Tin(IV) complexes of pyrrolidinedithiocarbamate: synthesis, characterisation and antifungal activity

The reaction of ammonium pyrrolidinedithiocarbamate, [NH4{S2CN(CH2)4}], with SnCl2, [Sn(C6H5)2Cl2], [Sn(C6H5)3Cl], [Sn(C4H9)2Cl2] and [Sn(C6H11)3Cl] produced in good yield the compounds [Sn{S2CN(CH2)4}2Cl2] (1), [Sn{S2CN(CH2)4}2Ph2] (2), [Sn{S2CN(CH2)4}Ph3] (3), [Sn{S2CN(CH2)4}2 n-Bu2] (4) and [Sn{S2CN(CH2)4}Cy3] (5). The complexes were characterised by infrared, multinuclear NMR (1H, 13C{1H} and 119Sn{1H}) and 119Sn M?ssbauer spectroscopies. In addition, the crystal structure of 4 was determined by X-ray crystallography. The in vitro antifungal activity of the tin(IV) complexes as well of the ligand was performed on human pathogenic fungi, Candida albicans, in concentrations of 0.025; 0.050; 0.100; 0.200; 0.400; 0.800; 1.600 and 3.200 mM. The microorganism presented resistance to the dithiocarbamate ligand and all tin(IV) complexes tested were actives. The highest activity was found for compounds 1 and 4.     

Synthesis and characterization of dinuclear macrocyclic cobalt(II), copper(II) and zinc(II) complexes derived from 2,2,2('),2(')-S,S[bis(bis-N,N-2-thiobenzimidazolyloxalato-1,2-ethane)]: DNA binding and cleavage studies

New homodinuclear macrocyclic complexes of cobalt(II), copper(II) and zinc(II) were isolated from the newly synthesized ligand 2,2,2',2'-S,S[bis(bis-N,N-2-thiobenzimidazolyloxalato-1,2-ethane)]. The structures of the complexes were elucidated by elemental analysis, molar conductance measurements, IR, 1H NMR, 13C NMR, electronic and ESI-MS spectroscopic techniques. In complex 1, Co(II) ions possess a tetrahedral coordination environment composed of O2S2 donor atoms while its Cu(II) and Zn(II) counterparts 2 and 3, respectively, reveal a six coordinate octahedral structure, defined by the O2S2 donors from the macrocyclic ring and two chloride ions. Molar conductance and spectroscopic data also support the proposed geometry of the complexes. DNA binding properties of complexes 1-3 were investigated using electronic absorption spectroscopy, fluorescence spectroscopy, viscosity measurements and cyclic voltammetry. The absorption spectra of complexes 2 and 3 with calf thymus DNA showed hypochromism, while complex 1 showed hyperchromism attributed to a partial intercalation and electrostatic binding modes, respectively. The intrinsic binding constant K(b) of complexes 1-3 were determined as 16.6 x 10(4) M(-1), 4.25 x 10(4) M(-1) and 3.0 x 10(4) M(-1), respectively. The decrease in the relative specific viscosity of calf thymus DNA with increasing concentration of the complexes authenticates the partial intercalation binding mode. Gel electrophoresis of complex 2 with plasmid DNA demonstrated that complex exhibits excellent "artificial" nuclease activity.     

Synthesis, characterization, cytotoxicity, antibacterial and antifungal evaluation of some new platinum (IV) and palladium (II) complexes of thiodiamines

Some new platinum (IV) and palladium (II) thiodiamine complexes of type [Pt(L)2Cl2] and [Pd(L)Cl2], [where, L=(cyclohexyl-N-thio)-1,2-ethylenediamine (L(1)) and (cyclohexyl-N-thio)-1,3-propanediamine (L(2))] have been synthesized. The thiodiamines coordinate as a bidentate N-S ligand. The synthesized platinum (IV) and palladium (II) complexes of the thiodiamines were characterized by elemental analysis, IR, mass, electronic and (1)H NMR spectroscopic studies. These complexes were also screened for cytotoxicity, in vitro antifungal and in vitro antibacterial activities. Thermodynamic parameters such as activation energy (Ea), apparent activation entropy (S(#)) and enthalpy change (DeltaH) for the dehydration and decomposition reactions of one complex has also been evaluated.     

