Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5'-GMP

Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by ¹H NMR, ¹⁹⁵Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5′-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.     

Dinuclear platinum anticancer complexes with fluorescent N,N′-bis(aminoalkyl)-1,4-diaminoanthraquinones: cellular processing in two cisplatin-resistant cell lines reflects the differences in their resistance profiles

The biological activity of N,N-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl is 2-aminoethyl, 3-aminoprop-1-yl and 4-aminobut-1-yl) and their dinuclear platinum complexes has been evaluated in the U2-OS human osteosarcoma cell line and its cisplatin-resistant U2-OS/Pt subline. All the compounds have been found to exhibit high cytotoxicity in the sensitive cell line, and to overcome cisplatin resistance in U2-OS/Pt cells. Cellular processing of N,N-bis(2-aminoethyl)-1,4-diaminoanthraquinone and the respective dinuclear platinum complex in the sensitive and resistant U2-OS cells has been studied over time using digital fluorescence microscopy. Cellular processing of the compounds has been found to be similar in sensitive and resistant U2-OS cells, which is in agreement with the lack of cross-resistance in the U2-OS/Pt cell line. Both the platinum complex and the free ligand quickly enter the cell and accumulate in the nucleus. The platinum complex is excreted from the cell via the Golgi apparatus, while the weakly basic anthraquinone ligand accumulates in the Golgi complex, where it is taken up by lysosomes and then transported to the cell surface. The cellular distribution of the fluorescent anthraquinones and their dinuclear platinum complexes in the sensitive/resistant pair of U2-OS osteosarcoma cell lines is compared with the earlier studied cellular processing in the sensitive/resistant pair of A2780 ovarian carcinoma cell lines. In the A2780cisR cell line, the platinum complexes (and not the free ligands) are sequestered in lysosomes, which is not the case in A2780 sensitive cells. The differences in cellular distribution of the compounds in these two sensitive/resistant pairs of cell lines most likely result from different resistance profiles in A2780cisR and U2-OS/Pt cells. Lysosomes of A2780cisR cells are less acidic than lysosomes of A2780 sensitive cells, which is likely to be the cause of a defect in endocytosis. The disruption of normal endocytosis might facilitate sequestration of the platinum complexes in lysosomes, which partly confers the cross-resistance of these complexes with cisplatin in the A2780cisR cell line. In contrast, sequestration in acidic vesicles does not occur in U2-OS/Pt cells that do not exhibit enhanced lysosomal pH and which are likely to have normal endocytosis.     

Contribution of intracellular ATP to cisplatin resistance of tumor cells

Decreased cellular accumulation of cisplatin is a frequently observed mechanism of resistance to the drug. Beside passive diffusion, several cellular proteins using ATP hydrolysis as an energy source are assumed to be involved in cisplatin transport in and out of the cell. This investigation aimed at clarifying the contribution of intracellular ATP as an indicator of energy-dependent transport to cisplatin resistance using the A2780 human ovarian adenocarcinoma cell line and its cisplatin-resistant variant A2780cis. Depletion of intracellular ATP with oligomycin significantly decreased cellular platinum accumulation (measured by flameless atomic absorption spectrometry) in sensitive but not in resistant cells, and did not affect cisplatin efflux in both cell lines. Inhibition of Na⁺,K⁺-ATPase with ouabain reduced platinum accumulation in A2780 cells but to a lesser extent compared with oligomycin. Western blot analysis revealed lower expression of Na⁺,K⁺-ATPase α₁ subunit in resistant cells compared with sensitive counterparts. The basal intracellular ATP level (determined using a bioluminescence-based assay) was significantly higher in A2780cis cells than in A2780 cells. Our results highlight the importance of ATP-dependent transport, among other processes mediated by Na⁺,K⁺-ATPase, for cisplatin influx in sensitive cells. Cellular platinum accumulation in resistant cells is reduced and less dependent on energy sources, which may partly result from Na⁺,K⁺-ATPase downregulation. Our data suggest the involvement of other ATP-dependent processes beside those regulated by Na⁺,K⁺-ATPase. Higher basal ATP level in cisplatin-resistant cells, which appears to be a consequence of enhanced mitochondrial ATP production, may represent a survival mechanism established during development of resistance.     

