New platinum(II) complexes [PtCl(O,O'-acac)(L)] (1) and [Pt(O,O'-acac)(γ-acac)(L)] (2) (L = DMSO, a; DMS, b) containing a single chelated (O,O'-acac) (1), or one chelated and one σ-bonded (γ-acac) acetylacetonate (2) have been synthesized. The new Pt(II) complexes exhibited high in vitro cytotoxicity on cisplatin sensitive and resistant cell lines and showed negligible reactivity with nucleobases (Guo and 5'-GMP) but selective substitution of DMSO/DMS with soft biological nucleophiles, such as L-methionine. In order to assess the ability of the new complexes with respect to cisplatin to induce apoptosis by interaction with nongenomic targets, the Ames' test, a standard reverse mutation assay, was carried out on two Salmonella typhimurium strains (TA98 and TA100). Interestingly, the new complexes did not show the well-known mutagenic activity exhibited by cisplatin and are, therefore, able to activate apoptotic pathways without interacting with DNA.

Platinum drugs are an important class of cancer chemotherapeutics. However, the use of these drugs is limited by the development of resistance during treatment with decreased accumulation being a common mechanism. Both Cu transporters CTR1 and CTR2 influence the uptake and cytotoxicity of cisplatin. Although it is structurally similar to CTR1, CTR2 functions in a manner opposite to that of CTR1 with respect to Pt drug uptake. Whereas knockout of CTR1 reduces Pt drug uptake, knockdown of CTR2 enhances cisplatin uptake and cytotoxicity. CTR2 is subject to transcriptional and posttranscriptional regulation by both Cu and cisplatin; this regulation is partly dependent on the Cu chaperone ATOX1. Insight into the mechanisms by which CTR1 and CTR2 regulate sensitivity to the Pt-containing drugs has served as the basis for novel pharmacologic strategies for improving their efficacy.

Platinum-containing chemotherapy agents (cisplatin, carboplatin, oxaliplatin) have been approved in the first-line setting of numerous malignancies, such as ovarian, bladder, head and neck, colorectal, and lung cancer. Their extensive use over the last decade has led to a significant increase in the incidence of hypersensitivity reactions, which are defined as unforeseen reactions whose signs and symptoms cannot be explained by the known toxicity of these drugs. Skin rash, flushing, abdominal cramping, itchy palms, and back pain are common symptoms. Cardiovascular and respiratory complications can prove fatal. Multiple pathogenetic mechanisms have been suggested. Hypersensitivity usually appears after multiple infusions, suggesting type I allergic reactions; however, other types of hypersensitivity also seem to be implicated. Several management options are available to treating physicians: discontinuation of chemotherapy, premedication, prolonging of infusion duration, desensitization protocols, and replacement with a different platinum compound after performing skin tests that rule out cross-reactions among platinum agents.

Three mechanisms have been proposed for the role of glutathione (GSH) in regulating cisplatin (CDDP) sensitivities that affects its ultimate cell-killing ability: (i) GSH may serve as a cofactor in facilitating multidrug resistance protein 2- (MRP2-) mediated CDDP efflux in mammalian cells, since MRP2-transfected cells were shown to confer CDDP resistance; (ii) GSH may serve as a redox-regulating cytoprotector based on the observations that many CDDP-resistant cells overexpress GSH and γ-glutamylcysteine synthesis (γ-GCS), the rate-limiting enzyme for GSH biosynthesis; (iii) GSH may function as a copper (Cu) chelator. Elevated GSH expression depletes the cellular bioavailable Cu pool, resulting in upregulation of the high-affinity Cu transporter (hCtr1) which is also a CDDP transporter. This has been demonstrated that overexpression of GSH by transfection with γ-GCS conferred sensitization to CDDP toxicity. This review describes how these three models were developed and critically reviews their importance to overall CDDP cytotoxicity in cancer cell treatments.