New transition metal ion complexes with benzimidazole-5-carboxylic acid hydrazides with antitumor activity

Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide (4a; L(1)) and its Schiff base 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide (5a; L(2)) with transition metal ions e.g., copper, silver, nickel, iron and manganese were prepared. The complexes formed were 1:1 or 1:2 M:L complexes and have the structural formulae [Cu(L(1))Cl(H(2)O)]Cl x 3 H(2)O (6), [Ag(L(1))NO(3)(H(2)O)] (7), [Ni(L(1))Cl(2)(H(2)O)(2)] x H(2)O (8), [Fe(L(1))Cl(3)(H(2)O)] x 3 H(2)O (9) and [Mn(L(1))(2)Cl(H(2)O)]Cl x 3 H(2)O (10) for ligand L(1), and [Cu(L(2))Cl(2)(H(2)O)(2)] x H(2)O (11), [Ag(L(2))(2)]NO(3) x H(2)O (12), [Ni(L(2))(2)Cl(2)] x 5 H(2)O (13), [Fe(L(2))(2)Cl(2)]Cl x 2 H(2)O (14) and [Mn(L(2))Cl(2)(H(2)O)(2)] x H(2)O (15) for ligand L(2). The antitumor activity of the synthesized compounds has been studied. The silver complex 7 was found to display cytotoxicity (IC(50)=2 microM) against both human lung cancer cell line A549 and human breast cancer cell line MCF-7.     

Synthesis and crystal structure of some transition metal complexes with a novel bis-Schiff base ligand and their antitumor activities

Mononuclear complex of Zn(II) with a new bis-Schiff base ligand derived from 2,3-butanedione and thiosemicarbazide, [Zn(II)L.H2O].2DMF [L = (2E,2'E)-2,2'-(butane-2,3-diylidene)bis(hydrazinecarbothioamide)], and other transition metal ions [Cu(II), Mn(II), Co(II), Ni(II)] complexes have been prepared. The Zn(II) complex has been structurally characterized by X-ray crystallography. Among the five complexes, the Cu(II) complex has the novel highest antitumor activity.     

Solvatochromism, DNA binding, antitumor activity and molecular modeling study of mixed-ligand copper(II) complexes containing the bulky ligand: bis[N-(p-tolyl)imino]acenaphthene

Four mixed-ligand copper(II) complexes of the nitrogen ligand bis[N-(p-tolyl)imino]acenaphthene 1 (p-Tol-BIAN). These complexes, namely [Cu(p-Tol-BIAN)2](ClO4)2 2, [Cu(p-Tol-BIAN)(acac)](ClO4) 3, [Cu(p-Tol-BIAN)Cl2] 4 and [Cu(p-Tol-BIAN)(AcOH)(2)](ClO4)2 5, were prepared and characterized. Solvatochromism of the novel copper complexes in various solvents has been studied. Molecular mechanics (MM+) and molecular dynamic simulations have been performed to learn more about the solvatochromic behaviour and the DNA binding affinity of these complexes.     

Synthesis, characterization and antimicrobial activity of Fe(II), Zn(II), Cd(II) and Hg(II) complexes with 2,6-bis(benzimidazol-2-yl) pyridine ligand

2,6-Bis(benzimidazol-2-yl)pyridine (L) ligand and complexes [M(L)Cl(2)] and [Fe(L)(2)](ClO(4))(2) (M=Zn, Cd, Hg) have been synthesized. The geometries of the [M(L)Cl(2)] complexes were derived from theoretical calculation in DGauss/DFT level (DZVP basis set) on CACHE. The central M(II) ion is penta-coordinated and surrounded by N(3)Cl(2) environment, adopting a distorted trigonal bipyramidal geometry. The ligand is tridentate, via three nitrogen atoms to metal centre and two chloride ions lie on each side of the distorted benzimidazole ring. In the [Fe(L)(2)](ClO(4))(2) complex, the central Fe(II) ion is surrounded by two (3N) units, adopting a octahedral geometry. The elemental analysis, molecular conductivity, FT-Raman, FT-IR (mid-, far-IR), (1)H, and (13)C NMR were reported. The antimicrobial activities of the free ligand, its hydrochloride salt, and the complexes were evaluated using the disk diffusion method in dimethyl sulfoxide (DMSO) as well as the minimal inhibitory concentration (MIC) dilution method, against 10 bacteria and the results compared with that for gentamycin. Antifungal activities were reported for Candida albicans, Kluyveromyces fragilis, Rhodotorula rubra, Debaryomyces hansenii, Hanseniaspora guilliermondii, and the results were referenced against nystatin, ketaconazole, and clotrimazole antifungal agents. In most cases, the compounds tested showed broad-spectrum (Gram positive and Gram negative bacteria) activities that were either more effective than or as potent as the references. The binding of two most biologically effective compounds of zinc and mercury to calf thymus DNA has also been investigated by absorption spectra.     