Platinum(II) Complexes with 1,10‐Phenanthroline and Hydrophilic Alkoxyacetate Ligands as Potential Antitumor Agents

Four platinum complexes, formulated as [Pt(phen)(OCOCH₂OR)₂] (phen=1,10‐phenanthroline, R=Me, Et, ⁱPr, or ^tBu), have been synthesized and well characterized by elemental analysis, IR, ¹H‐NMR, ¹³C‐NMR and ESI‐MS spectroscopy. Replacing chloride groups of the precursor Pt(phen)Cl₂ with alkoxyacetate anions greatly improved the aqueous solubility and cytotoxicity of the resulting platinum complexes. The in vitro cytotoxicity study revealed that complexes 1 – 3 were active in vitro towards four human tumor cell lines, especially complex 1 which exhibited prominent in vitro cytotoxic activity against HCT‐116 cell lines comparable to cisplatin and oxaliplatin. Flow cytometry assay indicated that representative complexes 1 and 2 exerted cytotoxicity on HCT‐116 cell lines through inducing cell apoptosis and blocking cell cycle progression in the S or G2/M phases. The interaction of representative complexes with pET28a plasmid DNA was tested by agarose gel electrophoresis, which demonstrated that complexes 1 and 2 were capable of distorting plasmid DNA mainly by covalent binding and degradation effect.     

Bifunctional Platinum(II) Complexes with Bisphosphonates Substituted Diamine Derivatives: Synthesis and In vitro Cytotoxicity

A series of N,N′‐dibisphosphonate‐containing 1,3‐propanediamine derivatives ( L1 – L6 ) and their corresponding dichloridoplatinum(II) complexes ( 1 – 6 ) have been synthesized and characterized by elemental analysis, ¹H‐NMR, ¹³C‐NMR, ³¹P‐NMR and HR‐MS spectra. The in vitro antitumor activities of compounds L1 – L6 and 1 – 6 were tested by WST‐8 assay with Cell Counting Kit‐8, indicating that platinum‐based complexes 1 – 6 showed higher cytotoxicity than corresponding ligands L1 – L6 against A549 and MG‐63, especially complex 2 which displayed comparable cytotoxicity to those of cisplatin and zoledronate after 48 h incubation. In addition, complexes 1 – 6 were more active in vitro on osteosarcoma cell line MG‐63 than normal osteoblast cell line hFOB 1.19. The structure‐activity relationship has been summarized based on the in vitro cytotoxicity of three series of platinum complexes from this and our previous studies. The in vitro bone affinity of platinum complexes was also tested by hydroxyapatite (HAP) chromatography in terms of capacity factor K′. Besides, in this paper, representative complex 2 , which has been proved to be a promising antitumor agent with high cytotoxicity and bone HAP binding property, was investigated for its mechanism of action producing cell death against MG‐63.     

Structure-activity relationship studies for three new asymmetric cis-platinum(II) aminoethanol-based complexes

The design and synthesis of three asymmetrical platinum(II) analogues of cisplatin with substituents on the amine, varying in polarity and steric bulk is presented. Their biological activities, as studied using in vitro cytotoxicity studies in cisplatin sensitive and the corresponding cisplatin resistant cell lines, cellular uptake experiments and in a reaction with model DNA base GMP, are presented. All compounds exhibit promising cytotoxicity in the cisplatin sensitive cell lines albeit lower than cisplatin. On the other hand, the complexes partly overcome cisplatin resistance in the resistant cell lines. A direct correlation between cytotoxicity and cellular uptake was found. Conversely, the rate of reaction of all compounds with the model base GMP was found to be very similar and faster than cisplatin. It was therefore concluded that the difference in activity observed for these complexes is due to differential cellular uptake rather than the reactivity towards the cellular target of platinum complexes, nuclear DNA.     