A new titanocenyl amide containing flavone as pendant group has been synthesized by reaction of titanocenyl carboxylic acid chloride and 7-Aminoflavone and structurally characterized by spectroscopic methods. This species and eight previously synthesized titanocenyl amide complexes have been tested in breast adenocarcinoma cancer cell line, MCF-7. The functionalization of titanocene dichloride with amides enhances the cytotoxic activity in MCF-7. Two sets of titanocenyl amides can be identified, with IC(50) <100 muM and IC(50)>100 muM. The most cytotoxic species is Cp(CpCO-NH-C(6)H(4)-(CH(2))(2)CH(3))TiCl(2) with an IC(50) of 24(2) muM, followed by Cp(CpCO-NH-C(6)H(4)-Br)TiCl(2), IC(50) of 46(4) muM and Cp(CpCO-NH-C(6)H(4)-OCF(3))TiCl(2), IC(50) of 49(6) muM. There is no correlation between the nature of the para substituent on the phenyl ring and the cytotoxic properties on MCF-7 cell line.

The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second ruthenium compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role.

Platinum(IV) compounds like oxoplatin (cis, cis, trans-diammine-dichlorido-dihydroxido-platinum(IV)) show increased stability and therefore can be applied orally. In a panel of 38 human cancer cell lines this drug induced S-phase arrest and cell death with IC(50) values 2.5-fold higher than cisplatin. Oxoplatin may be converted to cisplatin by intracellular reducing agents, however, exposure to 0.1 M HCl mimicking gastric acid yielded cis-diammine-tetrachlorido-platinum(IV) exhibiting twofold increased activity. Similar results were obtained for another platinum(IV) compound, JM 149 (ammine-dichlorido-(cyclohexylamine)-dihydroxido-platinum(IV)), but not for its parent drug JM 216/satraplatin. Genome-wide expression profiling of H526 small cell lung cancer cells treated with these platinum species revealed clear differences in the expression pattern of affected genes between oxoplatin and cisplatin. In conclusion, oxoplatin constitutes a potent oral agent that is either reduced or converted to distinct active compounds, for example, by gastric acid or acidic areas prevailing in solid tumors, in dependence of the respective pharmaceutical formulation.

A series of ferrocenyl ester complexes, varying the lipophilic character of the pendant groups, was prepared and characterized by spectroscopic and analytical methods. The syntheses of Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3)) (CpCOO CH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) are reported. The solid-state structure of Fe(C(5)H(4)CO(2)CH(3))(2) has been determined by X-ray crystallography. Fe(C(5)H(4)CO(2)CH(3))(2) has the cyclopentadienyl rings virtually in an eclipsed conformation with the pendant groups not completely opposite to each other. Cyclic voltammetry characterization showed that the functionalized ferrocenes oxidize at potentials, E(pa), higher than ferrocene as a result of the electro withdrawing effect of the pendant groups on the cyclopentadienyl ligand. The cytotoxicities of Fe(C(5)H(4)CO(2)CH(2)CH(2)OH)(2), Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2), Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3))(CpCOOCH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) in colon cancer HT-29 and breast cancer MCF-7 cell lines were measured by the MTT biological viability assay and compared to ferrocene and ferrocenium. Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2) showed the best IC(50) values, 180(10) muM for HT-29 and 190(30) muM for MCF-7 cell lines, with cytotoxicities similar to ferrocenium. The cytotoxic data suggest that as we increase the lipophilic character of the functionalized ferrocene, the cytotoxicity improves approaching to the cytotoxic activity of ferrocenium.

Photodynamic therapy (PDT) is a treatment modality that has been used in the successful treatment of a number of diseases and disorders, including age-related macular degeneration (AMD), psoriasis, and certain cancers. PDT uses a combination of a selectively localised light-sensitive drug (known as a photosensitiser) and light of an appropriate wavelength. The light-activated form of the drug reacts with molecular oxygen to produce reactive oxygen species (ROS) and radicals; in a biological environment these toxic species can interact with cellular constituents causing biochemical disruption to the cell. If the homeostasis of the cell is altered significantly then the cell enters the process of cell death. The first photosensitiser to gain regulatory approval for clinical PDT was Photofrin. Unfortunately, Photofrin has a number of associated disadvantages, particularly pro-longed patient photosensitivity. To try and overcome these disadvantages second and third generation photosensitisers have been developed and investigated. This Review highlights the key photosensitisers investigated, with particular attention paid to the metallated and non-metallated cyclic tetrapyrrolic derivatives that have been studied in vitro and in vivo; those which have entered clinical trials; and those that are currently in use in the clinic for PDT.

