Tibor J. Sabo

Novel platinum(IV) complexes induce rapid tumor cell death in vitro

The anticancer activity of platinum complexes has been known since the discovery of classical Pt(II)‐based drug cisplatin. However, Pt(IV) complexes have greater inertness than corresponding Pt(II) complexes, thus allowing the oral administration and reducing the toxicity associated with platinum‐based chemotherapy. Here, we describe the in vitro antitumor activity of some novel Pt(IV)‐based agents against mouse fibrosarcoma L929 cells and human astrocytoma U251 cells. The cytotoxicity of 2 Pt(IV) complexes with bidentate ethylenediamine‐N,N′‐di‐3‐propanoato esters was found to be markedly higher than that of their Pt(II) counterparts and comparable to the antitumor action of cisplatin. In contrast to cisplatin, which caused oxidative stress‐independent apoptotic cell death of tumor cells, these Pt(IV) complexes induced oxygen radical‐mediated tumor cell necrosis. Importantly, the cytotoxic action of novel Pt(IV) complexes was markedly more rapid than that of cisplatin, indicating their potential usefulness in anticancer therapy.

Aloe emodin decreases the ERK-dependent anticancer activity of cisplatin

Abstract.The present study describes the ability of an anthraquinone derivative aloe emodin (AE) to reduce the cytotoxic activity of the platinum(II)-based anticancer agent cisplatin toward murine L929 fibrosarcoma and C6 glioma cell lines. The protective effect of AE was demonstrated by MTT and crystal violet assays for cell viability, and involved supression of cisplatin-induced apoptosis and necrosis, as assessed by lactate dehydrogenase release and flow cytometric analysis of DNA fragmentation or phosphatidylserine exposure. Cell-based ELISA and Western blot analysis revealed that AE abolished cisplatin-triggered activation of extracellular signal-regulated kinase (ERK) in tumor cells, while activation of c-Jun N-terminal kinase was not significantly altered. A selective blockade of ERK activation with PD98059 mimicked the protective effect of AE treatment in both tumor cell lines. Moreover, AE failed to protect tumor cells against the ERK-independent toxicity of the Pt(IV)-based complex tetrachloro(O,O-dibutyl-ethylenediamine-N,N′-di-3-propanoate)platinum(IV). Taken together, these data indicate that herbal anthraquinone AE can downregulate the anticancer activity of cisplatin by blocking the activation of ERK in tumor cells.

Cytotoxic studies of substituted titanocene and ansa-titanocene anticancer drugs

A variety of substituted titanocene and ansa-titanocene complexes have been synthesized and characterized using traditional methods. The cytotoxic activity of the different titanocene complexes was tested against tumour cell lines human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x and normal immunocompetent cells, peripheral blood mononuclear cells PBMC. Alkenyl substitution, either on the cyclopentadienyl ring or on the silicon-atom ansa-bridge of the titanocene compounds [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(3){CMe(2)CH(2)CH(2)CHCH(2)})}Cl(2)] (8), [Ti{Me(CH(2)CH)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (9) and [Ti(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CHCH(2)})(2)Cl(2)] (12) showed higher cytotoxic activities (IC(50) values from 24+/-3 to 151+/-10 microM) relative to complexes bearing an additional alkenyl-substituted silyl substituent on the silicon bridge [Ti{Me{(CH(2)CH)Me(2)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (10) and [Ti{Me{(CH(2)CH)(3)SiCH(2)CH(2)}Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (11) which causes a dramatic decrease of the cytotoxicity (IC(50) values from 155+/-9 to >200 microM). In addition, the synthesis of the analogous niobocene complex [Nb(eta(5)-C(5)H(4){CMe(2)CH(2)CH(2)CH=CH(2)})(2)Cl(2)] (13), is described. Structural studies based on DFT calculations of the most active complexes 8, 9 and 12 and the X-ray crystal structure of 13 are reported.