Cellular accumulation and DNA platination of two new platinum(II) anticancer compounds based on anthracene derivatives as carrier ligands

The anticancer properties of two new fluorescent platinum(II) compounds, cis-[Pt(A9opy)Cl₂] and cis-[Pt(A9pyp)(dmso)Cl₂] are described. These compounds are highly active against several human tumor cell lines, including human ovarian carcinoma sensitive and cisplatin-resistant cell lines (A2780 and A2780R). To study the cellular processing of these new compounds, a series of in vitro studies have been performed, including the investigation of intracellular platinum accumulation and DNA-platination experiments in A2780 and A2780R cells. Compared to cisplatin, both compounds are accumulated highly in both sensitive and resistant cell lines, and more platinum has been found to bind to the nuclear DNA. Interestingly, cis-[Pt(A9opy)Cl₂] shows high accumulation and DNA adduct formation in the resistant cell line A2780R, as compared to the sensitive counterpart A2780 cell line. This suggests that cis-[Pt(A9opy)Cl₂] is able to overcome some of the well-known resistance mechanisms in this cell line, such as decreased cellular uptake and increased DNA repair.     

In vitro antitumor activity and interaction with DNA model bases of cis-[PtCl2(iPram)(azole)] complexes and comparison with their trans analogues

Asymmetric cis-platinum(II) complexes with isopropylamine and two different azole ligands were synthesized and characterized with different techniques. In addition, for one of the complexes the X-ray structure was determined. Cytotoxicity tests using several human tumor cell lines, including the cisplatin-sensitive cell line A2780 and its cisplatin-resistant analogue. These results were compared with the results obtained for the trans isomers of the presented complexes and a relation between the structure and the activity was established. It was found that complexes with cis geometry are less active than their trans analogues, in particular in the resistant cell line A2780R. However, complex 1 can overcome cisplatin resistance to a certain extent. In the interaction with GMP, the asymmetric cis-Pt(II) complexes react with similar rates as their trans analogues and they behave as bifunctional species.     

Studies of interaction of trichloro{eta2-cis-N,N-dimethyl-1-[6-(N',N'-dimethyl-ammoniummethyl)-cyclohex-3-ene-1-yl]-methylammonium}platinum(II) chloride with DNA: Effects on secondary and tertiary structures of DNA. Cytotoxic assays on human ovarian cancer cell lines, resistant and non-resistant to cisplatin

The studies of interaction with DNA and the cytotoxic activity of a new organometallic platinum(II) compound are presented. The ability of this new platinum complex to modify secondary DNA structure was explored by circular dichroism (CD). Electrophoretic mobility showed changes in tertiary DNA structure, and atomic force microscopy (AFM) revealed morphological changes of plasmid DNA (pBR322). This compound breaks the traditional structure-activity rules for cis-platinum compounds, but it could be of interest because of its different kinetics. An organometallic bond normally shows a trans-effect higher than that of an amine ligand, and that fact, a priori, could contribute to a higher DNA binding rate. Several ovarian cancer cell lines, resistant and non-resistant to cisplatin, were exposed to increasing concentrations of cisplatin and complex 5 for 24 h, after which time the cell number/viability was determined by the colorimetric MTT assay. A lower cytotoxicity but also a lower resistant factor was observed for organometallic compound 5 than for cisplatin, against A2780 and A2780cisR cell lines. This result is consistent with the DNA interaction degree observed by the aforementioned techniques.     

Novel C,N-chelate platinum(II) antitumor complexes bearing a lipophilic ethisterone pendant

The novel steroidal carrier ligand 17-α-[4′-ethynyl-dimethylbenzylamine]-17-β-testosterone (ET-dmba 1) and the steroid — C,N-chelate platinum(II) derivatives [Pt(ET-dmba)Cl(L)] (L = DMSO (2) and PTA (3; PTA = 1,3,5-triaza-7-phosphaadamantane)) have been prepared. Values of IC₅₀ were calculated for the new platinum complexes 2 and 3 against a panel of human tumor cell lines representative of ovarian (A2780 and A2780cisR) and breast cancers (T47D). At 48 h incubation time complexes 2 and 3 show very low resistance factors (RF of < 2) against an A2780 cell line which has acquired resistant to cisplatin and were more active than cisplatin (about 4-fold for 3) in T47D (AR+, AR = androgen receptor). Compound 1 retains a moderate degree of relative binding affinity (RBA = 0.94%) for androgen receptors. The cytotoxicity of the non steroidal platinum analogues [Pt(dmba)Cl(L)] (dmba = dimethylbenzylamine; L = DMSO (4) and PTA (5)) has also been studied for comparison purposes. Theoretical calculations at the BP86/def2-TZVP level of theory on complex 3 have been undertaken.     