Copper(II) complexes with substituted thiosemicarbazones of thiophene-2-carboxaldehyde: synthesis, characterization and antiamoebic activity against E. histolytica

In an effort to develop potent antiamoebic agents, a series of thiosemicarbazone (TSC) ligands 1-5 derived from thiophene-2-carboxaldehyde and N4-substituted thiosemicarbazides has been prepared and characterized using various spectroscopic techniques. Treatment of the ligands with cupric chloride produced the copper(II) complexes [Cu(TSC)2Cl2] 1a-5a where ligand bind through thionic sulfur and the azomethine nitrogen. The possible geometries of the complexes were assigned on the basis of magnetic moment, electronic and thermal patterns as well as infrared spectral studies. The thiosemicarbazones and their copper complexes were tested for their in vitro antiamoebic activity against HK-9 strain of Entamoeba histolytica and showed significant growth inhibition. The results revealed that these complexes are effective chemicals in inhibiting amoebal growth, with compound 5 (having -N(CH3)(C6H5) substituent at N4) and complexes 1a-5a being more effective than the commercial antiamoebic drug, metronidazole, based on IC50 values. These data also indicated that the compounds 3a and 5a are most effective among the complexes studied (IC50=0.26 microM of 3a and IC50=0.21 microM of 5a versus IC50=1.81 microM of metronidazole).     

Stereospecific ligands and their complexes. Part VII. Synthesis, characterization and in vitro antitumoral activity of platinum(II) complexes with O,O'-dialkyl esters of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid

Platinum(II) complexes (1-4) with bidentate N,N'-ligands, O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid were synthesized and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. DFT calculations were performed for the complexes and it was found that only one diastereoisomer could be formed. Cytotoxic activity of complexes 1-4 was determined against chronic lymphocytic leukemia cells (CLL) and compared to the activity of ligand precursors L1 · 2HCl-L4·2HCl and corresponding palladium(II) complexes, [PdCl(2)L] (L = L1-L4). The complexes were found to exhibit significantly higher antitumor activities than cisplatin on CLL cells. Cytotoxic effect of platinum(II) complexes on CLL cells was higher compared to corresponding palladium(II) complexes. In addition the mode of cell death induced by platinum(II) complexes was determined.     

Bioactivity of novel transition metal complexes of N'-[(4-methoxy)thiobenzoyl]benzoic acid hydrazide

Cu(II), Fe(III), and Mn(II) complexes of a novel ligand N'-[(4-methoxy)thiobenzoyl]benzoic acid hydrazide (H(2)mtbh) have been synthesized and characterized by elemental analyses, IR, UV-vis, NMR, mass, EPR and M?ssbauer spectroscopy. The results suggest a square planar structure for [Cu(Hmtbh)Cl] and [Cu(mtbh)] whereas an octahedral structure for [Mn(Hmtbh)(2)] and [Fe(Hmtbh)(mtbh)]. Mn(II) and Fe(III) complexes were found to inhibit proliferation of HT29 cells. [Mn(Hmtbh)(2)] and [Fe(Hmtbh)(mtbh)] inhibited proliferation of HT29 cells with half maximal inhibition (IC(50)) of 8.15+/-0.87 and 68.1+/-4.8 microM, respectively, whereas H(2)mtbh showed growth inhibition with IC(50) of 90.9+/-7.8 microM and were able to inhibit NMT activity in vitro. Mn(II) and Fe(III) complexes inhibited NMT activity in a dose dependent manner with IC(50) values of 20+/-2.2 and 60+/-7.2 microM, respectively, whereas ligand (H(2)mtbh) displayed IC(50) of 3.2+/-0.5 mM.     

