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1.
Dalton Trans ; 46(21): 7005-7019, 2017 May 30.
Article in English | MEDLINE | ID: mdl-28513693

ABSTRACT

This report describes the synthesis, characterization and biological activity of a series of platinum(iv) derivatives of [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] (Pt56MeSS) with non-bioactive, lipophilic and bioactive axial ligands. In an attempt to explore the anticancer activity potential of the Pt(iv) derivatives, 2D and 3D cytotoxic screening and a preliminary in vivo study were performed. The average IC50 values of the platinum(iv) derivatives ranged from 1.26 to 5.39 µM, compared with 1.24 µM for Pt56MeSS, suggesting that the axial ligands have a relatively minor effect on the potency of the compounds. Preliminary in vivo studies indicate that the platinum(iv) derivatives of Pt56MeSS are active in vivo and can reduce the tumor to a similar extent to cisplatin.

2.
ChemMedChem ; 12(7): 510-519, 2017 04 06.
Article in English | MEDLINE | ID: mdl-28206707

ABSTRACT

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its PtIV derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The PtII complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a Kd value of ∼1.5×10-6 m. All PtIV complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2 ](TFA)2 (Pt56MeSS(OAc)2 ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato)2 ](TFA)2 (Pt56MeSS(PhB)2 ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the PtIV complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.


Subject(s)
Coordination Complexes/chemistry , Platinum/chemistry , Ascorbic Acid/chemistry , Coordination Complexes/blood , Coordination Complexes/chemical synthesis , Cyclohexylamines/chemistry , Drug Stability , Electrochemical Techniques , Humans , Magnetic Resonance Spectroscopy , Oxidation-Reduction , Phenanthrolines/chemistry , Prohibitins
3.
J Inorg Biochem ; 163: 95-102, 2016 10.
Article in English | MEDLINE | ID: mdl-27453535

ABSTRACT

Platinum(II) complexes have demonstrated considerable success in the treatment of cancer, but severe toxic side effects drive the search for new complexes with increased tumour selectivity and better efficacy. A critical concept that has to be considered in the context of designing novel Pt complexes is their interactions with biomolecules other than DNA. To this end, here the interactions of 16 previously reported bisintercalating (2,2':6',2″-terpyridine)platinum(II) complexes, [{Pt(terpy)}2µ-(X)]n+ (where X is a linker) with glutathione (GSH) by means of 1H and 195Pt NMR spectroscopy were investigated. The GSH half-life (GSH t1/2) was determined following the incubation of each [{Pt(terpy)}2µ-(X)]n+ complex with GSH (8mM). It was observed that complexes 1-7, 11, 12 and 14-16 reacted more rapidly than cisplatin, whereas complexes 8-10, 13 and 17 reacted more slowly (≥200min). There was no apparent correlation between linker length and the GSH t1/2. In order to understand these interactions, two complexes: 1 (t1/2<1min) and a previously studied 17 [Pt(5,6-dimethyl-1,10-phenanthroline)(1S,2S-diaminocyclohexane)] (56MESS) (GSH t1/2=4080min) were incubated with rabbit plasma. A "metallomics" approach was used to analyse plasma for all platinum species at the 5 and the 60min time point and provided results that were congruent with the reaction of the selected Pt complexes with GSH. Our studies demonstrate that the combined application of NMR spectroscopy, cytotoxicity studies and a metallomics approach can contribute to better understand the interaction of [{Pt(terpy)}2µ-(X)]n+ complexes with biomolecules to better assess which compounds may be advanced to in vivo studies.


Subject(s)
Blood Proteins/chemistry , Glutathione/chemistry , Intercalating Agents , Plasma/chemistry , Platinum/chemistry , Animals , Intercalating Agents/chemical synthesis , Intercalating Agents/chemistry , Rabbits
4.
Chemistry ; 22(7): 2317-25, 2016 Feb 12.
Article in English | MEDLINE | ID: mdl-26670391

ABSTRACT

Four dinuclear terpyridineplatinum(II) (Pt-terpy) complexes were investigated for interactions with G-quadruplex DNA (QDNA) and duplex DNA (dsDNA) by synchrotron radiation circular dichroism (SRCD), fluorescent intercalator displacement (FID) assays and fluorescence resonance energy transfer (FRET) melting studies. Additionally, computational docking studies were undertaken to provide insight into potential binding modes for these complexes. The complexes demonstrated the ability to increase the melting temperature of various QDNA motifs by up to 17 °C and maintain this in up to a 600-fold excess of dsDNA. This study demonstrates that dinuclear Pt-terpy complexes stabilise QDNA and have a high degree of selectivity for QDNA over dsDNA.