Evaluation of anionic half generation 3.5-6.5 poly(amidoamine) dendrimers as delivery vehicles for the active component of the anticancer drug cisplatin

Aquated cisplatin was added to half-generation PAMAM dendrimers and the resultant complexes were purified by centrifuge. The drug-dendrimer complexes were then characterised by 1-D and diffusion ¹H NMR and ICP-AES. The amount of drug bound was found to increase in proportion with dendrimer size: G3.5, 22 cis-{Pt(NH₃)₂} molecules per dendrimer; G4.5, 37; G5.5, 54; and G6.5, 94, which represent only a fraction of the available binding sites on each dendrimer (68, 58, 42 and 37%, respectively). Drug release studies showed that some drug remains bound to the dendrimer even after prolonged incubation with 5′—GMP at temperatures of 60 °C for over a week (percentage of drug released 18, 30, 35 and 63%, respectively). Attachment of the drug was found to decrease the radius of the dendrimers. Finally, the effect of the dendrimer on drug cytotoxicity was determined using in vitro assays with the A2780, A2780cis and A2780cp ovarian cancer cell lines. The free dendrimers display no cytotoxicity whilst the drug-dendrimer complexes showed moderate activity. In vivo activity was examined using an A2780 tumour xenograft. Cisplatin, at its maximum tolerated dose of 6 mg/kg, reduced tumour size by 33% compared to an untreated control group. The G6.5 cisplatin-dendrimer complex was administered at two doses (6 and 8 mg/kg equivalent of cisplatin). Both were well tolerated by the mice. The lower dose displayed comparable activity to cisplatin with a tumour volume reduction of 32%, but the higher dose was significantly more active than free cisplatin with a tumour reduction of 45%.     

Design,synthesis and biological evaluation of six dinuclear platinum(II) complexes

Six dinuclear platinum(II) complexes with a chiral tetradentate ligand, (1R,1′R,2R,2′R)-N¹,N^1′-(1,4-phenylenebis(methylene))dicyclohexane-1,2-diamine, have been designed, synthesized and characterized. In vitro cytotoxicity evaluation of these metal complexes against human A549, HCT-116, MCF-7 and HepG-2 cell lines have been carried out. All compounds showed antitumor activity to HepG-2, HCT-116 and A549. Particularly, compounds A1 and A2 exhibited significant better activity than other four compounds and A2 even showed comparable cytotoxicity to cisplatin against HepG-2 cell line.     

DNA and glutathione interactions in cell-free media of asymmetric platinum(II) complexes cis- and trans-[PtCl2(isopropylamine)(1-methylimidazole)]: relations to their different antitumor effects

The global modification of mammalian and plasmid DNAs by the novel platinum compounds cis-[PtCl₂(isopropylamine)(1-methylimidazole)] and trans-[PtCl₂(isopropylamine)(1-methylimidazole)] and the reactivity of these compounds with reduced glutathione (GSH) were investigated in cell-free media using various biochemical and biophysical methods. Earlier cytotoxicity studies had revealed that the replacement of the NH₃ groups in cisplatin by the azole and isopropylamine ligands lowers the activity of cisplatin in both sensitive and resistant cell lines. The results of the present work show that this replacement does not considerably affect the DNA modifications by this drug, recognition of these modifications by HMGB1 protein, their repair, and reactivity of the platinum complex with GSH. These results were interpreted to mean that the reduced activity of this analog of cisplatin in tumor cell lines is due to factors that do not operate at the level of the target DNA. In contrast, earlier studies had shown that the replacement of the NH₃ groups in the clinically ineffective trans isomer (transplatin) by the azole and isopropylamine ligands results in a radical enhancement of its activity in tumor cell lines. Importantly, this replacement also markedly alters the DNA binding mode of transplatin, which is distinctly different from that of cisplatin, but does not affect reactivity with GSH. Hence, the results of the present work are consistent with the view and support the hypothesis systematically tested by us and others that platinum drugs that bind to DNA in a fundamentally different manner from that of conventional cisplatin may have altered pharmacological properties.     

