Andrew Kellett

Copper(II) Complexes of Salicylic Acid Combining Superoxide Dismutase Mimetic Properties with DNA Binding and Cleaving Capabilities Display Promising Chemotherapeutic Potential with Fast Acting in Vitro Cytotoxicity against Cisplatin Sensitive and Resistant Cancer Cell Lines

The complexes [Cu(salH)(2)(H(2)O)] (1), [Cu(dipsH)(2)(H(2)O)] (2), {Cu(3-MeOsal)(H(2)O)(0.75)}(n) (3), [Cu(dipsH)(2)(BZDH)(2)] (4), [Cu(dipsH)(2)(2-MeOHBZDH)(2)]·EtOH (5), [Cu(sal)(phen)] (6), [Cu(dips)(phen)]·H(2)O (7), and [Cu(3-MeOsal)(phen)]·H(2)O (8) (salH(2) = salicylic acid; dipsH(2) = 3,5-diisopropylsalicylic acid; 3-MeOsalH(2) = 3-methoxysalicylic acid; BZDH = benzimidazole; 2-MeOHBZDH = 2 methanolbenzimidazole and phen =1,10-phenanthroline) were prepared and characterized. Structures of 4, 5, and 8 were determined by X-ray crystallography. Compounds 1-8 are potent superoxide dismutase mimetics, and they are inactive as inhibitors of COX-2 activity. Compounds 1, 4, and 5 exhibit moderate inhibition of COX-1. Complexes 6-8 display rapid micromolar cytotoxicity against cisplatin sensitive (breast (MCF-7), prostate (DU145), and colon (HT29)) and cisplatin resistant (ovarian (SK-OV-3)) cell lines compared to 1-5, and they exhibit potent in vitro DNA binding and cleavage capabilities.

Copper(II) complexes of coumarin-derived Schiff bases and their anti-Candida activity.

The condensation of 7-amino-4-methyl-coumarin (1) with a number of substituted salicylaldehydes yielded a series of Schiff bases (2a-2k) in good yields. Subsequent reaction of these ligands with copper(II) acetate yielded Cu(II) complexes (3a-3k) and some were characterised using X-ray crystallography. All of the free ligands and their metal complexes were tested for their anti-Candida activity. A number of the ligands and complexes exhibited anti-Candida activity comparable to that of the commercially available antifungal drugs, ketoconazole and Amphotericin B.

Biological activity and coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands

The coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands, which had previously shown good anti-Candida activity, were investigated by pH-potentiometric and UV-Vis spectroscopic methods. These studies confirmed the coordination mode of the ligands to be through the N of the imine and deprotonated phenol of the coumarin-derived ligand in solution. In addition, the more active complexes and their corresponding ligands were investigated in the presence of copper(II) in liquid and frozen solution by ESR spectroscopic methods. A series of secondary amine derivatives of the Schiff base ligands, were isolated with good solubility characteristics but showed little anti-Candida activity. However, cytotoxicity studies of the secondary amines, together with the copper complexes and their corresponding ligands, against human colon cancer and human breast cancer cells identified the chemotherapeutic potential of these new ligands.

Potent oxidative DNA cleavage by the di-copper cytotoxin: [Cu2(μ-terephthalate)(1,10-phen)4]2+

The di-copper(II) cation, [Cu(2)(μ-terephthalate)(1,10-phen)(4)](2+), is a powerful, non-sequence-specific, minor-groove oxidizer of duplex DNA which, unlike copper(II) bis-1,10-phenanthroline chloride, operates independently of exogenous reagents. The agent displays excellent in vitro cytoxicity towards cisplatin-resistant ovarian cancer cells, producing intracellular reactive oxygen species upon nano-molar exposure.

Silver(I) complexes of 9-anthracenecarboxylic acid and imidazoles: synthesis, structure and antimicrobial activity

[Ag(2)(9-aca)(2)] (1) (9-acaH = 9-anthracenecarboxylic acid) reacts with a series of imidazoles to give [Ag(imidH)(2.3)(CH(3)CN)(0.7)](9-aca) (3), [Ag(6)(imidH)(4)(9-aca)(6)(MeOH)(2)] (4), {[Ag(1-Me-imid)(2)](2)[Ag(4)(9-aca)(6)]} (5), {[Ag(1-Bu-imid)(2)](2)[Ag(4)(9-aca)(6)]} (6) and [Ag(apim)](9-aca)·H(2)O (7) (imidH = imidazole; 1-Me-imid = 1-methylimidazole; 1-Bu-imid = 1-butylimidazole; apim = 1-(3-aminopropyl)imidazole). The mononuclear complex 3, hexanuclear 4-6, and polymeric 7, were all characterised using X-ray crystallography. While many of the complexes possess excellent in vitro antifungal and antibacterial activities they are, unanimously, more effective against fungal cells. The insect, Galleria mellonella, can survive high doses of the Ag(i) complexes administered in vivo, and a number of the complexes offer significant protection to larvae infected with a lethal dose of pathogenic Candida albicans cells.

