Development of Cytotoxic GW7604-Zeise's Salt Conjugates as Multitarget Compounds with Selectivity for Estrogen Receptor- Positive Tumor Cells.

()-3-(4-(()-1-(4-Hydroxyphenyl)-2-phenylbut-1-enyl)phenyl)acrylic acid () as a carrier was esterified with alkenols of various lengths and coordinated through the ethylene moiety to PtCl, similar to Zeise's salt (K[PtCl(CH)]). The resulting complexes (Alk = Prop, But, Pent, Hex) degraded in aqueous solution only by exchange of the chlorido ligands. For example, coordinated the amino acid alanine in the cell culture medium, bound the isolated nucleotide 5'-GMP, and interacted with the DNA (empty plasmid pSport1).

Multifunctional Pt(iv) prodrug candidates featuring the carboplatin core and deferoxamine.

The synergistic combination of the anticancer drug carboplatin and the iron chelator deferoxamine (DFO) served as a foundation for the development of novel multifunctional prodrugs. Hence, five platinum(iv) complexes, featuring the equatorial coordination sphere of carboplatin, and one or two DFO units incorporated at axial positions, were synthesized and characterized using ESI-HRMS, multinuclear (H, C, N, Pt) NMR spectroscopy and elemental analysis. Analytical studies demonstrated that the chelating properties of the DFO moiety were not compromised after coupling to the platinum(iv) core.

Screening-based approach to discover effective platinum-based chemotherapies for cancers with poor prognosis.

Drug combinations are extensively used to treat cancer and are often selected according to complementary mechanisms. Here, we describe a cell-based high-throughput screening assay for identification of synergistic combinations between broadly applied platinum-based chemotherapeutics and drugs from a library composed of 1280 chemically and pharmacologically diverse (mostly FDA approved) compounds. The assay was performed on chemoresistant cell lines derived from lung (A549) and pancreatic (PANC-1) carcinoma, where platinum-based combination regimens are currently applied though with limited success.

The impact of whole human blood on the kinetic inertness of platinum(iv) prodrugs - an HPLC-ICP-MS study.

The potential advantage of platinum(iv) complexes as alternatives to classical platinum(ii)-based drugs relies on their kinetic stability in the body before reaching the tumor site and on their activation by reduction inside cancer cells. In this study, an analytical workflow has been developed to investigate the reductive biotransformation and kinetic inertness of platinum(iv) prodrugs comprising different ligand coordination spheres (respectively, lipophilicity and redox behavior) in whole human blood. The distribution of platinum(iv) complexes in blood pellets and plasma was determined by inductively coupled plasma-mass spectrometry (ICP-MS) after microwave digestion.

Impact of the equatorial coordination sphere on the rate of reduction, lipophilicity and cytotoxic activity of platinum(IV) complexes.

The impact of the equatorial coordination sphere on the reduction behavior (i.e. rate of reduction) of platinum(IV) complexes with axial carboxylato ligands was studied.

Oxaliplatin reacts with DMSO only in the presence of water.

Herein we show that oxaliplatin reacts rapidly with DMSO in aqueous solutions, despite being stable in pure DMSO and pure water. Furthermore, the reactivity of the clinically applied Pt(ii) drugs in water/DMSO and PBS/DMSO mixtures, and the nature of the species formed were investigated by MS, NMR and RP-HPLC techniques.

The role of the equatorial ligands for the redox behavior, mode of cellular accumulation and cytotoxicity of platinum(IV) prodrugs.

The current study aims to elucidate the possible reasons for the significantly different pharmacological behavior of platinum(IV) complexes with cisplatin-, carboplatin- or nedaplatin-like cores and how this difference can be related to their main physicochemical properties. Chlorido-containing complexes are reduced fast (within hours) by ascorbate and are able to unwind plasmid DNA in the presence of ascorbate, while their tri- and tetracarboxylato analogs are generally inert under the same conditions. Comparison of the lipophilicity, cellular accumulation and cytotoxicity of the investigated platinum compounds revealed the necessity to define new structure-property/activity relationships (SPRs and SARs).

Prediction of logP for Pt(II) and Pt(IV) complexes: Comparison of statistical and quantum-chemistry based approaches.