Synthesis and characterization of palladium(II) and platinum(II) complexes with Schiff bases derivatives of 2-pyridincarboxyaldehyde. Study of their interaction with DNA

Several Schiff bases ligand derivatives of 2-pyridincarboxyaldehyde and different amines, together with their palladium(II) and platinum(II) complexes have been synthesised and characterised. The aim of this study is to probe the influence of substituents beared on the pyridyl/toulene ring at different position to their possible antitumor activity. The amines used were o-, m-, p-toluidine and 4-hydroxyaniline. All the compounds were characterised by elemental analysis, FT-IR spectroscopy, 1H and 195Pt NMR spectroscopy and matrix assisted laser desorption/ionization time-of-flight mass spectroscopy. The formation of DNA adducts were analysed by circular dichroism and electrophoretic mobility. Atomic force microscopy images of the compounds with plasmid DNA pBR322 were also obtained. In all cases changes in the second and tertiary structure of DNA could be observed as a consequence of the covalent interaction of the palladium(II) or platinum(II) ions with the N of the nucleobases. However, there are not significant differences in the behavior of the complexes related to the position of the methyl groups or the presence of the OH group. Values of IC50 were also calculated for the platinum(II) complexes for several pairs of ovarian tumor cell lines which were either sensitive or resistant to cisplatin. Finally in vitro apoptosis studies for platinum(II) complexes with ovarian tumor cell lines A2780/A2780cisR were carried out. The results indicated interesting antiproliferative activity and significant apoptosis induction.     

Bis‐ and Tetrakis(carboxylato)platinum(IV) Complexes with Mixed Axial Ligands – Synthesis,Characterization, and Cytotoxicity

A series of twelve novel diamminetetrakis(carboxylato)platinum(IV) and 18 novel bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) complexes with mixed axial carboxylato ligands was synthesized and characterized by multinuclear ¹H‐, ¹³C‐, ¹⁵N‐, and ¹⁹⁵Pt‐NMR spectroscopy. Their cytotoxic potential was evaluated (by MTT assay) against three human cancer cell lines derived from ovarian teratocarcinoma (CH1/PA‐1), lung (A549), and colon carcinoma (SW480). In the cisplatin‐sensitive CH1/PA‐1 cancer cell line, diamminetetrakis(carboxylato)platinum(IV) complexes showed IC₅₀ values in the low micromolar range, whereas, for the most lipophilic compounds of the bis(carboxylato)dichlorido(ethane‐1,2‐diamine)platinum(IV) series, IC₅₀ values in the nanomolar range were found.     

Side-on binding of p-sulphonatocalix[4]arene to the dinuclear platinum complex trans-[{PtCl(NH3)2}2μ-dpzm] and its implications for anticancer drug delivery

The utility of p-sulphonatocalix[4]arene (s-CX[4]) as a drug delivery vehicle for multinuclear platinum anticancer agents, using trans-[{PtCl(NH₃)₂}₂μ-dpzm]²⁺ (di-Pt; where dpzm = 4,4′-dipyrazolylmethane) as a model complex, has been examined using ¹H nuclear magnetic resonance, electrospray ionisation mass spectrometry, molecular modelling and in vitro growth inhibition assays. s-CX[4] binds di-Pt in a side-on fashion in a ratio of 1:1, with the dpzm ligand of the metal complex located within the s-CX[4] cavity with binding further stabilised by ion-ion interactions and hydrogen bonding between the metal complex am(m)ine groups and the s-CX[4] sulphate groups. Partial encapsulation of di-Pt within the cavity does not prevent binding of 5′-guanosine monophosphate to the metal complex. When bound to two individual guanosine molecules, di-Pt also remains partially bound by s-CX[4]. The cytotoxicity of free di-Pt and s-CX[4] and their host guest complex was examined using in vitro growth inhibition assays in the A2780 and A2780cis human ovarian cancer cell lines. Free di-Pt has an IC₅₀ of 100 and 60 μM, respectively, in the cell lines, which is significantly less active than cisplatin (1.9 and 8.1 μM, respectively). s-CX[4] displays no cytotoxicity at concentrations up to 1.5 mM and does not affect the cytotoxicity of di-Pt, probably because its low binding constant to the metal complex (6.8 × 10⁴ M⁻¹) means the host-guest complex is mostly disassociated at biologically relevant concentrations.     

