Hristo P. Varbanov

Synthesis and characterization of novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes with higher cytotoxicity than cisplatin

A series of six novel bis(carboxylato)dichloridobis(ethylamine)platinum(IV) complexes was synthesized and characterized in detail by elemental analysis, FT-IR, ESI-MS, HPLC, multinuclear (1H, 13C, 15N, 195Pt) NMR spectroscopy and in one case by X-ray diffraction. Cytotoxic properties of the complexes were evaluated in four human tumor cell lines originating from ovarian carcinoma (CH1 and SK-OV-3), colon carcinoma (SW480) and non-small cell lung cancer (A549) by means of the MTT colorimetrical assay. In addition, their octanol/water partition coefficients (log P values) were determined. Remarkably the most active (and also most lipophilic) compounds, having 4-propyloxy-4-oxobutanoato and 4-(2-propyloxy)-4-oxobutanoato axial ligands, showed IC50 values down to the low nanomolar range.

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 depth characterization is based on elemental analysis, ESI-MS, ATR-IR, and multinuclear ((1)H, (13)C, (15)N, and (195)Pt) NMR spectroscopy. Their cytotoxic activity in four cell lines (CH1, SK-OV-3, SW480, and A549), lipophilicity, electrochemistry and additionally the rate of reduction in the presence of ascorbic acid were investigated. In contrast to analogous diaminedicarboxylatodichloridoplatinum(IV) compounds, the cytotoxicity of novel diaminetetracarboxylato counterparts could not substantially be increased by simply enhancing their lipophilic character. It seems that not only the reduction potential, but also the rate of reduction has a tremendous influence on the cytotoxic properties. This has to be taken into account for the development of novel anticancer platinum(IV) agents.

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. The hybrid DFT functional wb97x was used for optimization of the structure geometry and calculation of the descriptors. Reliable and robust QSAR models with good explanatory and predictive properties were obtained for both the cisplatin sensitive cell line CH1 and the intrinsically cisplatin resistant cell line SW480, with a set of four descriptors.

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. Their in vitro cytotoxicity was determined in a panel of human tumor cell lines (CH1, SW480 and A549) by means of the MTT colorimetric assay. Furthermore, the lipophilicity and redox properties of the novel complexes were evaluated in order to better understand their pharmacological behavior. The most promising drug candidate, 4b (Pt(DACH)(mal)2), demonstrated low in vivo toxicity but profound anticancer activity against both the L1210 leukemia and CT-26 colon carcinoma models.

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. The error of the consensus model, 0.65 for Pt(IV) and 0.37 for Pt(II) complexes, indicates its good accuracy of predictions. The lower accuracy for Pt(IV) complexes was attributed to experimental difficulties with logP measurements for some poorly-soluble compounds. This model was developed using general-purpose descriptors such as extended functional groups, molecular fragments and E-state indices. Surprisingly, models based on quantum-chemistry calculations provided lower prediction accuracy. We also found that all the developed models strongly overestimate logP values for the three complexes measured in the presence of DMSO. Considering that DMSO is frequently used as a solvent to store chemicals, its effect should not be overlooked when logP measurements by means of the shake flask method are performed. The final models are freely available at http://ochem.eu/article/76903.

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). The higher activity and improved accumulation of platinum(IV) complexes bearing Cl(-) in equatorial position cannot only be attributed to passive diffusion facilitated by their lipophilicity. Therefore, further platinum accumulation experiments under conditions where active/facilitated transport mechanisms are suppressed were performed. Under hypothermic conditions (4°C), accumulation of dichloridoplatinum(IV) complexes is reduced down to 10% of the amount determined at 37°C. These findings suggest the involvement of active and/or facilitated transport in cellular uptake of platinum(IV) complexes with a cisplatin-like core. Studies with ATP depletion mediated by oligomycin and low glucose partially confirmed these observations, but their feasibility was severely limited in the adherent cell culture setting.