Structure and biological activity of cationic [PtLCl(DMSO)]NO(3).DMSO complex containing a chelated diaminosugar: methyl-3,4-diamino-2,3,4,6-tetradeoxy-alpha-L-lyxopyranoside

Cationic platinum(II) complex [Pt(C(7)H(16)N(2)O(2))(DMSO)Cl]NO(3).DMSO containing one chloride anion, methyl-3,4-diamino-2,3,4,6-tetradeoxy-alpha-L-lyxopyranoside (C(7)H(16)N(2)O(2)) and dimethylsulfoxide (DMSO) molecules forming a square-plane has been prepared and characterised, both spectroscopically and by single-crystal X-ray diffraction. Biological tests performed using leukemia L1210 cells have shown that toxicity of the title complex is similar to that of cisplatin.     

Synthesis, crystal structures, biological activities and fluorescence studies of transition metal complexes with 3-carbaldehyde chromone thiosemicarbazone

3-carbaldehyde chromone thiosemicarbazone (L) and its transition metal complexes were synthesized and characterized systematically. Crystal structures of Zn(II) and Ni(II) complexes were determined by single crystal X-ray diffraction analysis. Zn(II) complex exhibits blue fluorescence under UV light and its fluorescent property in solid state was investigated. Interactions of ligand and Cu(II), Zn(II) and Ni(II) complexes with DNA were investigated by spectral and viscosity studies, indicating the compounds bind to DNA via intercalation and Zn(II) complex binds to DNA most strongly. Antioxidant tests in vitro show the compounds possess significant antioxidant activity against superoxide and hydroxyl radicals, and the scavenging effects of Cu(II) complex are stronger than Zn(II), Ni(II) complexes and some standard antioxidants, such as mannitol and vitamin C.     

In vitro and in vivo antitumor activity of platinum(II) complexes with thiosemicarbazones derived from 2-formyl and 2-acetyl pyridine and containing ring incorporated at N(4)-position: synthesis, spectroscopic study and crystal structure of platinum(II) complexes with thiosemicarbazones, potential anticancer agents

Reactions of thiosemicarbazones of 2-formyl and 2-acetyl pyridine and containing an azepane ring (hexamethyleneiminyl ring) incorporated at N(4)-position, HL(1) (1) and HL(2) (2) with platinum(II) afforded the complexes, [Pt(L(1))Cl] (3) and [Pt(L(2))Cl] (4). Characterization of the compounds was accomplished by means of elemental analysis and spectroscopic techniques NMR, UV-vis and IR spectroscopy. The single-crystal X-ray structure of complex [Pt(L(2))Cl] (4) shows that the ligand monoanion coordinates in a planar conformation to the metal via the pyridyl N atom, the imine-N atom, and thiolato S-atom. Compounds 1-4 have been evaluated for antiproliferative activity in vitro against three human cancer cell lines: MCF-7 (human breast cancer cell line), T24 (bladder cancer cell line), A-549 (non-small cell lung carcinoma) and a mouse L-929 (a fibroblast-like cell line cloned from strain L). Ligand 2 exhibited high activity as anticancer agent against all four cancer cell lines, while ligand 1 exhibited selectivity against MCF-7, L-929 cell lines and complex 4 against A-549, T-24 cancer cell lines. Also, the acute toxicity and antitumor activity were evaluated on leukemia P388-bearing mice. Complex 3 afforded five to six cures against leukemia P388. The in vivo results of the antitumor activity show the two platinum complexes as very effective chemotherapeutic antileukemic agents.     

synthesis, characterization and in vitro antiamoebic activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones and their Palladium (II) and Ruthenium (II) complexes

