyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5,6-dimethyl-1,10-phenanthroline or 3,4,7,8-tetramethyl-1,10-phenanthroline, were synthesised, characterised and the cytotoxicity to the L1210 cell line was determined. The crystal structures of PHENRRDACP and PHENSS were obtained as monoclinic with a space group of P2(1) (a/angstrom = 11.4966, b/angstrom = 6.6983, c/angstrom = 12.0235) and P2(1) (a/angstrom = 11.5777, b/angstrom = 7.0009, c/angstrom = 12.5079), respectively. The R, R enantiomer of 1,2-diaminocyclopentane (RRDACP) produced the most cytotoxic metallointercalators. The most cytotoxic metallointercalators were 56MERRDACP and 47MERRDACP with IC50 values of 0.16 and 0.17 µM, respectively, in comparison to cisplatin (1 µM)

The synthesis of platinum(II) intercalators

The pharmacological properties of any drug are largely dependent on binding interactions with biomolecules. The investigation of such interactions is essential to gain some understanding of the mechanisms of drug action, and to determine which structural characteristics influence the pharmacological properties. Of particular interest are the interactions between anticancer agents and DNA, as DNA is considered to be the major cellular target for a large number of compounds that are effective in the treatment of various types of cancers. It has been reported that the binding of such drugs to DNA can inhibit cellular processes such as DNA replication and transcription, which are vital for the proliferation of cells. The inhibition or prevention of cell division is the primary objective for drug design as it most markedly affects rapidly dividing cells such as tumour cells, and ultimately prevents their spread throughout the body

Biomolecular ineractions of platinum complexes

The in vitro and in vivo effects of platinum complexes have been well reported. However, it is their interactions with biologically relevant structures and bio-macromolecules such as DNA and proteins that can determine their therapeutic effects. The pharmacological properties of platinum complexes are dependent on binding interactions, and the investigation of such interactions is essential to gain insight into the mechanisms of action. Interactions with DNA can inhibit cellular processes such as replication and transcription, which are vital for the proliferation of cells. By investigating how platinum complexes achieved these different interactions we may be able to determine the relationships between the structural characteristics, biophysical properties and biological activity in order to design more effective anticancer drugs

Advances in platinum chemotherapeutics

The approved platinum(II)-based anticancer agents cisplatin, carboplatin and oxaliplatin are widely utilised in the clinic, although with numerous disadvantages. With the aim of circumventing unwanted side-effects, a great deal of research is being conducted in the areas of cancer-specific targeting, drug administration and drug delivery. The targeting of platinum complexes to cancerous tissues can be achieved by the attachment of small molecules with biological significance. In addition, the administration of platinum complexes in the form of platinum(IV) allows for intracellular reduction to release the active form of the drug, cisplatin. Drug delivery includes such technologies as liposomes, dendrimers, polymers and nanotubes, with all showing promise for the delivery of platinum compounds. In this paper we highlight some of the recent advances in the field of platinum chemotherapeutics, with a focus on the technologies that attempt to utilise the cytotoxic nature of cisplatin, whilst improving drug targeting to reduce side-effects

Applications of fluorescence spectroscopy and confocal microscopy

In this chapter we describe the use of fluorescence spectroscopy and confocal microscopy to investigate the DNA binding capacity, uptake route and intracellular localisation of novel metallointercalators. Fluorescence is the property whereby some atoms or molecules absorb UV or visible light and then re-emit it at longer wavelengths after a brief interval, termed the fluorescence lifetime

The effects of 56MESS on mitochondrial and cytoskeletal proteins and the cell cycle in MDCK cells

Background: 56MESS has been shown to be cytotoxic but the mode of this action is unclear. In order to probe the mechanism of action for 56MESS, MDCK cells were utilised to investigate the effect on treated cells. Results: IC 50 values for 56MESS and cisplatin in the MDCK cell line, determined by a SRB assay, were 0.25 ± 0.03 and 18 ± 1.2 µM respectively. In a preliminary study, cells treated with 56MESS displayed no caspase-3/7 activity, suggesting that the mechanism of action is caspase independent. Protein expression studies revealed an increase the expression in the MTC02 protein associated with mitochondria in cells treated with 56MESS and cisplatin. Non-synchronised 56MESS-treated cells caused an arrest in the G2/M phase of the cell cycle, in comparison to the S phase arrest of cisplatin. In G0/G1 synchronised cells, both 56MESS and cisplatin both appeared to arrest within the S phase. Conclusions: these results suggest that 56MESS is capable of causing cell-cycle arrest, and that mitochondrial and cell cycle proteins may be involved in the mode of action of cytotoxicity of 56MESS

Transition metal based anticancer drugs

With an ageing baby-boomer population in the Western World, cancer is becoming a significant cause of death. The prevalence of cancer and all associated costs, both in human and financial terms, drives the search for new therapeutic drugs and treatments. Platinum anticancer agents, such as cisplatin have been highly successful but there are several disadvantages associated with their use. What is needed are new compounds with different mechanisms of action and resistance profiles. What needs to be recognised is that there are many other metals in the periodic table with therapeutic potential. Here we have highlighted metal complexes with activity and illustrate the different approaches to the design of anticancer complexes