Synthesis and in vitro Anticancer Activity of Octahedral Platinum(IV) Complexes with Cyclohexyl‐Functionalized Ethylenediamine‐N,N′‐Diacetate‐Type Ligands

The present study describes the synthesis and anticancer activity of novel octahedral PtIV complexes with cyclohexyl functionalized ethylenediamine‐N,N′‐diacetate‐type ligands. Molecular mechanics calculations and density functional theory analysis revealed that s‐cis is the preferred geometry of these PtIV complexes with tetradentate‐coordinated (S,S)‐ethylenediamine‐N,N′‐di‐2‐(3‐cyclohexyl)propanoate. The viability of cancer cell lines (U251 human glioma, C6 rat glioma, L929 mouse fibrosarcoma, and B16 human melanoma) was assessed by measuring mitochondrial dehydrogenase activity and lactate dehydrogenase release. Cell‐cycle distribution, oxidative stress, caspase activation, and induction of autophagy were analyzed by flow cytometry using appropriate fluorescent reporter dyes. The cytotoxic activity of novel PtIV complexes against various cancer cell lines (IC50 range: 1.9–8.7 μM) was higher than that of cisplatin (IC50 range: 10.9–67.0 μM) and proceeded through completely different mechanisms. Cisplatin induced caspase‐dependent apoptosis associated with the cytoprotective autophagic response. In contrast, the new PtIV complexes caused rapid, caspase‐independent, oxidative stress‐mediated non‐apoptotic cell death characterized by massive cytoplasmic vacuolization, cell membrane damage, and the absence of protective autophagy.

TRANSITION METAL COMPLEXES WITH EDDA-TYPE LIGANDS—A REVIEW

ABSTRACT The review summarizes the results of recent studies on edda-type metal complexes. It focuses on work published during the period 1984–2001. The metals include are Co, Cr, Cu, Ni, Zn, Mn, Sn, Fe, V, Rh, Pt, Ru, whereas edda-type represents ethylenediamine-N,N′-diacetate, ethylenediamine-N,N-di-acetate, N,N′-dimethylethylenediamine-N,N′-diacetate, N,N′-diethylethylenediamine-N,N′-diacetate, 1,2-cyclo-hexanediamine-N,N′-diacetate, N,N′-dimethyl-1,2-cyclohexanediamine-N,N′-diacetate, ethylenediamine-N,N′-di-3-propionate, N,N′-dimethylethylenediamine-N,N′-di-3-propionate, ethylenediamine-N,N′-di-S-α-propionate, N,N′-dimethyl-ethylenediamine-N,N′-di-α-propionate, 1,3-propanediamine-N,N′-diacetate (trimethylenediamine-N,N′-diacetate), 1,3-propanediamine-N,N′-di-3-propionate (trimethylenediamine-N,N′-di-3-propionate), N,N′-dimethylethylenediamine-N,N′-di-α-butyrate, N,N′-diethylethylenediamine-N,N′-di-α-butyrate, 1-diethylenetriamineacetate (8-amino-3,6-diazao-ctanoate), ethylenepropylenetriamineacetate (9-amino-3,6-diazaoc- tanoate), dipropylenetriamineacetate (10-amino-3,6-diazaoc-tanoate), N,N-bis(2-aminoethyl)glycinate, N,N-bis(3-aminopropyl)glycinate, N-(2-aminoethyl)-N-(3-aminopropyl)glycinate, N-(2-aminoethyl)iminodiacetate (N-(2-aminoethyl)-N-carboxymethylglycine), N-(3-aminopropyl)imino diacetate tetradentate ligands. This paper provides a review of these complexes including their syntheses and X-ray crystal structures, spectroscopic (IR, Raman, NMR, ESR, electronic absorption and CD) measurements, electrochemistry, kinetic and thermodynamic information, magnetic properties, hydrolysis phenomena as well as chromatographic studies.