The octanol/water partition coefficient, logP, is one of the most important physico-chemical parameters for the development of new metal-based anticancer drugs with improved pharmacokinetic properties. This study addresses an issue with the absence of publicly available models to predict logP of Pt(IV) complexes. Following data collection and subsequent development of models based on 187 complexes from literature, we validate new and previously published models on a new set of 11 Pt(II) and 35 Pt(IV) complexes, which were kept blind during the model development step.

Tetracarboxylatoplatinum(IV) complexes featuring monodentate leaving groups - A rational approach toward exploiting the platinum(IV) prodrug strategy.

A series of novel symmetrically and unsymmetrically coordinated platinum(IV) complexes with monodentate carboxylato ligands was synthesized. The compounds exhibit a general coordination sphere of [Pt(en)(OCOR)2(OCOR')(OCOR″)], where the carboxylato ligands are represented by acetato and succinic acid monoester ligands. Dicarboxylatoplatinum(II) complexes were synthesized and oxidized symmetrically or unsymmetrically to obtain platinum(IV) complexes, which were subsequently carboxylated with noncyclic anhydrides.

Tumor microenvironment in focus: LA-ICP-MS bioimaging of a preclinical tumor model upon treatment with platinum(IV)-based anticancer agents.

The selection of drug candidates for entering clinical development relies on in vivo testing in (solid) tumor animal models. However, the heterogeneity of tumor tissue (e.g.

Comparative in vitro and in vivo pharmacological investigation of platinum(IV) complexes as novel anticancer drug candidates for oral application.

Platinum(IV) complexes are promising candidates as prodrugs for oral application in anticancer chemotherapy. However, only a few Pt(IV) compounds entered (pre)clinical trials, e.g.

A novel class of bis- and tris-chelate diam(m)inebis(dicarboxylato)platinum(IV) complexes as potential anticancer prodrugs.

A novel class of platinum(IV) complexes of the type [Pt(Am)(R(COO)2)2], where Am is a chelating diamine or two monodentate am(m)ine ligands and R(COO)2 is a chelating dicarboxylato moiety, was synthesized. For this purpose, the reaction between the corresponding tetrahydroxidoplatinum(IV) precursors and various dicarboxylic acids, such as oxalic, malonic, 3-methylmalonic, and cyclobutanedicarboxylic acid, was utilized. All new compounds were characterized in detail, using 1D and 2D NMR techniques, ESI-MS, FTIR spectroscopy, elemental analysis, TGA, and X-ray diffraction.

Theoretical investigations and density functional theory based quantitative structure-activity relationships model for novel cytotoxic platinum(IV) complexes.

Octahedral platinum(IV) complexes are promising candidates in the fight against cancer. In order to rationalize the further development of this class of compounds, detailed studies on their mechanisms of action, toxicity, and resistance must be provided and structure-activity relationships must be drawn. Herein, we report on theoretical and QSAR investigations of a series of 53 novel bis-, tris-, and tetrakis(carboxylato)platinum(IV) complexes, synthesized and tested for cytotoxicity in our laboratories.

Novel tetracarboxylatoplatinum(IV) complexes as carboplatin prodrugs.

It is widely accepted that platinum(IV) complexes act as prodrugs and have to be activated by reduction to the respective platinum(II) analogs. Recently it could be shown that introduction of lipophilic carboxylato ligands in the axial position leads to diaminedichloridoplatinum(IV) compounds with exceptionally high cytotoxicity. With the aim of improving the antiproliferative properties of carboplatin, a series of twenty-one novel Pt(IV) complexes, featuring the equatorial ligand sphere of carboplatin as well as lipophilic axial carboxylato ligands, was synthesized.

In vitro biochemical and pharmacological evaluation of a novel cytotoxic dinuclear platinum(II) complex with 3-amino-5-methyl-5-phenylhydantoin.

An in vitro pharmacological evaluation of a novel dinuclear platinum complex ([KL(2)](2)[Pt(2)I(6)], where L is 3-amino-5-methyl-5-phenylhydantoin; Ad-1) was carried out. The cytotoxicity of [KL(2)](2)[Pt(2)I(6)] against human tumor cell lines was assessed using the MTT [-3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide] assay. The complex exerted concentration-dependent cytotoxic effects that were comparable or even superior to that of cisplatin.