Synthesis of new Palladium(II) and Ruthenium(II) complexes of the type, [Pd(L)Cl(2)] and [Ru(eta(4)-C(8)H(12))(L)Cl(2)] [where, L = thiosemicarbazones derived from 5-nitrothiophene-2-carboxaldehyde and cycloalkylaminothiocarbonyl hydrazines] have been isolated by the reaction of [Pd(DMSO)(2)Cl(2)] and [Ru(eta(4)-C(8)H(12))(CH(3)CN)(2)Cl(2)] with 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones. The spectral data revealed that the thiosemicarbazones act as bidentate ligands, making use of thionic sulphur and the azomethine nitrogen atom for coordination to the central metal ion. Microdilution method was used for the assessment of antiamoebic activity of all the compounds against HK-9 strain of Entamoeba histolytica. Among all the thiosemicarbazones, 5-NT-4-BPTSCN (3) showed significant antiamoebic activity (IC(50) - 2.56 microM). Enhancement of antiamoebic activity resulted by introducing palladium and ruthenium metals in the thiosemicarbazone moiety. All the Pd(II) and Ru(II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones were found more active then their respective ligands. The complexes 1a-4a, 1b and 3b showed antiamoebic activity.     

Novel Cu(II) quinoxaline N1,N4-dioxide complexes as selective hypoxic cytotoxins

As an effort to develop novel selective hypoxia-cytotoxins and to improve bioavailability and pharmacological and toxicological properties of quinoxaline N1,N4-dioxide derivatives (L1 = 3-amino-6(7)-chloroquinoxaline-2-carbonitrile N1,N4-dioxide, L2 = 3-amino-6(7)-bromoquinoxaline-2-carbonitrile N1,N4-dioxide and L3 = 3-amino-6(7)-methylquinoxaline-2-carbonitrile N1,N4-dioxide) and to get a synergism among metals and these type of bioreductive agents, L2 and three novel Cu(II) complexes of general formulae [Cu(II)(H2O)x(L - H)2], where L = L1 (x = 1), L2 (x = 0) or L3 (x = 2) were developed. L2 and complexes were synthesized and structurally characterized by elemental and thermal analyses, and FTIR, electronic, MS, NMR, and EPR spectroscopies. The new compounds were subjected to cytotoxic evaluation in V79 cells in hypoxic and aerobic conditions. The complexes showed excellent selective cytotoxicity in hypoxia, being their cytotoxicity similar to or higher than that of the ligands L1-L3. Besides, the copper complexes were so poorly cytotoxic in oxia as the free ligands. In addition, for the first time Cu(II)-quinoxaline complexes are reported as a family of hypoxic cytotoxins.     

Metal complexes of retinoid derivatives with antiproliferative activity: synthesis, characterization and DNA interaction studies

9-cis-Retinal thiosemicarbazone and its Co(III), Ni(II) and Cu(II) complexes are synthesized and characterized. Central Co(III) atom is in an octahedral environment while Ni(II) and Cu(II) atoms are in a square planar environment. DNA binding constants and spectroscopic data show an intercalative behavior for the nickel complex; an external binding mode is envisaged for the ligand and its copper complex. No DNA interaction can be hypothesized for the cobalt complex. The free ligand and its Ni(II) and Cu(II) complexes have a good lipophilic degree for an efficient uptake by the cells. The metal complexes exhibit a proliferation inhibition action against cell line U937 at micromolar concentration. Cu(II) complex also induces apoptosis, while Ni(II) complex has a strong interaction with CT-DNA.     

Synthesis, antimicrobial activity and molecular modeling of cobalt and nickel complexes containing the bulky ligand: bis[N-(2,6-diisopropylphenyl)imino] acenaphthene

Two cobalt and two Nickel complexes of bis[N-(2,6-diisopropylphenyl)imino]acenaphthene (Pr-BIAN) ligand, have been synthesized. These complexes, namely [Co(Pr-BIAN)Cl2] 1, [Co(OAc)2 (Pr-BIAN)2](ClO4) 2, [Ni(Pr-BIAN)(NO3)2] 3 and [Ni(Pr-BIAN)2](ClO4)2 4, were characterized by elemental analyses, molar conductance, spectral (IR, UV-Visible and NMR) and magnetic moment measurements. In these complexes the geometries about the metal center are significantly different. While for complexes 2 and 3 an octahedral structure is proposed, in complex 4, square-planar coordination with an almost perfect planar arrangement of two Pr-BIAN ligands around the nickel center is suggested. In 1, two imine nitrogen atoms of Pr-BIAN and two chloride atoms are coordinating in a tetrahedral fashion around the cobalt center. Molecular mechanics (MM+) and semiempirical molecular orbital calculations have been performed for the most biologically active complex 1 and its free ligand Pr-BIAN and compared with inactive ligand bis[N-(p-tolylphenyl)imino]acenaphthene 6, to get insight into their molecular structures and to learn more about their stable molecular conformations.     