MIXED-LIGAND COMPLEXES OF COBALT(III) WITH DITHIOCARBAMATES AND A CYCLIC TETRADENTATE SECONDARY AMINE

Abstract 4-Morpholine-, piperidine-, 4-piperazine- and N-methyl- piperazine-dithiocarbamate complexes of Cobalt (III) with 1, 4, 8, 11-tetraazacyclotetradecane, of general formula [Co(Rdtc)cyclam] (C104)2, have been prepared and have been characterized. The complexes adopt cis-octahedral geometry with folded macrocyclic ligand and with the dithiocarbamate bound as a bidentate. trans-influence of the dithiocarbamate ligands was studied by NMR spectroscopy and established the order piperidine-dtc > 4-morpholine-dtc > N-methyl-piperazine-dtc.

Synthesis and characterization of the cobalt(III) complexes with ethylenediamine-N, N'-di-3-propanoate ligand and its esters

Abstract The novel N,N-type bidentate ligands, diethyl-(deeddp·2HCl), dipropyl- (dpeddp·2HCl), dibutyl- (dbeddp·2HCl) and dipentyl- (dveddp·2HCl) esters of ethylenediamine-N,N′-di-3-propanoic acid dihydrochloride (H2eddp·2HCl), and the eddp-cobalt(III) complexes with the corresponding esters have been synthesized via an air oxidation method. During the preparation of these complexes, one part of the ester coordinated as a bidentate ligand, and the other part hydrolyzed and coordinated as a tetradentate ONNO ligand geospecifically to the cobalt(III) ion to give only one isomer, C1-symmetric, which has been characterized by electronic absorption, infrared, 1H and 13C NMR spectroscopy and elemental analysis. It is of interest that this is the first CoIII(eddp)(N,N′-R2-en)-type complex preparation, which gives only one isomer, without regard to the number of atoms in the alkyl chain.

Platinum(IV) complex with pyridoxal semicarbazone

Abstract The synthesis and characterization of a new ligand and the first complex with semicarbazide based ligand coordinated to platinum(IV) ion are reported. The new ligand, pyridoxal semicarbazone (H2PxSC), and complex [Pt(HPxSC)Cl3] are characterized by elemental analysis, molar conductivity, infrared, electronic and 1 H NMR spectroscopy. The novel complex of platinum(IV) ion contains monoanionic, tridentate ONO ligand, and three chlorine ions.

Palladium(II) complexes with R2edda-derived ligands. Part II. Synthesis, characterization and in vitro antitumoral studies of R2eddip esters and palladium(II) complexes.

New R(2)eddip-type esters (R = cyclopentyl, L3 x 2 HCl 1.5 H(2)O; cyclohexyl, L4 x 2 HCl x H(2)O) and corresponding palladium(II) complexes, [PdCl(2)L3] (3) and [PdCl(2)L4] x H(2)O (4), as well as [PdCl(2)L2] (2; L2 diisobutyl ester of eddip) were synthesized and characterized by IR, (1)H and (13)C NMR spectroscopies and elemental analysis. The crystal structure of L3 x 2 HCl x 2 CHCl(3) was resolved and is given herein. The NMR spectroscopy confirmed the presence of two isomers (from three possible) for each palladium(II) complex. DFT calculations support the formation of two diastereoisomers. In addition, antitumoral investigations were performed and these investigations also included the diisopropyl ester of eddip (L1) and corresponding palladium(II) complex, [PdCl(2)L1] (1). In vitro antiproliferative activity was determined against several tumor cell lines HeLa, Fem-x, K562 and rested and stimulated normal immunocompetent cells (human peripheral blood mononuclear cells--PBMCs) using MTT test.

PREPARATION AND CHARACTERIZATION OF FACIAL AND MERIDIONAL ISOMERS OF UNS-CIS-(ETHYLENEDIAMINE-N,N'-DI-3-PROPIONATO)(GLYCINATO)COBALT(III) SEMIHYDRATE

Abstract Both theoretically possible geometrical isomers, facial and meridional, of uns-cis-(ethylenediamine-N, N′-di-3-propionato)(glycinato)cobalt(III) semi hydrate have been prepared by reaction of sodium uns-cis-(ethylenediamine-N, N′-di-3-propionato) (carbonato) cobaltate(III) with glycine at 75°C. The complexes have been isolated chromatographically and characterized by elemental analysis, electron absorption, infrared and nuclear magnetic spectra.