In vitro and in vivo studies into the biological activities of 1,10-phenanthroline, 1,10-phenanthroline-5,6-dione and its copper(II) and silver(I) complexes

1,10-Phenanthroline (phen, 5), 1,10-phenanthroline-5,6-dione (phendione, 6), [Cu(phendione)3](ClO4)2·4H2O (12) and [Ag(phendione)2]ClO4 (13) are highly active, in vitro, against a range of normal and cancerous mammalian cells, fungal and insect cell lines, with the metal complexes offering a clear enhancement in activity. Cytoselectivity was not observed between the tumorigenic and non-tumorigenic mammalian lines. In in vivo tests, using Galleria mellonella and Swiss mice, all four compounds were well tolerated in comparison to the clinical agent, cisplatin. In addition, blood samples taken from the Swiss mice showed that the levels of the hepatic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), remained unaffected. Immunocompromised nude mice showed a much lower tolerance to 13 and, subsequently, when these mice were implanted with Hep-G2 (hepatic) and HCT-8 (colon) human-derived tumors, there was no influence on tumor growth.

Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity

The complexes [Ag2(OOC-(CH2)n-COO)] (n=1-10) (1-10) were synthesised and reacted with 1,10-phenanthroline (phen) to yield derivatives formulating as [Ag2(phen)x(OOC-(CH2)y-COO)]·zH2O (x=2 or 3; y=1-10; z=1-4) (11-20) which are highly water-soluble and photo-stable in aqueous solution. The phen derivatives 11-20 exhibit chemotherapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and against cisplatin-sensitive breast (MCF-7) and resistant ovarian (SKOV-3) cancer cell lines. Cyclic voltammetric analysis and DNA binding and intercalation studies indicate that the mechanism of action of 11-20 is significantly different to that of their silver(I) dicarboxylate precursors and they do not induce DNA damage or ROS generation in mammalian cells. The representative complexes 9 and 19 (containing the undecanedioate ligand) were both found to significantly reduce superoxide and hydrogen peroxide induced oxidative stress in the yeast S. cerevisiae.

A new phenanthroline–oxazine ligand: synthesis, coordination chemistry and atypical DNA binding interaction

1,10-Phenanthroline-5,6-dione and l-tyrosine methyl ester react to form phenanthroline-oxazine (PDT) from which [Cu(PDT)(2)](ClO(4))(2) and [Ag(PDT)(2)]ClO(4)·2MeOH are obtained. Binding to calf-thymus DNA by Ag(I) and Cu(II) PDT complexes exceed bis-1,10-phenanthroline analogues and the minor groove binding drugs, pentamidine and netropsin. Furthermore, unlike the artificial metallonuclease, [Cu(phen)(2)](2+), the [Cu(PDT)(2)](2+) complex does not cleave DNA in the presence of added reductant indicating unique interaction with DNA.

Deciphering the Antimicrobial Activity of Phenanthroline Chelators

The opportunistic fungal pathogen, Candida albicans, causes a range of diseases in susceptible individuals. The adverse side effects of many of the current anti-fungal prescription drugs and the emergence of C. albicans isolates and other Candida species which are resistant to these compounds have accelerated the search for new drug candidates which have different modes of action. A family of metal chelators, which are based on the 1,10-phenanthroline core, exhibit excellent growth inhibitory effects in vitro against a number of Candida species, including clinical isolates. The compounds sequester transition metal ions, damage mitochondrial function and uncouple cell respiration. Additionally, fungal cell morphology undergoes dramatic changes and there is evidence of apoptotic cell death. Importantly, in vivo studies have confirmed that the compounds have an acceptably low toxicity profile.

Synthesis, Superoxide Dismutase Mimetic and Anticancer Activities of Metal Complexes of 2,2-Dimethylpentanedioic Acid(2dmepdaH2) and 3,3-Dimethylpentanedioic acid(3dmepdaH2): X-Ray Crystal Structures of [Cu(3dmepda)(bipy)]2· 6H2O and [Cu(2dmepda)(bipy)(EtOH)]2· 4EtOH(bipy = 2,2′Bipyridine)

2,2-dimethylpentanedioic acid (2dmepdaH2) and 3,3-dimethylpentanedioic acid (3dmepdaH2) reacted with copper(II) acetate to give [Cu(2dmepda)(H2O)3]2 (1) and [Cu(3dmepda)(H2O)3]2 (2). Reaction of (1) and (2) with 1,10-phenanthroline and 2,2′-bipyridine yielded [Cu(2dmepda)(phen)(H2O)]20.5phen (3), [Cu(2dmepda)(bipy)(H2O)]2 (4), [Cu(2dmepda)(bipy)(EtOH)]2· 2EtOH (4A), [Cu(3dmepda)(phen)(H2O)]2 (5), and [Cu(3dmepda)(bipy)(H2O)]2· (6). The structures of (4A) and (6) each consists of a [Cu(bipy)(dicarboxylate)(solvent)]2 dimer. The superoxide dismutase (SOD) mimetic activity of the novel copper complexes and their manganese analogues was investigated. The dimethyl sulphoxide(DMSO) soluble complexes (1)–(4) and (6) were assessed for their cancer chemotherapeutic potential towards hepatocellular carcinoma and kidney adenocarcinoma cell lines. The 1,10-phenanthroline containing complex [Cu(2dmepda)(phen)(H2O)]20.5phen (3) was the most potent with activity that compares well to that of cisplatin.