Synthesis, characterization and antiamoebic activity of new indole-3-carboxaldehyde thiosemicarbazones and their Pd(II) complexes

In continuation of our research on thiosemicarbazones and their metal complexes as antiamoebic agents, a new series of indole-3-carboxaldehyde thiosemicarbazones (TSC) 1-7 were prepared by condensing indole-3-carboxaldehyde with cycloalkylaminothiocarbonyl hydrazines. Their palladium(II) complexes of the [Pd(TSC)Cl2] type, were synthesized upon coordination with [Pd(DMSO)2Cl2]. The chemical structures of all the compounds were established by elemental analyses, electronic, IR, (1)H NMR and (13)C NMR spectral data. The structure of the complexes was further established by thermogravimetric analysis and FAB MS. Spectroscopic data revealed that thiosemicarbazones act as bidentate ligands, making use of thione sulphur and azomethine nitrogen atom for coordination to the Pd(II) ion. Among all the compounds evaluated for antiamoebic activity using HM1:IMSS strain of Entamoeba histolytica, all palladium complexes were found to be more active than their respective ligands. Moreover, ligand 5 and complexes 1a-3a, 5a and 7a showed antiamoebic activity, at lower IC(50) doses when compared to the reference drug metronidazole with IC(50)=1.81 microM.     

Synthesis, characterization and biological activity of Pt(II) and Pt(IV) complexes with 5-methyl-5(4-pyridyl)-2,4-imidazolidenedione

New platinum(II) and platinum(IV) complexes with 5-methyl-5(4-pyridyl)-2,4-imidazolidenedione and various halogen ions with general formula [PtL(2)X(2)] and [PtL(2)Cl(4)], where L is the organic ligand and X is Cl(-), Br(-), J(-), were synthesized. The molecular formulae of all the complexes were confirmed by elemental analysis, IR, (1)H, (13)C NMR spectral analyses and molar conductivity. The cytotoxic effects of these complexes were examined on some human tumor cell lines. The newly synthesized cis-[PtL(2)Cl(2)] exerted cytotoxic activity against SKW-3, MCF-7, EJ, U-266 tumor cell lines, while cis-[PtL(2)Br(2)], trans-[PtL(2)I(2)] were less active. The higher oxidation state complex cis-[PtL(2)Cl(4)] was inactive in all cell lines but in SKW-3 some augmentation of the cytotoxicity was seen after co-administration of ascorbic acid but not when treated in combination with reduced glutathione or N-acetylcysteine. A DNA-fragmentation analysis revealed that the cytotoxicity of the dichloro analogue, characterized with superior activity compared to the other complexes, is mediated by induction of apoptotic cell death.     

Synthesis, crystal structure and pharmacological evaluation of two new Cu(II) complexes of 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (benzoyl) hydrazone: a comparative investigation

Two new copper(II) complexes have been synthesized by reacting 2-oxo-1,2-dihydroquinoline-3-carbaldehyde (benzoyl) hydrazone (H(2)L) with CuCl(2)·2H(2)O or Cu(NO(3))(2)·3H(2)O. The structures of the complexes have been determined by single crystal X-ray diffraction studies. Results obtained using spectroscopic methods strongly suggested that the ligand and its Cu(II) complexes could interact with calf thymus DNA through intercalation. In the case of protein binding, the obtained results indicated that all the three compounds could quench the intrinsic fluorescence of bovine serum albumin through static quenching process. In addition, antioxidant activity tests showed that H(2)L and its copper(II) complexes possess significant scavenging effect against free radicals. Further, the two copper(II) complexes exhibited effective cytotoxic activity against a panel of human cancer cell lines.