New bidentate or tridentate Schiff bases and their VO(II) and Co(II) complexes formed by the condensation of methyl isobutyl ketone with nicotinamide (mna)/2-amino-4-chlorophenol (map) and 2-hydroxy acetophenone with nicotinamide (han)/isoniazide (hai). Physicochemical characterization has been carried out to determine the structure of the complexes. The FAB mass and thermal data show degradation pattern of the complexes. XRD analysis reveals that all the studied complexes crystallize as tetragonal crystal system. Some of the complexes have been screened for their antimicrobial activity by the well diffusion technique using DMSO as solvent on different species of pathogenic bacteria/fungi, that is, E. coli, S. aureus, S. fecalis, A. niger, T. polysporum, and their antimicrobial potency have been discussed. It has been found that all the complexes are antimicrobially active and show higher activity than the free ligand. Metal chelation affects significantly the antimicrobial/bioactive behavior of the organic ligands.

Medicinal inorganic chemistry has been stimulating largely by the success of the anticancer drug, cisplatin. Various metal complexes are currently used as therapeutic agents (e.g., Pt, Au, and Ru) in the treatment of malignant diseases, including several types of cancers. Understanding the mechanism of action of these metal-based drugs is for the design of more effective drugs. Proteomic approaches combined with other biochemical methods can provide comprehensive understanding of responses that are involved in metal-based anticancer drugs-induced cell death, including insights into cytotoxic effects of metal-based anticancer drugs, correlation of protein alterations to drug targets, and prediction of drug resistance and toxicity. This information, when coupled with clinical data, can provide rational basses for the future design and modification of present used metal-based anticancer drugs.

A class of Ag(I) N-heterocyclic carbene silver complexes, 1-3, derived from 4,5-dichloro-1H-imidazole has been evaluated for their anticancer activity against the human cancer cell lines OVCAR-3 (ovarian), MB157 (breast), and Hela (cervical). Silver complexes 1-3 are active against the ovarian and breast cancer cell lines. A preliminary in vivo study shows 1 to be active against ovarian cancer in mice. The results obtained in these studies warrant further investigation of these compounds in vivo.

Cancerous diseases present a formidable health problem worldwide. While the chemotherapy of cancer, in conjunction with other treatment modalities, has reached a significant level of maturity, efficacious use of such agents is still restricted by numerous pharmacological deficiencies, such as poor water solubility, short serum circulation lifetimes, and low bioavailability resulting from lack of affinity to cancer tissue and inadequate mechanisms of cell entry. More critically still, most drugs suffer from toxic side effects and a risk of drug resistance. The class of platinum anticancer drugs, although outstandingly potent, is particularly notorious in that respect. Among the countless methods developed in recent years in an effort to overcome these deficiencies, the technology of polymer-drug conjugation stands out as a particularly advanced treatment modality. The strategy involves the bioreversible binding, conjugating, of a medicinal agent to a water-soluble macromolecular carrier. Following pharmacokinetic pathways distinctly different from those of the common, nonpolymeric drugs, the conjugate so obtained will act as a prodrug providing safe transport of the bioactive agent to and into the affected, that is, cancerous cell for its ultimate cell-killing activity. The present treatise will acquaint us with the pharmacological fundamentals of this drug delivery approach, applied here specifically to the metalorganic platinum-type drug systems and the organometallic ferrocene drug model. We will see just how this technology leads to conjugates distinctly superior in antiproliferative activity to cisplatin, a clinically used antitumor agent used here as a standard. Polymer-drug conjugation involving metal-based and other medicinal agents has unquestionably matured to a practical tool to the pharmaceutical scientist, and all indications point to an illustrious career for this nascent drug delivery approach in the fight against cancer and other human maladies.

Some antifertility inhibitors of 18 to 24-membered tetraazamacrocyclic complexes of iron(II) and manganese(II) have been synthesised by the template condensation using 1,3-phenylenediamine with malonic acid, succinic acid, glutaric acid and adipic acid. The reaction proceed smoothly to completion. The complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic, magnetic moment, mössbaur and mass spectral studies. The elemental analyses are consistent with the formation of the complexes [M(N(4)L(n))Cl(2)] (M = Fe(lI) or Mn(II)). All these complexes are stable and monomeric in nature as indicated by the molecular weight determinations. The spectral studies confirm the octahedral geometry around the central metal atom. The complexes have been screened in vitro against a number of fungi and bacteria to assess their growth inhibiting potential. The testicular sperm density and testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in mating trials and biochemical parameters of reproductive organs have been examined and discussed.