Platinum Complexes with 5-Methyl-5(4-pyridyl)hydantoin and Its 3-Methyl Derivatives: Synthesis and Cytotoxic Activity - Quantitative Structure-Activity Relationships

3,5‐Dimethyl‐5‐(4‐pyridyl)hydantoin (L) and its platinum(II) and platinum(IV) complexes with the general formula cis‐[PtL2X2] · n H2O and [PtL2Cl4], where XCl, I and n = 2‐4 were synthesized. A new Pt(IV) complex with 5‐methyl‐5‐(4‐pyridyl)hydantoin (L′) with the formula cis‐[Pt(L′)2Cl2(OH)2] · 5 H2O was also synthesized. The novel compounds were characterized by elemental analysis, IR, 1H‐, 13C‐, 195Pt‐NMR spectra and molar conductivity. The cytotoxic effects of these complexes were examined on three human tumor cell lines by MTT‐dye reduction assay. These four new Pt(II) and Pt(IV) complexes and a set of another twelve Pt(II), Pt(IV), and Pd(II) complexes previously synthesized and tested were compiled and a QSAR model was derived in order to direct the further rational synthesis.

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. Moreover, the influence of equatorial ligands on the stability, lipophilicity and cytotoxicity of platinum(IV) compounds was evaluated. For this purpose, a series of platinum(IV) complexes featuring axial carboxylato ligands (succinic acid monoesters) was synthesized; anionic carboxylato (OAc-, oxalate) and halido (Cl-, Br-, I-) ligands served as leaving groups and am(m)ine carrier ligands were provided by monodentately (isopropylamine, ammine+cyclohexaneamine) or bidentately (ethane-1,2-diamine) coordinating am(m)ines. All platinum(IV) products were fully characterized based on elemental analysis, high resolution mass spectrometry and multinuclear (1H, 13C, 15N, 195Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The rate of reduction in the presence of ascorbic acid was determined by NMR spectroscopy and the lipophilicity of the complexes was investigated by analytical reversed phase HPLC measurements. Cytotoxic properties were studied by means of a colorimetric microculture assay in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1) as well as cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549).

Synthesis and crystal structure of a Pt(II) complex with 3-amino-5-methyl-5-phenylhydantoin

The reaction of K2PtCl4 with 3-amino-5-methyl-5-phenylhydantoin (amphh, L) and KI in aqueous ethanol yields dark violet crystals of a binuclear platinum(II) complex. The molecular structure of the complex was determined by single-crystal X-ray diffraction methods. The complex crystallizes in the triclinic space group with a = 8.458(3), b = 11.016(2), c = 16.249(3) (Å), α = 94.630(14), β = 100.63(2), γ = 108.55(4)° and Z = 2. The structure consists of [K2L4]2+ cations and [Pt2I6]2− anions bridged by K–I bonds to form quasi-one-dimensional chains along the b axis. Chains are linked by K+ ··· π(Ph) interactions and N–H ··· O hydrogen bonds. The complex is compared with data for related structures.

Repositioning approved drugs for the treatment of problematic cancers using a screening approach.

Advances in treatment strategies together with an earlier diagnosis have considerably increased the average survival of cancer patients over the last four decades. Nevertheless, despite the growing number of new antineoplastic agents introduced each year, there is still no adequate therapy for problematic malignancies such as pancreatic, lung and stomach cancers. Consequently, it is important to ensure that existing drugs used to treat other types of cancers, and potentially other diseases, are not overlooked when searching for new chemotherapy regimens for these problematic cancer types. We describe a screening approach that identifies chemotherapeutics for the treatment of lung and pancreatic cancers, based on drugs already approved for other applications. Initially, the 1280 chemically and pharmacologically diverse compounds from the Prestwick Chemical Library® (PCL) were screened against A549 (lung cancer) and PANC-1 (pancreatic carcinoma) cells using the PrestoBlue fluorescent-based cell viability assay. More than 100 compounds from the PCL were identified as hits in one or both cell lines (80 of them, being drugs used to treat diseases other than cancer). Selected PCL hits were further evaluated in a dose-response manner. Promising candidates for repositioning emanating from this study include antiparasitics, cardiac glycosides, as well as the anticancer drugs vorinostat and topotecan.