Subject(s)
DNA/chemistry , Organoplatinum Compounds/chemistry , Circular Dichroism , Fluorescence Resonance Energy Transfer , G-Quadruplexes
5.
Dalton Trans ; 44(1): 87-96, 2015 Jan 07.
Article in English | MEDLINE | ID: mdl-25407567

ABSTRACT

Dinuclear (2,2':6',2''-terpyridine)platinum(II) (PtTerpy) complexes were synthesised by tethering either thiol or pyridine based linkers. All intermediates and resulting complexes were characterised using a combination of (1)H and (195)Pt NMR, two-dimensional (1)H correlation spectroscopy (NOSY/COSY), two-dimensional (1)H/(195)Pt heteronuclear multiple bond correlation spectroscopy (HMQC), elemental analysis and electrospray ionisation mass spectrometry (ESI-MS). The cytotoxicity of the complexes was determined against human A2780 ovarian carcinoma cells and its cisplatin-resistant sub-line A2780cis, as well as L1210 murine leukemia cells.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Female , Humans , Leukemia L1210/drug therapy , Mice , Organoplatinum Compounds/chemical synthesis , Ovarian Neoplasms/drug therapy , Ovary/drug effects , Pyridines/chemical synthesis
6.
Metallomics ; 6(1): 126-31, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24084749

ABSTRACT

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.


Subject(s)
Buthionine Sulfoximine/pharmacology , Carboplatin/pharmacology , Cisplatin/pharmacology , Organoplatinum Compounds/pharmacology , Pyruvates/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/chemistry , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Buthionine Sulfoximine/administration & dosage , Buthionine Sulfoximine/chemistry , Carboplatin/administration & dosage , Carboplatin/chemistry , Cell Line , Cell Line, Tumor , Cell Survival/drug effects , Cisplatin/administration & dosage , Cisplatin/chemistry , Dose-Response Relationship, Drug , Drug Synergism , Glutathione/metabolism , Humans , Inhibitory Concentration 50 , Molecular Structure , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/chemistry , Platinum/chemistry , Pyruvates/administration & dosage , Pyruvates/chemistry
7.
Metallomics ; 5(8): 1061-7, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23784536

ABSTRACT

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: IC50 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.


Subject(s)
Antineoplastic Agents/chemistry , Cell Cycle/drug effects , Cisplatin/chemistry , Cytoskeletal Proteins/metabolism , Mitochondrial Proteins/metabolism , Organoplatinum Compounds/chemistry , Platinum Compounds/chemistry , Animals , Apoptosis , Caspase 3/metabolism , Caspase 7/metabolism , Cytoskeleton/drug effects , Dogs , Drug Screening Assays, Antitumor , Flow Cytometry , Gene Expression Regulation, Neoplastic , Inhibitory Concentration 50 , Madin Darby Canine Kidney Cells , Mitochondria/drug effects , Time Factors
8.
Curr Top Med Chem ; 11(5): 521-42, 2011.
Article in English | MEDLINE | ID: mdl-21189131

ABSTRACT

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 need are new compounds with different mechanisms of action and resistance profiles. What needs to be recognised is that there are many other metal in the periodic table with therapeutic potential. Here we have highlighted metal complexes with activity and have illustrate the different approaches to the design of anticancer complexes.


Subject(s)
Antineoplastic Agents/pharmacology , Neoplasms/drug therapy , Organometallic Compounds/pharmacology , Transition Elements/chemistry , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , DNA, Neoplasm/chemical synthesis , DNA, Neoplasm/chemistry , DNA, Neoplasm/drug effects , Drug Screening Assays, Antitumor , Humans , Neoplasms/diagnosis , Neoplasms/pathology , Organometallic Compounds/chemistry
9.
Chemistry ; 16(24): 7064-77, 2010 Jun 25.
Article in English | MEDLINE | ID: mdl-20533453

ABSTRACT

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.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cisplatin/therapeutic use , Dendrimers/chemistry , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/therapeutic use , Serum Albumin/chemistry , Carboplatin/chemistry , Carboplatin/therapeutic use , Cisplatin/chemistry , Drug Delivery Systems , Humans , Molecular Structure , Nanotubes, Carbon/chemistry , Neoplasms/drug therapy , Organoplatinum Compounds/chemistry , Prodrugs/chemistry , Prodrugs/therapeutic use , Serum Albumin/therapeutic use
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