GDF15基因在卵巢上皮性癌组织中的表达及其临床意义

目的:探讨生长分化因子GDF15(Growth Differentiation Factor 15)基因在卵巢上皮性癌组织中的表达及其与铂类耐药的相关性。方法:应用免疫组化、western blot、RT-PCR等方法对80例原发性卵巢癌组织和卵巢癌顺铂敏感/耐药株A2780和CP70、SKOV3和SKOV3/DDP中生长分化因子GDF15表达水平进行测定。结果:生长分化因子GDF15的表达强度与卵巢癌铂类耐药性显著相关。在卵巢癌顺铂耐药株CP70、SKOV3/DDP中GDF15表达水平较顺铂敏感株A2780、SKOV3明显增高。结论:GDF15表达水平与卵巢癌发生发展及铂类耐药相关,对于卵巢癌患者早期筛选、预测预后具有一定的临床指导价值。     

Dinuclear platinum complexes with<Emphasis Type="Italic"> N</Emphasis>,<Emphasis Type="Italic">N</Emphasis>′-bis(aminoalkyl)-1,4-diaminoanthraquinones as linking ligands. Part II. Cellular processing in A2780 cisplatin-resistant human ovarian carcinoma cells: new insights into the mechanism of resistance

The cellular processing of three fluorescent N,N-bis(aminoalkyl)-1,4-diaminoanthraquinones (aminoalkyl=2-aminoethyl, 3-aminoprop-1-yl or 4-aminobut-1-yl) and their dinuclear platinum complexes in A2780 human ovarian carcinoma cells with acquired resistance to cisplatin has been monitored over time by time-lapse fluorescence microscopy. The results were compared with the previously reported observations in the parent A2780 cell line. The cellular distribution pattern for the free ligands is similar in sensitive and resistant cells, whereas significant differences in cellular distribution were observed in the case of the platinum complexes. In the cisplatin-resistant cell line the platinum complexes were found to be sequestrated in acidic vesicles in the cytosol from the very beginning of the incubation. This sequestration was not observed in the case of sensitive cells. Platinum accumulation in vesicles possibly presents a mechanism of resistance to platinum complexes. This mechanism appears to be unrelated to the mechanism of deactivation of platinum compounds by glutathione. Encapsulation of the dinuclear platinum complexes in lysosomal vesicles provides a plausible explanation for the decreased activity of these compounds in the resistant cell line, as compared to the sensitive cell line.Abbreviations AQ2 N,N-bis(2-aminoethyl)-1,4-diaminoanthracene-9,10-dione - AQ3 N,N-bis(3-aminoprop-1-yl)-1,4-diaminoanthracene-9,10-dione - AQ4 N,N-bis(4-aminobut-1-yl)-1,4-diaminoanthracene-9,10-dione - l-BSO l-buthionine-S,R-sulfoximine - dien diethylenetriamine - MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide - PAQ2 [{trans-PtCl(NH₃)₂}₂(-AQ2)](NO₃)₂ - PAQ3 [{trans-PtCl(NH₃)₂}₂(-AQ3)](NO₃)₂ - PAQ4 [{trans-PtCl(NH₃)₂}₂(-AQ4)](NO₃)₂ - PAM [{Pt(dien)}₂(-AQ2)](NO₃)₄ - PBS phosphate buffered saline     

Novel cyclopalladated and coordination palladium and platinum complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazones): structural studies and cytotoxic activity against human A2780 and A2780cisR carcinoma cell lines

The preparation of new palladium(II) and platinum(II) complexes derived from alpha-diphenyl ethanedione bis(thiosemicarbazone), 1, and alpha-diphenyl ethanedione bis(4-ethylthiosemicarbazone), 2, is described. The palladium complexes 3 and 4 and platinum complexes 5 and 6 have been characterized by elemental analyses, fast atom bombardment mass spectrometry (FAB(+)) and spectroscopic studies (IR, (1)HNMR). The crystal and molecular structures of the dimeric cyclopalladated compound 4 and the mononuclear platinum complex 6 have been determined by single crystal X-ray diffraction. The cytotoxic activity of the free ligands and palladium and platinum complexes against human A2780 and A2780cisR (acquired resistance to cisplatin) epithelial ovarian carcinoma cells lines is also reported. The IC(50) values for compounds 1, 5 and 6 were found to be higher than that of cisplatin but the maximum antiproliferative activity was similar. Furthermore, the compounds largely retain their activity in the A2780cisR cell line, having a much better resistance factor than cisplatin in the pair of cell lines tested.